sincFold: end-to-end learning of short- and long-range interactions in RNA secondary structure.

MOTIVATION: Coding and noncoding RNA molecules participate in many important biological processes. Noncoding RNAs fold into well-defined secondary structures to exert their functions. However, the computational prediction of the secondary structure from a raw RNA sequence is a long-standing unsolved problem, which after decades of almost unchanged performance has now re-emerged due to deep learning. Traditional RNA secondary structure prediction algorithms have been mostly based on thermodynamic models and dynamic programming for free energy minimization. More recently deep learning methods have shown competitive performance compared with the classical ones, but there is still a wide margin for improvement. RESULTS: In this work we present sincFold, an end-to-end deep learning approach, that predicts the nucleotides contact matrix using only the RNA sequence as input. The model is based on 1D and 2D residual neural networks that can learn short- and long-range interaction patterns. We show that structures can be accurately predicted with minimal physical assumptions. Extensive experiments were conducted on several benchmark datasets, considering sequence homology and cross-family validation. sincFold was compared with classical methods and recent deep learning models, showing that it can outperform the state-of-the-art methods.

Metastability and discrete spectrum of long-range systems.

Long-lived quasi-stationary states (QSSs) are a signature characteristic of long-range interacting systems both in the classical and in the quantum realms. Often, they emerge after a sudden quench of the Hamiltonian internal parameters and present a macroscopic lifetime, which increases with the system size. Despite their ubiquity, the fundamental mechanism at their root remains unknown. Here, we show that the spectrum of systems with power-law decaying couplings remains discrete up to the thermodynamic limit. As a consequence, several traditional results on the chaotic nature of the spectrum in many-body quantum systems are not satisfied in the presence of long-range interactions. In particular, the existence of QSSs may be traced back to the finiteness of Poincaré recurrence times. This picture justifies and extends known results on the anomalous magnetization dynamics in the quantum Ising model with power-law decaying couplings. The comparison between the discrete spectrum of long-range systems and more conventional examples of pure point spectra in the disordered case is also discussed.

Cellular reprogramming is driven by widespread rewiring of promoter-enhancer interactions.

BACKGROUND: Long-range interactions between promoters and cis-regulatory elements, such as enhancers, play critical roles in gene regulation. However, the role of three-dimensional (3D) chromatin structure in orchestrating changes in transcriptional regulation during direct cell reprogramming is not fully understood. RESULTS: Here, we performed integrated analyses of chromosomal architecture, epigenetics, and gene expression using Hi-C, promoter Capture Hi-C (PCHi-C), ChIP-seq, and RNA-seq during trans-differentiation of Pre-B cells into macrophages with a ß-estradiol inducible C/EBPαER transgene. Within 1h of ß-estradiol induction, C/EBPα translocated from the cytoplasm to the nucleus, binding to thousands of promoters and putative regulatory elements, resulting in the downregulation of Pre-B cell-specific genes and induction of macrophage-specific genes. Hi-C results were remarkably consistent throughout trans-differentiation, revealing only a small number of TAD boundary location changes, and A/B compartment switches despite significant changes in the expression of thousands of genes. PCHi-C revealed widespread changes in promoter-anchored loops with decreased interactions in parallel with decreased gene expression, and new and increased promoter-anchored interactions in parallel with increased expression of macrophage-specific genes. CONCLUSIONS: Overall, our data demonstrate that C/EBPα-induced trans-differentiation involves few changes in genome architecture at the level of TADs and A/B compartments, in contrast with widespread reorganization of thousands of promoter-anchored loops in association with changes in gene expression and cell identity.

Oxygen-Bridged Long-Range Dual Sites Boost Ethanol Electrooxidation by Facilitating C-C Bond Cleavage.

Optimizing the interatomic distance of dual sites to realize C-C bond breaking of ethanol is critical for the commercialization of direct ethanol fuel cells. Herein, the concept of holding long-range dual sites is proposed to weaken the reaction barrier of C-C cleavage during the ethanol oxidation reaction (EOR). The obtained long-range Rh-O-Pt dual sites achieve a high current density of 7.43 mA/cm2 toward EOR, which is 13.3 times that of Pt/C, as well as remarkable stability. Electrochemical in situ Fourier transform infrared spectroscopy indicates that long-range Rh-O-Pt dual sites can increase the selectivity of C1 products and suppress the generation of a CO intermediate. Theoretical calculations further disclose that redistribution of the surface-localized electron around Rh-O-Pt can promote direct oxidation of -OH, accelerating C-C bond cleavage. This work provides a promising strategy for designing oxygen-bridged long-range dual sites to tune the activity and selectivity of complicated catalytic reactions.

Monte Carlo Based Techniques for Quantum Magnets with Long-Range Interactions.

Long-range interactions are relevant for a large variety of quantum systems in quantum optics and condensed matter physics. In particular, the control of quantum-optical platforms promises to gain deep insights into quantum-critical properties induced by the long-range nature of interactions. From a theoretical perspective, long-range interactions are notoriously complicated to treat. Here, we give an overview of recent advancements to investigate quantum magnets with long-range interactions focusing on two techniques based on Monte Carlo integration. First, the method of perturbative continuous unitary transformations where classical Monte Carlo integration is applied within the embedding scheme of white graphs. This linked-cluster expansion allows extracting high-order series expansions of energies and observables in the thermodynamic limit. Second, stochastic series expansion quantum Monte Carlo integration enables calculations on large finite systems. Finite-size scaling can then be used to determine the physical properties of the infinite system. In recent years, both techniques have been applied successfully to one- and two-dimensional quantum magnets involving long-range Ising, XY, and Heisenberg interactions on various bipartite and non-bipartite lattices. Here, we summarise the obtained quantum-critical properties including critical exponents for all these systems in a coherent way. Further, we review how long-range interactions are used to study quantum phase transitions above the upper critical dimension and the scaling techniques to extract these quantum critical properties from the numerical calculations.

On the possibility of the existence of orienting hydrodynamic steering effects in the kinetics of receptor-ligand association.

In the vast majority of biologically relevant cases of receptor-ligand complex formation, the binding site of the receptor is a small part of its surface, and moreover, formation of a biologically active complex often requires a specific orientation of the ligand relative to the binding site. Before the formation of the initial form of the complex, only long-range, electrostatic and hydrodynamic interactions can act between the ligand approaching the binding site and the receptor. In this context, the question arises whether as a result of these interactions, there is a pre-orientation of the ligand towards the binding site, which to some extent would accelerate the formation of the complex. The role of electrostatic interactions in the orientation of the ligand relative to the binding site of the receptor is well documented. The analogous role of hydrodynamic interactions, although assessed as very significant by Brune and Kim (PNAS 91, 2930-2934, (1994)), is still debatable. In this article, I present the current state of knowledge on this subject and consider the possibilities of demonstrating the orienting effect of hydrodynamic interactions in the processes of receptor-ligand association, in an experimental way supported by computer simulations.

Hooked Up from a Distance: Charting Genome-Wide Long-Range Interaction Maps in Neural Cells Chromatin to Identify Novel Candidate Genes for Neurodevelopmental Disorders.

DNA sequence variants (single nucleotide polymorphisms or variants, SNPs/SNVs; copy number variants, CNVs) associated to neurodevelopmental disorders (NDD) and traits often map on putative transcriptional regulatory elements, including, in particular, enhancers. However, the genes controlled by these enhancers remain poorly defined. Traditionally, the activity of a given enhancer, and the effect of its possible alteration associated to the sequence variants, has been thought to influence the nearest gene promoter. However, the obtainment of genome-wide long-range interaction maps in neural cells chromatin challenged this view, showing that a given enhancer is very frequently not connected to the nearest promoter, but to a more distant one, skipping genes in between. In this Perspective, we review some recent papers, who generated long-range interaction maps (by HiC, RNApolII ChIA-PET, Capture-HiC, or PLACseq), and overlapped the identified long-range interacting DNA segments with DNA sequence variants associated to NDD (such as schizophrenia, bipolar disorder and autism) and traits (intelligence). This strategy allowed to attribute the function of enhancers, hosting the NDD-related sequence variants, to a connected gene promoter lying far away on the linear chromosome map. Some of these enhancer-connected genes had indeed been already identified as contributive to the diseases, by the identification of mutations within the gene's protein-coding regions (exons), validating the approach. Significantly, however, the connected genes also include many genes that were not previously found mutated in their exons, pointing to novel candidate contributors to NDD and traits. Thus, long-range interaction maps, in combination with DNA variants detected in association with NDD, can be used as "pointers" to identify novel candidate disease-relevant genes. Functional manipulation of the long-range interaction network involving enhancers and promoters by CRISPR-Cas9-based approaches is beginning to probe for the functional significance of the identified interactions, and the enhancers and the genes involved, improving our understanding of neural development and its pathology.

The Sticking of N2 on W(100) Surface: An Improvement in the Description of the Adsorption Dynamics Further Reconciling Theory and Experiment.

The adsorption of nitrogen molecules on a (100) tungsten surface has been studied using a new potential energy surface in which long-range interactions are suitably characterized and represented by the Improved Lennard-Jones function. The new potential energy surface is used to carry out molecular dynamics simulations by adopting a semiclassical collisional method that explicitly includes the interaction with the surface phonons. The results of the sticking probability, evaluated as a function of the collision energy, are in good agreement with those obtained in the experiments and improve the already good comparison recently obtained with calculations performed using interactions from the Density Functional Theory method and corrected for long-range van der Waals contributions. The dependence of trapping probability on the surface temperature for a well-defined collision energy has also been investigated.

The Effect of On-Site Potentials on Supratransmission in One-Dimensional Hamiltonian Lattices.

We investigated a class of one-dimensional (1D) Hamiltonian N-particle lattices whose binary interactions are quadratic and/or quartic in the potential. We also included on-site potential terms, frequently considered in connection with localization phenomena, in this class. Applying a sinusoidal perturbation at one end of the lattice and an absorbing boundary on the other, we studied the phenomenon of supratransmission and its dependence on two ranges of interactions, 0<α<∞ and 0<ß<∞, as the effect of the on-site potential terms of the Hamiltonian varied. In previous works, we studied the critical amplitude As(α,Ω) at which supratransmission occurs, for one range parameter α, and showed that there was a sharp threshold above which energy was transmitted in the form of large-amplitude nonlinear modes, as long as the driving frequency Ω lay in the forbidden band-gap of the system. In the absence of on-site potentials, it is known that As(α,Ω) increases monotonically the longer the range of interactions is (i.e., as α⟶0). However, when on-site potential terms are taken into account, As(α,Ω) reaches a maximum at a low value of α that depends on Ω, below which supratransmission thresholds decrease sharply to lower values. In this work, we studied this phenomenon further, as the contribution of the on-site potential terms varied, and we explored in detail their effect on the supratransmission thresholds.

Cotton D genome assemblies built with long-read data unveil mechanisms of centromere evolution and stress tolerance divergence.

BACKGROUND: Many of genome features which could help unravel the often complex post-speciation evolution of closely related species are obscured because of their location in chromosomal regions difficult to accurately characterize using standard genome analysis methods, including centromeres and repeat regions. RESULTS: Here, we analyze the genome evolution and diversification of two recently diverged sister cotton species based on nanopore long-read sequence assemblies and Hi-C 3D genome data. Although D genomes are conserved in gene content, they have diversified in gene order, gene structure, gene family diversification, 3D chromatin structure, long-range regulation, and stress-related traits. Inversions predominate among D genome rearrangements. Our results support roles for 5mC and 6mA in gene activation, and 3D chromatin analysis showed that diversification in proximal-vs-distal regulatory-region interactions shape the regulation of defense-related-gene expression. Using a newly developed method, we accurately positioned cotton centromeres and found that these regions have undergone obviously more rapid evolution relative to chromosome arms. We also discovered a cotton-specific LTR class that clarifies evolutionary trajectories among diverse cotton species and identified genetic networks underlying the Verticillium tolerance of Gossypium thurberi (e.g., SA signaling) and salt-stress tolerance of Gossypium davidsonii (e.g., ethylene biosynthesis). Finally, overexpression of G. thurberi genes in upland cotton demonstrated how wild cottons can be exploited for crop improvement. CONCLUSIONS: Our study substantially deepens understanding about how centromeres have developed and evolutionarily impacted the divergence among closely related cotton species and reveals genes and 3D genome structures which can guide basic investigations and applied efforts to improve crops.

Pronounced cohabitation of active immunoglobulin genes from three different chromosomes in transcription factories during maximal antibody synthesis.

To understand the relationships between nuclear organization and gene expression in a model system, we employed three-dimensional imaging and chromatin immunoprecipitation (ChIP)-chromosome conformation capture (3C) techniques to investigate the topographies of the immunoglobulin (Ig) genes and transcripts during B-cell development. Remarkably, in plasma cells, when antibody synthesis peaks, active Ig genes residing on three different chromosomes exhibit pronounced colocalizations in transcription factories, often near the nuclear periphery, and display trans-chromosomal enhancer interactions, and their transcripts frequently share interchromatin trafficking channels. Conceptually, these features of nuclear organization maximize coordinated transcriptional and transcript trafficking control for potentiating the optimal cytoplasmic assembly of the resulting translation products into protein multimers.

Bridging between Mouse and Human Enhancer-Promoter Long-Range Interactions in Neural Stem Cells, to Understand Enhancer Function in Neurodevelopmental Disease.

Non-coding variation in complex human disease has been well established by genome-wide association studies, and is thought to involve regulatory elements, such as enhancers, whose variation affects the expression of the gene responsible for the disease. The regulatory elements often lie far from the gene they regulate, or within introns of genes differing from the regulated gene, making it difficult to identify the gene whose function is affected by a given enhancer variation. Enhancers are connected to their target gene promoters via long-range physical interactions (loops). In our study, we re-mapped, onto the human genome, more than 10,000 enhancers connected to promoters via long-range interactions, that we had previously identified in mouse brain-derived neural stem cells by RNApolII-ChIA-PET analysis, coupled to ChIP-seq mapping of DNA/chromatin regions carrying epigenetic enhancer marks. These interactions are thought to be functionally relevant. We discovered, in the human genome, thousands of DNA regions syntenic with the interacting mouse DNA regions (enhancers and connected promoters). We further annotated these human regions regarding their overlap with sequence variants (single nucleotide polymorphisms, SNPs; copy number variants, CNVs), that were previously associated with neurodevelopmental disease in humans. We document various cases in which the genetic variant, associated in humans to neurodevelopmental disease, affects an enhancer involved in long-range interactions: SNPs, previously identified by genome-wide association studies to be associated with schizophrenia, bipolar disorder, and intelligence, are located within our human syntenic enhancers, and alter transcription factor recognition sites. Similarly, CNVs associated to autism spectrum disease and other neurodevelopmental disorders overlap with our human syntenic enhancers. Some of these enhancers are connected (in mice) to homologs of genes already associated to the human disease, strengthening the hypothesis that the gene is indeed involved in the disease. Other enhancers are connected to genes not previously associated with the disease, pointing to their possible pathogenetic involvement. Our observations provide a resource for further exploration of neural disease, in parallel with the now widespread genome-wide identification of DNA variants in patients with neural disease.

Scattering of N2 Molecules from Silica Surfaces: Effect of Polymorph and Surface Temperature.

The inelastic scattering of N2 molecules from silica surfaces, taken at 100 K, has been investigated by adopting a semiclassical collision model in conjunction with the appropriate treatment of the long-range interaction forces. Such forces promote the formation of the precursor state that controls all basic elementary processes occurring at the gas-surface interphase. The probabilities for the different elementary surface processes triggered by quartz are determined and compared with those recently obtained for another silica polymorph (cristobalite). In addition, the final roto-vibrational distributions of N2 molecules undergoing inelastic scattering have been characterized. N2 molecules, impinging on both considered surfaces in low-medium vibrational states, preserve the initial vibrational state, while those inelastically scattered are rotationally excited and translationally colder. The surface temperature effect, investigated by raising the temperature itself from 100 K up to 1000 K, emerges more sharply for the cristobalite polymorph, mainly for the molecules impinging in the ground roto-vibrational state and with low collision energies.

Long-Range Interactions in Diatomic Catalysts Boosting Electrocatalysis.

The simultaneous presence of two active metal centres in diatomic catalysts (DACs) leads to the occurrence of specific interactions between active sites. Such interactions, referred to as long-range interactions (LRIs), play an important role in determining the rate and selectivity of a reaction. The optimal combination of metal centres must be determined to achieve the targeted efficiency. To date, various types of DACs have been synthesised and applied in electrochemistry. However, LRIs have not been systematically summarised. Herein, the regulation, mechanism, and electrocatalytic applications of LRIs are comprehensively summarised and discussed. In addition to the basic information above, the challenges, opportunities, and future development of LRIs in DACs are proposed in order to present an overall view and reference for future research.

The nature of persistent interactions in two model ß-grasp proteins reveals the advantage of symmetry in stability.

Two proteins within the ß-grasp superfamily, the B1-domain of protein G and the small archaeal modifier protein 1, were investigated to elucidate the key determinants of structural stability at the level of individual interactions. These symmetrical proteins both contain two ß-hairpins which form a sheet flanked by a central α-helix. They were subjected to high temperature molecular dynamics simulations and the detailed behavior of each long-range interaction was characterized. The results revealed that in GB1 the most stable region was the C-terminal hairpin and in SAMP1 it was the opposite, the N-terminal hairpin. Experimental results for GB1 support this finding. In conclusion, it appears that the difference in the location and number of hydrophobic interactions dictate the differential stability which is accommodated due to structural symmetry of the ß-grasp fold. Thus, the hairpins are interchangeable and in nature this lends itself to adaptability and flexibility.

RETRACTED: MZF1 regulates α-globin gene transcription via long-range interactions in erythroid differentiation.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). The article has been retracted at the request of the editor. The journal was informed by Dr Xiangmin Xu and Dr Yongzhong Zhao that they were not involved in the study or research and that the article was submitted without their knowledge. As such this article represents a misuse of the scientific publishing system. The scientific community takes a very strong view on this matter and apologies are offered to readers of the journal that this was not detected during the submission process. All authors were informed of the article retraction however Dr Li and Dr Zeng did not respond to the enquiries.

Nonmonotonic spatial structure of interneuronal correlations in prefrontal microcircuits.

Correlated fluctuations of single neuron discharges, on a mesoscopic scale, decrease as a function of lateral distance in early sensory cortices, reflecting a rapid spatial decay of lateral connection probability and excitation. However, spatial periodicities in horizontal connectivity and associational input as well as an enhanced probability of lateral excitatory connections in the association cortex could theoretically result in nonmonotonic correlation structures. Here, we show such a spatially nonmonotonic correlation structure, characterized by significantly positive long-range correlations, in the inferior convexity of the macaque prefrontal cortex. This functional connectivity kernel was more pronounced during wakefulness than anesthesia and could be largely attributed to the spatial pattern of correlated variability between functionally similar neurons during structured visual stimulation. These results suggest that the spatial decay of lateral functional connectivity is not a common organizational principle of neocortical microcircuits. A nonmonotonic correlation structure could reflect a critical topological feature of prefrontal microcircuits, facilitating their role in integrative processes.

The Density Functional Theory Account of Interplaying Long-Range Exchange and Dispersion Effects in Supramolecular Assemblies of Aromatic Hydrocarbons with Spin.

Aromatic hydrocarbons with fused benzene rings and regular triangular shapes, called n-triangulenes according to the number of rings on one edge, form groundstates with n-1 unpaired spins because of topological reasons. Here, we focus on methodological aspects emerging from the density functional theory (DFT) treatments of dimer models of the n = 2 triangulene (called also phenalenyl), observing that it poses interesting new problems to the issue of long-range corrections. Namely, the interaction comprises simultaneous spincoupling and van der Waals effects, i.e., a technical conjuncture not considered explicitly in the benchmarks calibrating long-range corrections for the DFT account of supramolecular systems. The academic side of considering dimer models for calculations and related analysis is well mirrored in experimental aspects, and synthetic literature revealed many compounds consisting of stacked phenalenyl cores, with intriguing properties, assignable to their long-range spin coupling. Thus, one may speculate that a thorough study assessing the performance of state-of-the-art DFT procedures has relevance for potential applications in spintronics based on organic compounds.

Macromolecular Crowding In Vitro, In Vivo, and In Between.

Biochemical processes take place in heterogeneous and highly volume-occupied or crowded environments that can considerably influence the reactivity and distribution of participating macromolecules. We summarize here the thermodynamic consequences of excluded-volume and long-range nonspecific intermolecular interactions for macromolecular reactions in volume-occupied media. In addition, we summarize and compare the information content of studies of crowding in vitro and in vivo. We emphasize the importance of characterizing the behavior not only of labeled tracer macromolecules but also the composition and behavior of unlabeled macromolecules in the immediate vicinity of the tracer. Finally, we propose strategies for extending quantitative analyses of crowding in simple model systems to increasingly complex media up to and including intact cells.

Nonlinear Fokker-Planck Equation Approach to Systems of Interacting Particles: Thermostatistical Features Related to the Range of the Interactions.

Nonlinear Fokker-Planck equations (NLFPEs) constitute useful effective descriptions of some interacting many-body systems. Important instances of these nonlinear evolution equations are closely related to the thermostatistics based on the S q power-law entropic functionals. Most applications of the connection between the NLFPE and the S q entropies have focused on systems interacting through short-range forces. In the present contribution we re-visit the NLFPE approach to interacting systems in order to clarify the role played by the range of the interactions, and to explore the possibility of developing similar treatments for systems with long-range interactions, such as those corresponding to Newtonian gravitation. In particular, we consider a system of particles interacting via forces following the inverse square law and performing overdamped motion, that is described by a density obeying an integro-differential evolution equation that admits exact time-dependent solutions of the q-Gaussian form. These q-Gaussian solutions, which constitute a signature of S q -thermostatistics, evolve in a similar but not identical way to the solutions of an appropriate nonlinear, power-law Fokker-Planck equation.