mGluR5 binding changes during a mismatch negativity task in a multimodal protocol with [11C]ABP688 PET/MR-EEG

Currently, the metabotropic glutamate receptor 5 (mGluR5) is the subject of several lines of research in the context of neurology and is of high interest as a target for positron-emission tomography (PET). Here, we assessed the feasibility of using [11C]ABP688, a specific antagonist radiotracer for an allosteric site on the mGluR5, to evaluate changes in glutamatergic neurotransmission through a mismatch-negativity (MMN) task as a part of a simultaneous and synchronized multimodal PET/MR-EEG study. We analyzed the effect of MMN by comparing the changes in nondisplaceable binding potential (BPND) prior to (baseline) and during the task in 17 healthy subjects by applying a bolus/infusion protocol. Anatomical and functional regions were analyzed. A small change in BPND was observed in anatomical regions (posterior cingulate cortex and thalamus) and in a functional network (precuneus) after the start of the task. The effect size was quantified using Kendall’s W value and was 0.3. The motor cortex was used as a control region for the task and did not show any significant BPND changes. There was a significant ΔBPND between acquisition conditions. On average, the reductions in binding across the regions were - 8.6 ± 3.2% in anatomical and - 6.4 ± 0.5% in the functional network (p ≤ 0.001). Correlations between ΔBPND and EEG latency for both anatomical (p = 0.008) and functional (p = 0.022) regions were found. Exploratory analyses suggest that the MMN task played a role in the glutamatergic neurotransmission, and mGluR5 may be indirectly modulated by these changes.

The Layer 7 Cortical Interface: A Scalable and Minimally Invasive Brain-Computer Interface Platform

Progress toward the development of brain-computer interfaces has signaled the potential to restore, replace, or augment lost or impaired neurological function in a variety of disease states. Existing brain-computer interfaces rely on invasive surgical procedures or brain-penetrating electrodes, which limit addressable applications of the technology and the number of eligible patients. Here we describe a novel approach to constructing a neural interface, comprising conformable thin-film electrode arrays and a minimally invasive surgical delivery system that together facilitate communication with large portions of the cortical surface in bidirectional fashion (enabling both recording and stimulation). We demonstrate the safety and feasibility of rapidly delivering reversible implants containing over 2,000 microelectrodes to multiple functional regions in both hemispheres of the Gottingen minipig brain simultaneously, without requiring a craniotomy, at an effective insertion rate faster than 40 ms per channel, without damaging the cortical surface. We further demonstrate the performance of this system for high-density neural recording, focal cortical stimulation, and accurate neural decoding. Such a system promises to accelerate efforts to better decode and encode neural signals, and to expand the patient population that could benefit from neural interface technology.

Delineating the Spatial Boundaries of Megaregions in China: A City Network Perspective

Globalization and informatization have significantly reshaped the map of the global economy. Mega cities and regions have become the battlegrounds in the interplay between globalization and localization, with megaregions becoming the most globally significant spatial configurations in this regard. However, academics and government departments disagree on how to define the spatial boundaries of megaregions. In this study, on the basis of highway traffic flow data between cities, we integrate the community detection and core-periphery profile algorithms to characterize the city networks in China and identify the city groups and delineate the core structures of city groups, which are the underlying megaregional structures in China. Based on this, we identify 21 megaregions among city groups in China, including the Yangtze River Delta, Pearl River Delta, Beijing-Tianjin-Hebei, and Chengdu-Chongqing megaregions, and preliminarily delineate their spatial boundaries. On the whole, there are spatial differences among China’s megaregions to a certain extent. Central and eastern China have numerous, large, and a high density of megaregions, while the western region has relatively few megaregions. The latter also differs notably from mature megaregions in terms of rank sizes, urban systems, and functional divisions of labor. Generally, this study develops a novel analytical framework for identifying the functional regions of megaregional space in China from a perspective of relational geography, with methodological implications for other fields of inquiry.

Structure prediction of the druggable fragments in SARS-CoV-2 untranslated regions

The outbreak of the COVID-19 pandemic has led to intensive studies of both the structure and replication mechanism of SARS-CoV-2. In spite of some secondary structure experiments being carried out, the 3D structure of the key functional regions of the viral RNA has not yet been well understood. At the beginning of COVID-19 breakout, the RNA-Puzzles community attempted to envisage the three-dimensional structure of 5′- and 3′-Un-Translated Regions (UTRs) of the SARS-CoV-2 genome. Here, we report the results of this prediction challenge, presenting the methodologies developed by six participating groups and discussing 100 RNA 3D models (60 models of 5′-UTR and 40 of 3′-UTR) predicted through applying both human experts and automated server approaches. We describe the original protocol for the reference-free comparative analysis of RNA 3D structures designed especially for this challenge. We elaborate on the deduced consensus structure and the reliability of the predicted structural motifs. All the computationally simulated models, as well as the development and the testing of computational tools dedicated to 3D structure analysis, are available for further study.

The Landscape-Based Protein Stability Analysis and Network Modeling of Multiple Conformational States of the SARS-CoV-2 Spike D614 Mutant: Conformational Plasticity and Frustration-Driven Allostery as Energetic Drivers of Highly Transmissible Spike Variant

The structural and functional studies of the SARS-CoV-2 spike protein variants revealed an important role of the D614G mutation that is shared across many variants of concern(VOCs), suggesting the effect of this mutation on the enhanced virus infectivity and transmissibility. The recent structural and biophysical studies provided important evidence about multiple conformational substates of the D614G spike protein. The development of a plausible mechanistic model which can explain the experimental observations from a more unified thermodynamic perspective is an important objective of the current work. In this study, we employed efficient and accurate coarse-grained simulations of multiple structural substates of the D614G spike trimers together with the ensemble-based mutational frustration analysis to characterize the dynamics signatures of the conformational landscapes. By combining the local frustration profiling of the conformational states with residue-based mutational scanning of protein stability and network analysis of allosteric interactions and communications, we determine the patterns of mutational sensitivity in the functional regions and sites of variants. We found that the D614G mutation may induce a considerable conformational adaptability of the open states in the SARS-CoV-2 spike protein without compromising folding stability and integrity of the spike protein. The results suggest that the D614G mutant may employ a hinge-shift mechanism in which the dynamic couplings between the site of mutation and the inter-protomer hinge modulate the inter-domain interactions, global mobility change and the increased stability of the open form. This study proposes that mutation-induced modulation of the conformational flexibility and energetic frustration at the inter-protomer interfaces may serve as an efficient mechanism for allosteric regulation of the SARS-CoV-2 spike proteins.

Human rDNA and Cancer

In human cells, each rDNA unit consists of the ~13 kb long ribosomal part and ~30 kb long intergenic spacer (IGS). The ribosomal part, transcribed by RNA polymerase I (pol I), includes genes coding for 18S, 5.8S, and 28S RNAs of the ribosomal particles, as well as their four transcribed spacers. Being highly repetitive, intensively transcribed, and abundantly methylated, rDNA is a very fragile site of the genome, with high risk of instability leading to cancer. Multiple small mutations, considerable expansion or contraction of the rDNA locus, and abnormally enhanced pol I transcription are usual symptoms of transformation. Recently it was found that both IGS and the ribosomal part of the locus contain many functional/potentially functional regions producing non-coding RNAs, which participate in the pol I activity regulation, stress reactions, and development of the malignant phenotype. Thus, there are solid reasons to believe that rDNA locus plays crucial role in carcinogenesis. In this review we discuss the data concerning the human rDNA and its closely associated factors as both targets and drivers of the pathways essential for carcinogenesis. We also examine whether variability in the structure of the locus may be blamed for the malignant transformation. Additionally, we consider the prospects of therapy focused on the activity of rDNA.

The Contribution of Spatial Interaction Modelling to Spatial History: The Case of Central Places and their Hinterlands in the Territory of the Austro-Hungarian Empire

Research on spatial history can be enriched by using approaches from quantitative geography. We analyse an historical regional system and highlight three basic assumptions, building upon Christaller’s central place theory: cities do not stand alone in space, they interact with their hinterlands, and they are hierarchically organised. We investigate the relative position of central places in space and define their hinterlands using a spatial interaction modelling approach. We present the example of functional regional taxonomy in past environments, which therefore has a higher degree of uncertainty in the results and in their interpretation. We use a variant of Reilly’s model to define the functional regions in Austria-Hungary at the beginning and at the end of the 20th century. We present a possible interpretation of the model results based on the identification of the major factors responsible for developments in the urban and regional systems of Austria-Hungary over 100 years. We conclude that the development of urban and regional systems in the territory of the former Austria-Hungary was not considerably affected by the role of political-economic systems, the administrative organisation of states, nor by the different stages in economic development of its formerly constituent territories.