Loop Interactions Research Articles

JMJD6 Rewires ATF4-Dependent Glutathione Metabolism to Confer Ferroptosis Resistance in SPOP-Mutated Prostate Cancer.

Ferroptosis inducers have shown therapeutic potential in prostate cancer (PCa), but tumor heterogeneity poses a barrier to their efficacy. Distinguishing the regulators orchestrating metabolic crosstalk between cancer cells could shed light on therapeutic strategies to more robustly activate ferroptosis. Here, we found that aberrant accumulation of jumonji domain containing 6 (JMJD6) proteins correlated with poorer prognosis of PCa patients. Mechanistically, PCa-associated speckle type BTB/POZ protein (SPOP) mutants impaired the proteasomal degradation of JMJD6 proteins. Elevated JMJD6 and ATF4 coordinated enhancer-promoter loop interactions to stimulate the glutathione biosynthesis pathway. Independent of androgen receptor, JMJD6 recruited mediator subunits (Med1/14) to assemble de novo enhancers mapping to pivotal genes associated with glutathione metabolism, including SLC7A11, GCLM, ME1, and others. SPOP mutations thus induced intrinsic resistance to ferroptosis, dependent on enhanced JMJD6-ATF4 activity. Consequently, targeting JMJD6 rendered SPOP-mutated PCa selectively sensitive to ferroptosis. The JMJD6 antagonist SKLB325 synergized with erastin in multiple pre-clinical PCa models. Together, this study identifies JMJD6 as a druggable vulnerability in SPOP-mutated PCa to increase sensitivity to ferroptosis inducers.

Dysfunctional BCAA degradation triggers neuronal damage through disrupted AMPK-mitochondrial axis due to enhanced PP2Ac interaction

Metabolic and neurological disorders commonly display dysfunctional branched-chain amino acid (BCAA) metabolism, though it is poorly understood how this leads to neurological damage. We investigated this by generating Drosophila mutants lacking BCAA-catabolic activity, resulting in elevated BCAA levels and neurological dysfunction, mimicking disease-relevant symptoms. Our findings reveal a reduction in neuronal AMP-activated protein kinase (AMPK) activity, which disrupts autophagy in mutant brain tissues, linking BCAA imbalance to brain dysfunction. Mechanistically, we show that excess BCAA-induced mitochondrial reactive oxygen species (ROS) triggered the binding of protein phosphatase 2 A catalytic subunit (PP2Ac) to AMPK, suppressing AMPK activity. This initiated a dysregulated feedback loop of AMPK-mitochondrial interactions, exacerbating mitochondrial dysfunction and oxidative neuronal damage. Our study identifies BCAA imbalance as a critical driver of neuronal damage through AMPK suppression and autophagy dysfunction, offering insights into metabolic-neuronal interactions in neurological diseases and potential therapeutic targets for BCAA-related neurological conditions.

Molecular architecture of human LYCHOS involved in lysosomal cholesterol signaling.

Lysosomal membrane protein LYCHOS (lysosomal cholesterol signaling) translates cholesterol abundance to mammalian target of rapamycin activation. Here we report the 2.11-Å structure of human LYCHOS, revealing a unique fusion architecture comprising a G-protein-coupled receptor (GPCR)-like domain and a transporter domain that mediates homodimer assembly. The NhaA-fold transporter harbors a previously uncharacterized intramembrane Na+ pocket. The GPCR-like domain is stabilized, by analogy to canonical GPCRs, in an inactive state through 'tethered antagonism' by a lumenal loop and strong interactions at the cytosol side preventing the hallmark swing of the sixth transmembrane helix seen in active GPCRs. A cholesterol molecule and an associated docosahexaenoic acid (DHA)-phospholipid are entrapped between the transporter and GPCR-like domains, with the DHA-phospholipid occupying a pocket previously implicated in cholesterol sensing, indicating inter-domain coupling via dynamic lipid-protein interactions. Our work provides a high-resolution framework for functional investigations of the understudied LYCHOS protein.

Tumor microenvironment in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is a highly aggressive and malignant tumor of oral cavity with a poor prognosis and high mortality due to the limitations of existing therapies. The significant role of tumor microenvironment (TME) in the initiation, development, and progression of OSCC has been widely recognized. Various cells in TME, including tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), T lymphocytes, tumor-associated neutrophils (TANs), myeloid-derived suppressor cells (MDSCs) and dendritic cells (DCs), form a complicated and important cellular network to modulate OSCC proliferation, invasion, migration, and angiogenesis by secreting RNAs, proteins, cytokines, and metabolites. Understanding the interactions among cells in TME provides the foundation for advanced clinical diagnosis and therapies. This review summarizes the current literature that describes the role of various cellular components and other TME factors in the progression of OSCC, hoping to provide new ideas for the novel OSCC treatment strategies targeting the complicated cellular network and factors that mediate the interactive loops among cells in TME.

Divergences in the Effective Loop Interaction of the Chern–Simons Bosons with Leptons. The Unitary Gauge Case

Divergences in the Effective Loop Interaction of the Chern–Simons Bosons with Leptons. The Unitary Gauge Case

Extension of the Standard Model with Chern–Imons Type Interaction

Extension of the Standard Model (SM) with a Chern–Simons type interaction contains a new vector massive boson (Chern–Simons boson) that couples to electroweak gauge bosons by the so-called effective Chern–Simons interaction. There is no direct interaction between the Chern–Simons bosons and SM fermions. We consider the existing restrictions on the parameters of this SM extension, the effective loop interaction of a new vector boson with SM fermions, and the possibility of the manifestation of the long-lived GeV-scale Chern–Simons bosons in collider experiments.

The conformation of the nSrc specificity-determining loop in the Src SH3 domain is modulated by a WX conserved sequence motif found in SH3 domains.

Cellular signaling networks are modulated by multiple protein-protein interaction domains that coordinate extracellular inputs and processes to regulate cellular processes. Several of these domains recognize short linear motifs, or SLiMs, which are often highly conserved and are closely regulated. One such domain, the Src homology 3 (SH3) domain, typically recognizes proline-rich SLiMs and is one of the most abundant SLiM-binding domains in the human proteome. These domains are often described as quite versatile, and indeed, SH3 domains can bind ligands in opposite orientations dependent on target sequence. Furthermore, recent work has identified diverse modes of binding for SH3 domains and a wide variety of sequence motifs that are recognized by various domains. Specificity is often attributed to the RT and nSrc loops near the peptide-binding cleft in this domain family, particularly for Class I binding, which is defined as RT and nSrc loop interactions with the N-terminus of the ligand. Here, we used the Src and Abl SH3 domains as a model to further investigate the role of the RT and nSrc loops in SH3 specificity. We created chimeric domains with both the RT and nSrc loop sequences swapped between these SH3 domains, and used fluorescence anisotropy assays to test how relative binding affinities were affected for Src SH3- and Abl SH3-specific ligands. We also used Alphafold-Multimer to model our SH3:peptide complexes in combination with molecular dynamics simulations. We identified a position that contributes to the nSrc loop conformation in Src SH3, the amino acid immediately following a highly conserved Trp that creates a hydrophobic pocket critical for SH3 ligand recognition. We defined this as the WX motif, where X = Trp for Src and Cys for Abl. A broad importance of this position for modulating nSrc loop conformation in SH3 domains is suggested by analyses of previously deposited SH3 structures, multiple sequence alignment of SH3 domains in the human proteome, and our biochemical and computational data of mutant Src and Abl SH3 domains. Overall, our work uses experimental approaches and structural modeling to better understand specificity determinants in SH3 domains.

The societal impact of meaningful social interactions during online focus groups

Against a backdrop of increasing levels of discontent and division reported in democratic societies, meaningful social interactions (especially between strangers) are clearly important to study. Drawing on observations during previous research projects, this article explores whether and how online focus groups (OFGs) can be leveraged to facilitate meaningful social interactions between unfamiliar interaction partners, and the extent to which these interactions have the potential to create societal impact. Our findings suggest that OFGs can facilitate a combination of “emotional”, “informational”, and “tangible” impacts for participants, helping to make social interactions meaningful. Meanwhile, these “individual impacts” could translate to “societal impacts” by empowering people to better participate (and participate better) in the public sphere. This outcome could be accelerated if individuals share newly acquired knowledge onwards with their community, generating a positive feedback loop of further meaningful social interactions. Our findings imply that researchers should strive to ensure that qualitative social research delivers direct value to the participants who take part, separate from the potential (thematic) value it has for the academic(s) involved. This ambition could be supported by academic funding frameworks that recognize “direct value for participants” as a desirable (and assessed) criterion.

Microscale analysis of geomembrane–geotextile interface cyclic shear behavior using DEM

Given that the material-wearing process is the key factor influencing the dynamic shear strength at the interface between the geomembrane (GMB) and nonwoven geotextile (NWGT), this study investigates the cyclic shear behavior of the GMB–NWGT interface from a microscale perspective using the three-dimensional discrete element method (DEM). The textured GMB is simulated with breakable asperities and the thermally bonded NWGT is generated by spatially randomly distributed fibers which could be stretched and untangled. The established model is validated against the experimental data. The wearing process during cyclic loading is evaluated by quantifying the embedded depth of GMB asperities and fiber breakage within NWGT. The simulation results demonstrate that the maximum asperity embedment (inter-embedding effect), affected by the normal stress and displacement amplitude, induces the hook and loop interactions between asperities and fibers (inter-locking effect), accounting for the cyclic shear resistance at the interface. The inter-locking effect dominates the strain-hardening behavior of the GMB–NWGT interface when the percentage of inter-fiber bond breakage is less than 22% and the maximum asperity embedment ratio is lower than 60%; otherwise, the inter-embedding effect dominates the strain-softening behavior of the interface.

Sex-specific DNA methylation differences in Amyotrophic lateral sclerosis.

Sex is an important covariate in all genetic and epigenetic research due to its role in the incidence, progression and outcome of many phenotypic characteristics and human diseases. Amyotrophic lateral sclerosis (ALS) is a motor neuron disease with a sex bias towards higher incidence in males. Here, we report for the first time a blood-based epigenome-wide association study meta-analysis in 9274 individuals after stringent quality control (5529 males and 3975 females). We identified a total of 226 ALS saDMPs (sex-associated DMPs) annotated to a total of 159 unique genes. These ALS saDMPs were depleted at transposable elements yet significantly enriched at enhancers and slightly enriched at 3'UTRs. These ALS saDMPs were enriched for transcription factor motifs such as ESR1 and REST. Moreover, we identified an additional 10 genes associated with ALS saDMPs through chromatin loop interactions, suggesting a potential regulatory role for these saDMPs on distant genes. Furthermore, we investigated the relationship between DNA methylation at specific CpG sites and overall survival in ALS using Cox proportional hazards models. We identified two ALS saDMPs, cg14380013 and cg06729676, that showed significant associations with survival. Overall, our study reports a reliable catalogue of sex-associated ALS saDMPs in ALS and elucidates several characteristics of these sites using a large-scale dataset. This resource will benefit future studies aiming to investigate the role of sex in the incidence, progression and risk for ALS.

Dynamic Lithium Transport Pathway via Crack Formation in Phase-Separating Materials

Degradation of electrode particles during cycling is chemo-mechanically coupled and needs to be systematically investigated for the Li-ion battery development. The effect of Li transport pathway on internal stress and crack formation during cycling remains elusive. The opposite effect of cracked, newly exposed active surface on Li transport pathway alteration, accelerating the chemo-mechanical degradation, also remains poorly known. Using operando scanning transmission X-ray microscopy on [100]-oriented LiFePO4 single particles, we demonstrated that lithium insertion from the edge of the non-cracked particle dynamically generate tensile stress within the particle, thereby initiating crack formation during lithiation. The exposed crack surface acts as a Li (de)insertion hotspot, redirecting Li transport pathway and internal stress-fields. Delithiation process induces the Li-poor phase around the crack, creating tensile stress, propagating the crack, and subsequently exposing fresh surface which serves as active hot-spot. On the other hands, lithiation process induces the Li-rich phases around the crack, creating compressive stress and suppressing crack propagation. Phase-field simulations demonstrate chemo-mechanically interactive loop that lithium (de)insertion pathway determines dynamic tensile/compressive stress distribution, which recursively determines (de)insertion pathway. This study offers insights that can help develop high-performance and long-lasting batteries, as well as cycling protocols that suppress crack formation. Figure 1

The quantum vortices dynamics: spatio-temporal scale hierarchy and origin of turbulence

Abstract This study investigates the evolution and interaction of quantum vortex loops with a small but non-zero radius of core a. The quantization scheme of the classical vortex system is based on the approach proposed by the author Talalov S V (2022 Eur. Journ. Mech B/Fluids 92 100-6), Talalov S V (2023 Physical Review Fluids 8 034 607-1-03460712). We consider small perturbations in the ring-shaped loops, which include both helical-type shape variations and small excitations of the flow in the vortex core. The quantization of the circulation Γ is deduced from the first principles of quantum theory. As a result of our approach, the set of quantized circulation values is wider than the standard one. The developed theory introduces a hierarchical spatio-temporal scale in the quantum evolution of vortices. We also explore the applicability of this model for describing the origins of turbulence in quantum fluid flows. To achieve this specific objective, we employ the method of random Hamiltonians to describe the interaction of quantum vortex loops.

Molecular dynamics simulation of punched loop detachment during helium bubble growth in nickel

The coarsening of helium (He) bubbles in nickel-based alloys significantly impacts their service performance. Understanding the underlying mechanisms is crucial for ensuring the long-term durability and reliability of these alloys in reactor radiation environments. Molecular dynamics simulations of single bubble growth at temperatures of 300 and 900 K were conducted using the sequential He atom injection method to investigate the He bubble growth and evolution in nickel. A noteworthy phenomenon observed during bubble growth is the detachment of punched prismatic loops. The critical bubble size for punched loop detachment can be reduced by growing the bubble at a slower rate or lower temperature. The reduction is attributed to the additional time available for the punched loop to dissociate or the higher pressure within the bubble pushing it out. Meanwhile, the formation mechanism of bubble-loop complexes is explored through the interaction of punched loops with nearby punched loops or bubbles. In addition, the integration of these simulation results with variations in material mechanical performance yields valuable insights for interpreting material degradation. This study provides a foundation for improving in-reactor service performance, contributing to a broader understanding of the complex interplay between helium bubble coarsening and material behavior.

RNA fold prediction by Monte Carlo in graph space and the statistical mechanics of tertiary interactions.

Using a graph representation of RNA structures, we have studied the ensembles of secondary and tertiary graphs of two sets of RNA with Monte Carlo simulations. The first consisted of 91 target ribozyme and riboswitch sequences of moderate lengths (<150 nt) having a variety of secondary, H-type pseudoknots and kissing loop interactions. The second set consisted of 71 more diverse sequences across many RNA families. Using a simple empirical energy model for tertiary interactions and only sequence information for each target as input, the simulations examined how tertiary interactions impact the statistical mechanics of the fold ensembles. The results show that the graphs proliferate enormously when tertiary interactions are possible, producing an entropic driving force for the ensemble to access folds having tertiary structures even though they are overall energetically unfavorable in the energy model. For each of the targets in the two test sets, we assessed the quality of the model and the simulations by examining how well the simulated structures were able to predict the native fold, and compared the results to fold predictions from ViennaRNA. Our model generated good or excellent predictions in a large majority of the targets. Overall, this method was able to produce predictions of comparable quality to Vienna, but it outperformed Vienna for structures with H-type pseudoknots. The results suggest that while tertiary interactions are predicated on real-space contacts, their impacts on the folded structure of RNA can be captured by graph space information for sequences of moderate lengths, using a simple tertiary energy model for the loops, the base pairs, and base stacks.

Activation of polycystin-1 signaling by binding of stalk-derived peptide agonists.

Polycystin-1 (PC1) is the protein product of the PKD1 gene whose mutation causes autosomal dominant Polycystic Kidney Disease (ADPKD). PC1 is an atypical G protein-coupled receptor (GPCR) with an autocatalytic GAIN domain that cleaves PC1 into extracellular N-terminal and membrane-embedded C-terminal (CTF) fragments. Recently, activation of PC1 CTF signaling was shown to be regulated by a stalk tethered agonist (TA), resembling the mechanism observed for adhesion GPCRs. Here, synthetic peptides of the first 9- (p9), 17- (p17), and 21-residues (p21) of the PC1 stalk TA were shown to re-activate signaling by a stalkless CTF mutant in human cell culture assays. Novel Peptide Gaussian accelerated molecular dynamics (Pep-GaMD) simulations elucidated binding conformations of p9, p17, and p21 and revealed multiple specific binding regions to the stalkless CTF. Peptide agonists binding to the TOP domain of PC1 induced close TOP-putative pore loop interactions, a characteristic feature of stalk TA-mediated PC1 CTF activation. Additional sequence coevolution analyses showed the peptide binding regions were consistent with covarying residue pairs identified between the TOP domain and the stalk TA. These insights into the structural dynamic mechanism of PC1 activation by TA peptide agonists provide an in-depth understanding that will facilitate the development of therapeutics targeting PC1 for ADPKD treatment.

Activation of polycystin-1 signaling by binding of stalk-derived peptide agonists

Polycystin-1 (PC1) is the protein product of the PKD1 gene whose mutation causes autosomal dominant Polycystic Kidney Disease (ADPKD). PC1 is an atypical G protein-coupled receptor (GPCR) with an autocatalytic GAIN domain that cleaves PC1 into extracellular N-terminal and membrane-embedded C-terminal (CTF) fragments. Recently, activation of PC1 CTF signaling was shown to be regulated by a stalk tethered agonist (TA), resembling the mechanism observed for adhesion GPCRs. Here, synthetic peptides of the first 9- (p9), 17- (p17), and 21-residues (p21) of the PC1 stalk TA were shown to re-activate signaling by a stalkless CTF mutant in human cell culture assays. Novel Peptide Gaussian accelerated molecular dynamics (Pep-GaMD) simulations elucidated binding conformations of p9, p17, and p21 and revealed multiple specific binding regions to the stalkless CTF. Peptide agonists binding to the TOP domain of PC1 induced close TOP-putative pore loop interactions, a characteristic feature of stalk TA-mediated PC1 CTF activation. Additional sequence coevolution analyses showed the peptide binding regions were consistent with covarying residue pairs identified between the TOP domain and the stalk TA. These insights into the structural dynamic mechanism of PC1 activation by TA peptide agonists provide an in-depth understanding that will facilitate the development of therapeutics targeting PC1 for ADPKD treatment.

The Interaction Fidelity Model: A Taxonomy to Communicate the Different Aspects of Fidelity in Virtual Reality

Fidelity describes how closely a replication resembles the original. It can be helpful to analyze how faithful interactions in virtual reality (VR) are to a reference interaction. In prior research, fidelity has been restricted to the simulation of reality—also called realism. Our definition includes other reference interactions, such as superpowers or fiction. Interaction fidelity is a multilayered concept. Unfortunately, different aspects of fidelity have either not been distinguished in scientific discourse or referred to with inconsistent terminology. Therefore, we present the Interaction Fidelity Model (IntFi Model). Based on the human-computer interaction loop, it systematically covers all stages of VR interactions. The conceptual model establishes a clear structure and precise definitions of eight distinct components. As a communication tool, it helps teams to understand and discuss fidelity in VR. It was reviewed through workshops with fourteen VR experts. We provide guidelines, diverse examples, and educational material to apply the IntFi Model universally to any VR experience and propose foundational research opportunities.

High-throughput studies and machine learning for design of β titanium alloys with optimum properties

Based on experimental data, machine learning (ML) models for Young’s modulus, hardness, and hot-working ability of Ti-based alloys were constructed. In the models, the interdiffusion and mechanical property data were high-throughput re-evaluated from composition variations and nanoindentation data of diffusion couples. Then, the Ti−(22±0.5)at.%Nb−(30±0.5)at.%Zr−(4±0.5)at.%Cr (TNZC) alloy with a single body-centered cubic (BCC) phase was screened in an interactive loop. The experimental results exhibited a relatively low Young’s modulus of (58±4) GPa, high nanohardness of (3.4±0.2) GPa, high microhardness of HV (520±5), high compressive yield strength of (1220±18) MPa, large plastic strain greater than 30%, and superior dry- and wet-wear resistance. This work demonstrates that ML combined with high-throughput analytic approaches can offer a powerful tool to accelerate the design of multicomponent Ti alloys with desired properties. Moreover, it is indicated that TNZC alloy is an attractive candidate for biomedical applications.

Numerical investigation of the collision of a vortex pair upon a solid wavy wall

The vortex dynamics produced by the collision of a vortex pair with a solid wavy wall are examined numerically using a proposed high-order vortex particle method. The influences of the Reynolds number (ReΓ) of the vortex pair, the wavelength (λw), and the wave amplitude (Aw) of the wall on the induced vortex structures, interactions among vortices, and the instability and reconnection of secondary vortices are discussed. The boundary layers at the top of ripples separate first to form the secondary vortices moving around the primary tubes. Meanwhile, the boundary layers at the bottom of ripples detach late, move vertically upward, and then form incomplete vortex loops due to an unsuccessful reconnection of the secondary vortices. The ReΓ effects cause the appearance of various vortex structures, such as incomplete primary vortex loops from the bottom of ripples at ReΓ=1000, secondary vortex loops due to interactions of the first loops with the wall at ReΓ=2000, and hairpin vortices at ReΓ=4000. The wavelength of the wall induces instability in the secondary vortex tubes. This instability on the secondary tubes appears at the top of ripples at λw=2r0, while it spreads over the whole secondary vortices at λw=4r0, where r0 is the initial spacing between the primary vortex tubes. This instability results in various wavy tubes that robustly interact with the primary tubes. Due to the effects of Aw, the primary vortex tubes significantly decay with time compared to those in the flat wall case.

Synchronization Stability Analysis and Parameter Design of Grid-Following Inverters Considering the Interactions of Current Control and Phase-Locked Loop

Synchronization Stability Analysis and Parameter Design of Grid-Following Inverters Considering the Interactions of Current Control and Phase-Locked Loop