Proximity Interactions Research Articles

Exploring Multiple Hypergraphs for Heterogeneous Graph Neural Networks

Graph neural networks have demonstrated significant power in learning graph representations for homogeneous networks. However, real-world network data can often be denoted by heterogeneous networks with different types of nodes and edges, such as social, traffic, and molecular networks. Network heterogeneity presents significant challenges for network analysis and mining. Motif-based hypergraphs preserve high-order proximity and capture composite semantic interactions. Because not all nodes and edges in the original network always exist in a specific hypergraph, it is essential that multiple motif-based hypergraphs are considered to enhance the network representation. Therefore, we propose a novel framework for exploring Multiple Motif-based Hypergraphs for Heterogeneous Graph Neural Networks to learn network representations, named MoH-HGNN, which leverages hypergraph convolution and attention operations to capture complex connectivity patterns. Specifically, we conducted two levels of attention networks with hierarchical structures, namely hyperedge-level attention to learn the importance among different types of nodes and comprehensive semantic-level attention to capture the importance of different types of motif structures. We extensively experimented on four real-world datasets to verify the effectiveness of our proposed framework.

Proximity-induced chiral quantum light generation in strain-engineered WSe2/NiPS3 heterostructures.

Quantum light emitters capable of generating single photons with circular polarization and non-classical statistics could enable non-reciprocal single-photon devices and deterministic spin-photon interfaces for quantum networks. To date, the emission of such chiral quantum light relies on the application of intense external magnetic fields, electrical/optical injection of spin-polarized carriers/excitons or coupling with complex photonic metastructures. Here we report the creation of free-space chiral quantum light emitters via the nanoindentation of monolayer WSe2/NiPS3 heterostructures at zero external magnetic field. These quantum light emitters emit with a high degree of circular polarization (0.89) and single-photon purity (95%), independent of pump laser polarization. Scanning diamond nitrogen-vacancy microscopy and temperature-dependent magneto-photoluminescence studies reveal that the chiral quantum light emission arises from magnetic proximity interactions between localized excitons in the WSe2 monolayer and the out-of-plane magnetization of defects in the antiferromagnetic order of NiPS3, both of which are co-localized by strain fields associated with the nanoscale indentations.

Using TLC-MALDI-TOF to Interrogate In Vitro Peptidyl Proximal Preferences of PARP14 and Glycohydrolase Specificity.

The transfer of ADP-ribose (ADPr) from nicotinamide adenine dinucleotide (NAD+) to target proteins is mediated by a class of human diphtheria toxin-like ADP-ribosyltransferases (ARTDs; previously referred to as poly-ADP-ribose polymerases or PARPs) and the removal of ADPr is catalyzed by a family of glycohydrolases. Although thousands of potential ADPr modification sites have been identified using high-throughput mass-spectrometry, relatively little is known about the sequence specificity encoded near the modification site. Herein, we present a matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) method that facilitates the in vitro analysis of proximal factors that guide ARTD target selection. We identify a minimal 5-mer peptide sequence that is necessary and sufficient to drive glutamate/aspartate targeting using PARP14 while highlighting the importance of the adjacent residues in PARP14 targeting. We measure the stability of the resultant ester bond and show that non-enzymatic removal is pH and temperature dependent, sequence independent, and occurs within hours. Finally, we use the ADPr-peptides to highlight differential activities within the glycohydrolase family and their sequence preferences. Our results highlight (1) the utility of MALDI-TOF in analyzing proximal ARTD-substrate interactions and (2) the importance of peptide sequences in governing ADPr transfer and removal.

Role of face masks and ventilation rates in mitigating respiratory disease transmission in ICU

Indoor environments are major contributing locations where the respiratory virus transmission occurs. Higher air change rate (ACH) values (up to 12) have been recommended in hospital environments to reduce virus transmission. In the present study, the Large Eddy Simulation (LES) data of particle transport in a typical intensive care unit (ICU) is used to calculate the infection risk in close proximity interaction. Three different ACH (6, 9, 12) rates with face masks and one case with a healthy person wearing a face shield are considered. The average resident time of the droplets in the ICU is calculated to find the optimal ACH rate. Of the different types of masks analyzed in the present study, the triple-layer mask has shown the most resistance (0 % probability of infection) to the penetration of virus-laden droplets, while the single-layer mask has shown the highest risk of infection (up to 97 %). The results show that the ACH rate has little effect on close proximity transmission. The ACH 9 case provided optimal value for the particle removal, while the ACH 12 has inferior performance to that of ACH 9. From an energy consumption view, our results recommend not using higher ACH in similar indoor environments. Inside indoor environments, it is advised to wear a three-layer face mask and face shield to reduce the risk of infection.

Distance from human settlements favors wild‐type appearance of feral cats (Felis catus) in Mediterranean woodland

AbstractCamouflage is a common trait enabling animals to avoid detection by predators and prey. Patterns such as spots and stripes are convergent across carnivore families, including felids, and are hypothesized to have adaptive value through camouflage. House cats (Felis catus) were domesticated thousands of years ago, but despite artificial selection for a wide variety of coat colors, the wild‐type pattern of tabby cats is very common. We aimed to determine whether this pattern grants an advantage over other morphs in natural environments. We collected cat images taken with camera traps in natural areas near and far from 38 rural settlements in Israel, to compare the habitat use by feral cats of different colors. We tested the effect of proximity to villages and habitat vegetation (normalized difference vegetation index, NDVI) on the probability of space use by the tabby morph compared to the others. NDVI had a positive effect on site use in both morphs, but non‐tabby cats had a 2.1 higher probability of using the near sites than the far sites, independent of NDVI. The wild‐type tabby cats' probability of site use were equally likely to be unaffected by proximity, or have an interaction of proximity with NDVI whereby the far transects are used with increasing probability in sites of denser vegetation. We hypothesize that the camouflage of tabby cats, more than other colors and patterns, confers an advantage in roaming the woodland habitats for which this pattern evolved. This has both theoretical implications as rare empirical evidence of the adaptive value of fur coloration, and practical implications on managing the ecological impact of feral cats worldwide.

Safe human-robot collaboration in construction: A conceptual perspective

Introduction: Small mobile robots have become increasingly popular in the construction domain over the last few years. They are stable on rough terrains, can walk over small obstacles, climb stairs, and carry various sensors or arms to perform diverse functions and sub-tasks required to complete construction-related tasks. Saving time, improving accessibility to difficult or unsafe spaces, and reducing costs while accomplishing construction tasks are some of the benefits of using small, mobile robots in construction. However, serious concerns about new workplace hazards could arise from having mobile robots on the jobsite. Unfortunately, no study has attempted to evaluate these risks, especially in the construction domain. Therefore, there was a significant need to develop a holistic understanding of the direct and indirect risks of mobile robot applications in construction. Method: In this paper, we used inferential and Virtual Reality (VR) visualization techniques to: (1) construct conceptual visualizations of proximal and distant human-robot interaction within the construction context; and (2) identify potential safety challenges of robots, which were categorized into three groups: (a) physical risks, (b) attentional costs, and (c) psychological impacts. These identified safety challenges were then validated and ranked by a group of construction safety and robotic experts who had knowledge and experience using such robots in construction. Practical Applications: The outcomes of the study provided a detailed understanding of how robots might adversely affect workers’ safety and health. The study outcomes could also be ultimately used in creating regulatory and administrative guidelines for the safe operations of small mobile robots in construction.

Functional LTCC-β2AR Complex Needs Caveolin-3 and Is Disrupted in Heart Failure.

Beta-2 adrenergic receptors (β2ARs) but not beta-2 adrenergic receptors (β1ARs) form a functional complex with L-type Ca2+ channels (LTCCs) on the cardiomyocyte membrane. However, how microdomain localization in the plasma membrane affects the function of these complexes is unknown. We aim to study the coupling between LTCC and β adrenergic receptors in different cardiomyocyte microdomains, the distinct involvement of PKA and CAMKII (Ca2+/calmodulin-dependent protein kinase II) and explore how this functional complex is disrupted in heart failure. Global signaling between LTCCs and β adrenergic receptors was assessed with whole-cell current recordings and western blot analysis. Super-resolution scanning patch-clamp was used to explore the local coupling between single LTCCs and β1AR or β2AR in different membrane microdomains in control and failing cardiomyocytes. LTCC open probability (Po) showed an increase from 0.054±0.003 to 0.092±0.008 when β2AR was locally stimulated in the proximity of the channel (<350 nm) in the transverse tubule microdomain. In failing cardiomyocytes, from both rodents and humans, this transverse tubule coupling between LTCC and β2AR was lost. Interestingly, local stimulation of β1AR did not elicit any change in the Po of LTCCs, indicating a lack of proximal functional interaction between the two, but we confirmed a general activation of LTCC via β1AR. By using blockers of PKA and CaMKII and a Caveolin-3-knockout mouse model, we conclude that the β2AR-LTCC regulation requires the presence of caveolin-3 and the activation of the CaMKII pathway. By contrast, at a cellular "global" level PKA plays a major role downstream β1AR and results in an increase in LTCC current. Regulation of the LTCC activity by proximity coupling mechanisms occurs only via β2AR, but not β1AR. This may explain how β2ARs tune the response of LTCCs to adrenergic stimulation in healthy conditions. This coupling is lost in heart failure; restoring it could improve the adrenergic response of failing cardiomyocytes.

Chromatin alternates between A and B compartments at kilobase scale for subgenic organization

Nuclear compartments are prominent features of 3D chromatin organization, but sequencing depth limitations have impeded investigation at ultra fine-scale. CTCF loops are generally studied at a finer scale, but the impact of looping on proximal interactions remains enigmatic. Here, we critically examine nuclear compartments and CTCF loop-proximal interactions using a combination of in situ Hi-C at unparalleled depth, algorithm development, and biophysical modeling. Producing a large Hi-C map with 33 billion contacts in conjunction with an algorithm for performing principal component analysis on sparse, super massive matrices (POSSUMM), we resolve compartments to 500 bp. Our results demonstrate that essentially all active promoters and distal enhancers localize in the A compartment, even when flanking sequences do not. Furthermore, we find that the TSS and TTS of paused genes are often segregated into separate compartments. We then identify diffuse interactions that radiate from CTCF loop anchors, which correlate with strong enhancer-promoter interactions and proximal transcription. We also find that these diffuse interactions depend on CTCF’s RNA binding domains. In this work, we demonstrate features of fine-scale chromatin organization consistent with a revised model in which compartments are more precise than commonly thought while CTCF loops are more protracted.

Proximity-enhanced valley Zeeman splitting at the WS2/graphene interface

The valley Zeeman physics of excitons in monolayer transition metal dichalcogenides provides valuable insight into the spin and orbital degrees of freedom inherent to these materials. Being atomically-thin materials, these degrees of freedom can be influenced by the presence of adjacent layers, due to proximity interactions that arise from wave function overlap across the 2D interface. Here, we report 60 T magnetoreflection spectroscopy of the A- and B- excitons in monolayer WS2, systematically encapsulated in monolayer graphene. While the observed variations of the valley Zeeman effect for the A- exciton are qualitatively in accord with expectations from the bandgap reduction and modification of the exciton binding energy due to the graphene-induced dielectric screening, the valley Zeeman effect for the B- exciton behaves markedly different. We investigate prototypical WS2/graphene stacks employing first-principles calculations and find that the lower conduction band of WS2 at the valleys (the band) is strongly influenced by the graphene layer on the orbital level. Specifically, our detailed microscopic analysis reveals that the conduction band at the Q point of WS2 mediates the coupling between and graphene due to resonant energy conditions and strong coupling to the Dirac cone. This leads to variations in the valley Zeeman physics of the B- exciton, consistent with the experimental observations. Our results therefore expand the consequences of proximity effects in multilayer semiconductor stacks, showing that wave function hybridization can be a multi-step energetically resonant process, with different bands mediating the interlayer interactions. Such effects can be further exploited to resonantly engineer the spin-valley degrees of freedom in van der Waals and moiré heterostructures.

Crosstalk between Interleukin-1 Receptor-Like 1 and Transforming Growth Factor-β Receptor Signaling Promotes Renal Fibrosis

IL-33, a member of the IL-1 family, acts as an alarmin in immune response. Epithelial-mesenchymal transition and transforming growth factor-β (TGF-β)–induced fibroblast activation are key events in the development of renal interstitial fibrosis. The current study found increased expression of IL-33 and interleukin-1 receptor-like 1 (IL1RL1, alias ST2), the receptor for IL-33, in human fibrotic renal tissues. In addition, IL-33– or ST2-deficient mice showed significantly reduced levels of fibronectin, α-smooth muscle actin, and vimentin, and increased E-cadherin levels. In HK-2 cells, IL-33 promotes the phosphorylation of the TGF-β receptor (TGF-βR), Smad2, and Smad3, and the production of extracellular matrix (ECM), with reduced expression of E-cadherin. Blocking TGF-βR signaling or suppressing ST2 expression impeded Smad2 and Smad3 phosphorylation, thereby reducing ECM production, suggesting that IL-33–induced ECM synthesis requires cooperation between the two pathways. Mechanistically, IL-33 treatment induced a proximate interaction between ST2 and TGF-βRs, activating downstream Smad2 and Smad3 for ECM production in renal epithelial cells. Collectively, this study identified a novel and essential role for IL-33 in promoting TGF-β signaling and ECM production in the development of renal fibrosis. Therefore, targeting IL-33/ST2 signaling may be an effective therapeutic strategy for renal fibrosis.

Valence moderates the effect of stimulus-hand proximity on conflict processing and gaze-cueing.

An effective interaction with the environment requires adaptation of one's own behaviour to environmental demands. We do so by using cues from our environment and relating these cues to our body to predict the outcomes of events. The recent literature on embodied cognition suggests that task-relevant stimuli, presented near the hands, receive more attentional capacity and are processed differently than stimuli, presented spatially more distant to our body. It has also been proposed that near-hand processing is beneficial to conflict resolution. In the current study, we tested the assumption of an attentional bias towards the near hand space in the context of our previous work by combining a cueing paradigm (allocation of visual attention) with a conflict processing paradigm (Simon task) in the near vs far hand space. In addition, the relevance of processing was manipulated by using affective (angry vs neutral smileys) gaze cues (i.e., varying the valence of the cues). Our results indicate that (a) the interaction of valence × cue congruency × hand proximity was significant, indicating that the cueing effect was larger for negative valence in the proximal condition. (b) The interaction of valence × Simon compatibility × stimulus-hand proximity interaction was significant, indicating that for negative valence processing, the Simon effect was smaller in the proximal than in the distal stimulus-hand condition. This effect was at least numerically but not significantly reversed in the neutral valence condition. (c) Overall, cue congruency, indicating the correct vs incorrect attention allocation to the target stimulus onset, did not reveal any effect on Simon compatibility × stimulus-hand proximity. Our results suggest that valence, the allocation of attention, and conflict, seem to be decisive factors determining the direction and strength of hand proximity effects.

Early threat perception is independent of later cognitive and behavioral control. A virtual reality-EEG-ECG study.

Research on social threat has shown influences of various factors, such as agent characteristics, proximity, and social interaction on social threat perception. An important, yet understudied aspect of threat exposure concerns the ability to exert control over the threat and its implications for threat perception. In this study, we used a virtual reality (VR) environment showing an approaching avatar that was either angry (threatening body expression) or neutral (neutral body expression) and informed participants to stop avatars from coming closer under five levels of control success (0, 25, 50, 75, or 100%) when they felt uncomfortable. Behavioral results revealed that social threat triggered faster reactions at a greater virtual distance from the participant than the neutral avatar. Event-related potentials (ERPs) revealed that the angry avatar elicited a larger N170/vertex positive potential (VPP) and a smaller N3 than the neutral avatar. The 100% control condition elicited a larger late positive potential (LPP) than the 75% control condition. In addition, we observed enhanced theta power and accelerated heart rate for the angry avatar vs. neutral avatar, suggesting that these measures index threat perception. Our results indicate that perception of social threat takes place in early to middle cortical processing stages, and control ability is associated with cognitive evaluation in middle to late stages.

Biosurfactant-functionalized Silver nanoparticles infer intrinsic proximal interaction via Lysine and glutamic acid for reduced in vivo molecular biotoxicity with embryonic zebrafish through oxidative stress and apoptosis

The surge of silver nanoparticles (AgNPs) utilization in daily products has raised the concern over their biotoxicity. The concerned biomedical and environmental biotoxicity has raised the quest of biomolecules for the synthesis of AgNPs with better biocompatibility. The emergence of biogenic biosurfactants has sought attention to solve the limitation of synthesizing controlled, stable and biocompatible nanoparticles; owing to their peculiar property of amphiphilic nature. This study provides a novel approach for functionalizing the silver nanoparticles (AgNPs) using lipopeptide biosurfactant extracted from Brevibacterium casei LS14 for higher in vivo environmental biocompatibility. Microbial surfactant was extracted, purified, and characterized using nuclear magnetic resonance (NMR) showing the presence of chemical moieties like carboxyl, methoxy, and amide. Successful functionalization of AgNP termed “F-AgNP” was done to produce AgNPs with a size of 45.0 ± 2.1 nm. The optical characterization of F-AgNP showed an SPR peak at 404 nm in UV-Visible spectra and zeta potential of − 25.5 ± 8.5 mV. In vivo molecular cytotoxicity analysis with embryonic zebrafish determined an LC50 of 50.2 µg/ml for F-AgNP compared to 33.6 µg/ml of unfunctionalized AgNP (U-AgNP). The mechanistic evaluation depicted the concentration-dependent higher cellular and molecular biocompatibility of F-AgNP compared to U-AgNP with less ROS and apoptosis induction due internalization and interaction of F-AgNP with different amino acids of metabolic proteins like Sod1 and P53 proteins via hydrogen bonds having a variable bond-length to influence their expression. The study delineated the molecular mechanism and suggested a sustainable approach to functionalize AgNP using biosurfactants with for biomedical and environmental applications.

Application of linear iterative methods for the proximity effect correction in electron beam lithography

The Jacobi linear iterative method and weight Jacobi method (WJM) are introduced for solving the large-scale linear problem in the proximity effect correction (PEC) of electron beam lithography. Based on the discussion of PEC physics, a symmetrical and positive defined proximity interaction matrix is constructed to ensure the convergence of the methods. It shows that zeroing the center exposure fraction in the point spread function matrix is equal to the operation of splitting the proximity interaction matrix. Then, the Jacobi method is ready for the PEC calculation. The iterative can be performed in the Fourier domain due to the inherent parallelization of the Jacobi method. The convergent property of the Jacobi method is discussed and then testified by the PEC simulation. Compared with the classical Jacobi method, an improvement of 100% in convergence efficiency can be achieved by introducing the optimized relaxation parameter quasi-ωopt in the WJM. By combining the WJM and Gold nonlinear iteration method, a new method that shows an order of magnitude superior in accuracy to the WJM is proposed. Results indicate the methods introduced here could be used to calculate the PEC problem efficiently.

Abstract 4802: Identification of critical hypoxia induced factors in castrate resistant prostate cancer

Abstract Background: Prostate cancer (PCa) is the second most diagnosed cancer in men and the second cause of cancer-related death amongst men worldwide. PCa is a heterogeneous disease, and the outcome is worse for patients when the disease progresses from localized PCa to a castrate-resistant disease. Androgen receptor (AR) signaling is crucial for PCa development and has been a major therapeutic target for decades. Despite the success made with hormone therapy to block AR signaling, castration resistant disease can arise through mutations and amplifications of the androgen receptor (AR) and AR splice variants (AR-Vs). Amongst them, AR-V7 and AR-V12 can promote AR signaling independent of androgen. Furthermore, prostate tumors are highly hypoxic due to abnormal tumor vasculature. Hypoxia influences the efficacy of local and systemic treatment strategies, such as radiotherapy, hormone therapy, and chemotherapy, resulting in poorer clinical outcomes for PCa patients. Therefore, a complete understanding of AR and AR variant function, as well as how they are modulated by hypoxia and therapy is warranted for developing new strategies to treat PCa. Methods: To identify the transcriptional apparatus associated with the AR and its variants under normal and hypoxic conditions, we carried out Bio-ID proximity labeling mass spectrometry (BioID-MS). We generated stable androgen-independent human prostate cancer cell lines, PC-3 and DU145, expressing AR and the AR-V7 and AR-V12 variants fused to a MiniTurboID (MTID) enzyme. To delineate the AR proximal interaction network, we treated cells with androgen or vehicle for 3 hours and affinity-purified biotinylated proteins after the addition of biotin for the final 2 hours. Cells were grown in normoxia (20% O2) or treated with hypoxia (95% N2,5% CO2 and 0.5% O2) for 24 h. Nonspecific interactions were filtered using controls and statistical methods to identify high-confidence interactomes. Results: BioID proximity labeling in PC3 cells identified several AR-associated proteins, including many knowninteractors, validating the approach. Hypoxic conditions led to a striking alteration in proximal interactions and many metabolic proteins were highly enriched with AR upon exposure of cells to hypoxia for 24h. Among these, phosphoglycerate kinase 1 (PGK1) was a top hit. PGK1 has been reported to interact with AR to mediate the expression of genes that regulates cell proliferation and apoptosis. Additionally, PGK1 has an essential role in metabolic reprogramming induced by c-MYC and HIF-1α, leading to enhanced tumorigenesis. Conclusion: Bio-ID mass spectrometry was used to map the proximal interactome of AR and its variants, identifying novel interactions partners for further analysis. We found that hypoxia strongly alters interactors with the AR, and we identified PGK1 as a hypoxia induced AR interaction in PCA. Current work to functionally validate this interaction will be presented. Citation Format: Oloruntoba I. Osagie, Jordann Smakk, Deborah E. Citrin, Travis H. Stracker. Identification of critical hypoxia induced factors in castrate resistant prostate cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4802.

Astrocytes express aberrant immunoglobulins as putative gatekeeper of astrocytes to neuronal progenitor conversion

Using multi-omics analyses including RNAseq, RT-PCR, RACE-PCR, and shotgun proteomic with enrichment strategies, we demonstrated that newborn rat astrocytes produce neural immunoglobulin constant and variable heavy chains as well as light chains. However, their edification is different from the ones found in B cells and they resemble aberrant immunoglobulins observed in several cancers. Moreover, the complete enzymatic V(D)J recombination complex has also been identified in astrocytes. In addition, the constant heavy chain is also present in adult rat astrocytes, whereas in primary astrocytes from human fetus we identified constant and variable kappa chains as well as the substitution lambda chains known to be involved in pre-B cells. To gather insights into the function of these neural IgGs, CRISPR-Cas9 of IgG2B constant heavy chain encoding gene (Igh6), IgG2B overexpression, proximal labeling of rat astrocytes IgG2B and targets identification through 2D gels were performed. In Igh6 KO astrocytes, overrepresentation of factors involved in hematopoietic cells, neural stem cells, and the regulation of neuritogenesis have been identified. Moreover, overexpression of IgG2B in astrocytes induces the CRTC1-CREB-BDNF signaling pathway known to be involved in gliogenesis, whereas Igh6 KO triggers the BMP/YAP1/TEAD3 pathway activated in astrocytes dedifferentiation into neural progenitors. Proximal labeling experiments revealed that IgG2B is N-glycosylated by the OST complex, addressed to vesicle membranes containing the ATPase complex, and behaves partially like CD98hc through its association with LAT1. These experiments also suggest that proximal IgG2B-LAT1 interaction occurs concomitantly with MACO-1 and C2CD2L, at the heart of a potentially novel cell signaling platform. Finally, we demonstrated that these chains are synthesized individually and associated to recognize specific targets. Indeed, intermediate filaments Eif4a2 and Pdia6 involved in astrocyte fate constitute targets for these neural IgGs. Taken together, we hypothese that neural aberrant IgG chains may act as gatekeepers of astrocytes' fate.

Three-dimensional and single-cell sequencing of liver cancer reveals comprehensive host-virus interactions in HBV infection.

Hepatitis B virus (HBV) infection is a major risk factor for chronic liver diseases and liver cancer (mainly hepatocellular carcinoma, HCC), while the underlying mechanisms and host-virus interactions are still largely elusive. We applied HiC sequencing to HepG2 (HBV-) and HepG2-2.2.15 (HBV+) cell lines and combined them with public HCC single-cell RNA-seq data, HCC bulk RNA-seq data, and both genomic and epigenomic ChIP-seq data to reveal potential disease mechanisms of HBV infection and host-virus interactions reflected by 3D genome organization. We found that HBV enhanced overall proximal chromatin interactions (CIs) of liver cells and primarily affected regional CIs on chromosomes 13, 14, 17, and 22. Interestingly, HBV altered the boundaries of many topologically associating domains (TADs), and genes nearby these boundaries showed functional enrichment in cell adhesion which may promote cancer metastasis. Moreover, A/B compartment analysis revealed dramatic changes on chromosomes 9, 13 and 21, with more B compartments (inactive or closed) shifting to A compartments (active or open). The A-to-B regions (closing) harbored enhancers enriched in the regulation of inflammatory responses, whereas B-to-A regions (opening) were enriched for transposable elements (TE). Furthermore, we identified large HBV-induced structural variations (SVs) that disrupted tumor suppressors, NLGN4Y and PROS1. Finally, we examined differentially expressed genes and TEs in single hepatocytes with or without HBV infection, by using single-cell RNA-seq data. Consistent with our HiC sequencing findings, two upregulated genes that promote HBV replication, HNF4A and NR5A2, were located in regions with HBV-enhanced CIs, and five TEs were located in HBV-activated regions. Therefore, HBV may promote liver diseases by affecting the human 3D genome structure. Our work promotes mechanistic understanding of HBV infection and host-virus interactions related to liver diseases that affect billions of people worldwide. Our findings may also have implications for novel immunotherapeutic strategies targeting HBV infection.

Estimation of multi-infeed HVDC inter converter direct current interaction in close electric proximity

This paper aims at investigating the direct current interaction between various converters of High Voltage Direct Current (HVDC) system, which lie in close electric proximity within the multi-infeed configuration. The interaction between converters in multi-infeed DC system are highly possible events which need to be evaluated in order to avoid the adverse operational results. The various indices such as multi-infeed interaction factor (MIIF) considering AC busbar voltages, local and concurrent commutation failures (CF) in converter stations under different AC disturbances, influence of AC system’s strength on fault recovery time (FRT), transient over-voltage (TOV) under permanent DC faults, voltage and power stability of multi-infeed DC system are comprehensively illustrated in literatures. However, there is lack of literature regarding the investigation of current interaction in multi-infeed DC system. Therefore, in this paper, a power flow approach is adopted to estimate the inter converter direct current interaction. An index, multi-infeed current interaction factor (MICIF) is proposed that can effectively depicts the interaction between converters. The MICIF index is verified through electromagnetic transient simulations of dual infeed HVDC system developed in PSCAD/EMTDC. The results show that MICIF index can accurately assess the interaction between different converter stations of HVDC system under steady and transient states.

The role of the mitochondrial outer membrane protein SLC25A46 in mitochondrial fission and fusion.

Mutations in SLC25A46 underlie a wide spectrum of neurodegenerative diseases associated with alterations in mitochondrial morphology. We established an SLC25A46 knock-out cell line in human fibroblasts and studied the pathogenicity of three variants (p.T142I, p.R257Q, and p.E335D). Mitochondria were fragmented in the knock-out cell line and hyperfused in all pathogenic variants. The loss of SLC25A46 led to abnormalities in the mitochondrial cristae ultrastructure that were not rescued by the expression of the variants. SLC25A46 was present in discrete puncta at mitochondrial branch points and tips of mitochondrial tubules, co-localizing with DRP1 and OPA1. Virtually, all fission/fusion events were demarcated by a SLC25A46 focus. SLC25A46 co-immunoprecipitated with the fusion machinery, and loss of function altered the oligomerization state of OPA1 and MFN2. Proximity interaction mapping identified components of the ER membrane, lipid transfer proteins, and mitochondrial outer membrane proteins, indicating that it is present at interorganellar contact sites. SLC25A46 loss of function led to altered mitochondrial lipid composition, suggesting that it may facilitate interorganellar lipid flux or play a role in membrane remodeling associated with mitochondrial fusion and fission.

Influence of the Solvent on the Stability of Aminopurine Tautomers and Properties of the Amino Group

Amino derivatives of purine (2-, 6-, 8-, and N-NH2) have found many applications in biochemistry. This paper presents the results of a systematic computational study of the substituent and solvent effects in these systems. The issues considered are the electron-donating properties of NH2, its geometry, π-electron delocalization in purine rings and tautomeric stability. Calculations were performed in ten environments, with 1 < ε < 109, using the polarizable continuum model of solvation. Electron-donating properties were quantitatively described by cSAR (charge of the substituent active region) parameter and π-electron delocalization by using the HOMA (harmonic oscillator model of aromaticity) index. In aminopurines, NH2 proximity interactions depend on its position and the tautomer. The results show that they are the main factor determining how solvation affects the electron-donating strength and geometry of NH2. Proximity with the NH∙∙∙HN repulsive interaction between the NH2 and endocyclic NH group results in stronger solvent effects than the proximity with two attractive NH∙∙∙N interactions. The effect of amino and nitro (previously studied) substitution on aromaticity was compared; these two groups have, in most cases, the opposite effect, with the largest being in N1H and N3H purine tautomers. The amino group has a smaller effect on the tautomeric preferences of purine than the nitro group. Only in 8-aminopurine do tautomeric preferences change: N7H is more stable than N9H in H2O.