Loop Formation Research Articles (Page 1)

Molecular dynamics simulations of nanoindentation were conducted to compare the dislocation behavior in a pure V and a TiVTa multi-principal element alloy (MPEA) with [100] and [111] crystal orientations. It is found that the significant resistance to dislocation motion and loop formation in the TiVTa MPEA compared to pure V, attributed to its substantial lattice distortion. While dislocation nucleation was heterogeneous in both materials with similar activation volumes and nucleation stresses (approximately 0.2 G), the dislocation density and plastic zone volume in TiVTa were substantially lower. Under standard indentation conditions, independent dislocation loops readily formed in pure V but were absent in TiVTa. With a larger indenter size and a greater nanoindentation depth, the results demonstrated that forming loops in TiVTa requires significantly higher force, directly linking this effect to the hindrance of dislocation glide by chemical disorder and lattice distortion. This study provides atomic-scale insights into the deformation mechanisms of TiVTa MPEAs, offering guidelines for future alloy design.

Purpose To introduce a modified intrascleral suture technique (MIST) for repairing iridodialysis combined with phacoemulsification cataract surgery and evaluate its efficacy. Methods We retrospectively analyzed the clinical characteristics and surgical outcomes of patients undergoing iridodialysis repair and cataract surgery (2018–2023). Twelve eyes received MIST, and eleven received the modified sewing-machine technique (MSMT). Both techniques utilized the closed-chamber sewing-machine principle of suture loop formation. MIST utilized a 10-0 polypropylene suture with long straight and short curved needles, guided by a 26-gauge syringe tip for intrascleral suturing. MSMT involved creating a partial-thickness scleral tunnel, through which a prethreaded needle with 10-0 polypropylene suture was passed for fixation. Results Iridodialysis was successfully repaired in all patients. The median procedure time was significantly shorter in the MIST group (25 min, IQR: 24.0–27.5) than in the MSMT group (34 min, IQR: 29.0–35.0; p < 0.0001). Although postoperative day 1 best-corrected visual acuity (BCVA) did not differ significantly between groups (p = 0.08), the median BCVA was better in the MIST group (0.1 logMAR, IQR: 0.0–0.4) than the MSMT group (0.4 logMAR, IQR: 0.1–0.6). Complication rates were comparable between groups. Conclusion The MIST technique provides a minimally invasive alternative for iridodialysis repair by eliminating the need for conjunctival or scleral dissection. This approach significantly reduces operative time while maintaining surgical efficacy and safety, making it a valuable option for combined iridodialysis and cataract surgery.

Targeting cancer cell plasticity through chromatin organization is an emerging research area, yet the molecular mechanisms that govern chromatin loop formation remain unclear. Here, we develop a CRISPR screen based on our engineered live-cell CTCF-cohesin contact reporters to identify regulators of chromatin loops. Our findings reveal that tousled-like kinase 2 (TLK2) functions as a key regulator of chromatin loop formation during the cancer stemness transition. Mechanistically, TLK2 phosphorylates DYNLL1, enhancing its interaction with CTCF to promote CTCF-cohesin hub formation at the KLF4 locus. Suppressing TLK2 impairs cancer stemness plasticity, sensitizes cancer cells to cytotoxic stress in vitro, and reduces lung metastases and enhances immunotherapy response in breast cancer mouse models. Clinically, elevated TLK2 expression correlates with poor prognosis in breast cancer patients. Collectively, these findings identify TLK2 as a potential therapeutic target for mitigating cancer stemness plasticity, highlighting chromatin loop-targeting therapy as a promising strategy to eradicate cancer stem cells.

Abstract Background and Aims The development of effective preventive therapies for glomerulopathy is critically needed. Current pre-clinical research utilizes in vitro 2D cell cultures and in vivo animal models, both of which present significant limitations. Two-dimensional cultures fail to adequately replicate the complex cellular interactions present in physiological environments, while ethical considerations necessitate a reduction in the use of animal models. Although kidney organoid cultures demonstrate enhanced tissue-specific characteristics, they remain insufficient for a comprehensive evaluation of the glomerular filtration barrier (GFB) due to the absence of capillary loop formation. As a complementary approach, the organ-on-chip approach relies on microfluidic to control the organization of the co-culture of differentiated cells [1, 2]. Method We present a glomerulus-on-chip (GoC) fabricated through photolithography, enabling the creation of durable polydimethylsiloxane (PDMS) culture chambers. This model incorporates dual-layer PDMS systems designed to mimic glomerular architecture, featuring dimensional parameters that are consistent with physiological conditions with a 100μm vascular space and a 50μm urinary space. The GoC utilizes three immortalized human cell types: podocytes [3] and parietal epithelial cells (PECs) [4] in the lower chamber, and glomerular endothelial cells (GEnC) [5] cells on the upper side of the porous membrane. Results We propose an innovative opto-microfluidic organ-on-chip, that constitutes a unique integrated system to comprehensively probe complex pathophysiological processes from molecular events to cell/tissue functional behavior in a physiologically relevant environment. Our GoC utilizes immortalized human cell types to reconstitute glomerular organization and facilitate in situ measurements. The model successfully addresses challenges associated with the maturation of the filtration barrier, providing a robust platform for investigating intricate cellular interactions and conducting drug screening. Conclusion Existing commercial systems fail in accurately mimicking the glomerular organization and lack the requisite versatility for systematic screening of diverse stimuli. Our GoC model, characterized by its innovative design and functional filtration capabilities, represents a pivotal advancement in glomerular research. This approach offers a powerful, animal-free platform for pharmacological evaluation and pre-clinical studies, paving the way for novel analyses and therapeutic strategies in kidney pathology.

Achieving high folding yield remains a challenge in DNA origami, particularly as structures increase in complexity and scale. Here, how DNA origami design influences folding is investigated using a combination of real-time fluorometry, gel electrophoresis, electron microscopy, and theoretical analysis. Results reveal a balance of free energy changes from loop formation and hybridization that govern nucleation of nanostructure assembly, while the extent of cooperativity determines the overall assembly. The effect of structural complexity, staple design, and scaffold design on each energetic parameter, folding yield, kinetics, and cooperativity is measured. The results show that the scaffold pattern determines the extent of cooperativity, where fewer scaffold crossovers result in more cooperative folding. These findings use a tool developed in this work to estimate the extent of cooperativity in any structure. It is also found that limiting the number of crossovers per staple should be prioritized over extending staple binding domains, as the entropic penalty dominates the favorable binding. Finally, a 1-2 h focused annealing ramp strategy is demonstrated, that can increase yield up to 17% relative to traditional multi-day ramps. Optimizing energy changes and cooperativity through design can significantly enhance assembly yield and reduce time, particularly for complex structures, aiding large-scale DNA materials.

Cohesin (SMC1-SMC3-RAD21) constantly extrudes DNA loops to organize chromosomes into structural domains, pausing and anchoring at specific DNA-bound CTCF molecules. To study the detailed consequences of cohesin loop extrusion, we developed TArgeted Cohesin Loader (TACL) for controlled pan-cellular activation of chromatin loop formation at defined genomic locations in living cells. With TACL, we show that highly complex looping networks can exist, with extruding cohesin complexes that block each other, drive cohesin queuing and induce loop anchoring at nearly all CTCF-bound sites. TACL loops extend upon acute depletion of STAG2, PDS5A or WAPL. Activated cohesin loop extrusion hinders local gene transcription and can alter chromatin accessibility and H3K27ac distribution. TACL shows that the loading/extrusion complex NIPBL-MAU2 can be transported by cohesin to CTCF sites but, together with SMC1, to enhancers in a RAD21-independent manner. TACL thus enables studying the consequences of activated loop extrusion at defined genomic locations.

Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) show initial efficacy in EGFR-mutated lung cancer, but residual disease persists. This study aimed to investigate cluster of differentiation 24 (CD24) as a translational immunotherapeutic target for enhancing third-generation EGFR-TKI efficacy. We conducted RNA-sequencing (RNA-seq) on drug-responsive, drug-tolerant persister, and drug-resistant cells to identify therapeutic targets to pair with EGFR-TKIs. For validation, we integrated single-cell RNA-seq data from 29 lung cancer specimens and used single-nucleus RNA-seq and immunohistochemistry on clinical residual tumor samples following TKI therapy (TKI-residual). With CRISPR/Cas9, we studied the effect of CD24 on proliferation and phagocytic clearance during EGFR-TKI treatment. We tested CD24 knockout or ATG-031 (a first-in-class CD24 antibody) with EGFR-TKIs in vitro, xenografts, and spontaneous lung cancer models. To explore mechanisms, we used DNA affinity precipitation, chromatin immunoprecipitation sequencing, and luciferase assays to identify transcription factors regulating CD24. Co-immunoprecipitation combined with mass spectrometry and phosphoproteomics were used to study YIN-YANG-1 (YY1) S247 phosphorylation's expression and function, while kinase inhibitors assessed upstream phosphorylation of YY1 S247 and its regulation of CD24. CD24 expression rose in drug-responsive, -resistant, and -tolerant lung cancer cells and post-EGFR-TKI treatment clinical specimens. This elevation promoted cell proliferation and shielded tumor cells from macrophage-mediated phagocytosis. Genetic depletion of CD24 or treatment with ATG-031 significantly enhanced phagocytosis and tumor eradication in vitro, in xenografts, and in mice harboring EGFRL858R·T790M-driven spontaneous lung tumors. Furthermore, we revealed that YY1 S247 phosphorylation was responsible for the upregulation of CD24 upon EGFR-TKI treatment, facilitating YY1 dimerization and the formation of promoter-enhancer loops that regulate CD24 expression. CD24 is a promising target in EGFR-mutated lung cancers, potentially enhancing efficacy of third-generation EGFR-TKIs.

ABSTRACT In this study, 15 MeV Ni3+ ion irradiation was carried out on several kinds of Fe-Mn model alloys containing Ni and Si. Our main aim was to investigate the effect of solute elements on irradiation hardening behavior and microstructural evolution in reactor pressure vessel steels using nanoindentation hardness tests and transmission electron microscopy. Our results show that the addition of Ni enhances dislocation loop formation and irradiation hardening, while Si addition suppresses both. It is suggested that Ni atoms reduce the mobility of b = a/2 < 111 > dislocation loops by interacting with their strain field, leading to their accumulation and enhanced hardening. On the other hand, Si atoms make vacancies stable through Si-vacancy pairs, which enhance recombination with self-interstitial atoms and suppress dislocation loop nucleation or growth in the matrix. In Fe-Mn-Ni-Si alloys, the effects of Ni and Si additions on irradiation hardening and microstructural evolution were competitive.

BackgroundAlthough liquid-liquid phase separation (LLPS) proteins are known to participate in genome organization and transcriptional regulation through the formation of biomolecular condensates, their functional interplay with other regulatory proteins and histone modifications in chromatin loop formation remains poorly characterized. By combining Hi-C chromatin interaction data with ChIP-seq profiles of 12, 27, and 24 LLPS proteins in GM12878, K562, and HepG2 cell lines, respectively, we identified chromatin loops associated with LLPS proteins and systematically analysed patterns of cooperative protein binding and histone modification enrichment within these loop-associated peaks.ResultsWe identified 162, 313, and 431 chromatin loops associated with LLPS proteins in GM12878, K562, and HepG2 cell lines, respectively. These loops were relatively small in size and predominantly anchored at enhancer regions. Examination of cooperative binding of proteins within loop-associated peaks revealed that transcriptional repressor IKZF1, HDAC1, and SAP130 most frequently co-localized with LLPS proteins in GM12878, K562, and HepG2 cells, respectively. Further analysis of histone modification enrichment patterns revealed that active histone modifications, such as H3K4me2, H3K4me3, H3K9ac, and H3K27ac, co-localized at loop-associated peaks, with H3K4me1 exhibiting additional specific co-localization with these four histone modifications at enhancer-localized loop-associated peaks. Notably, bivalent chromatin domains where H3K27me3 co-localized with active histone modifications were identified at promoter-localized loop-associated peaks in HepG2 cells, and elevated H3K27me3 occupancy at these peaks was associated with transcriptional repression of target genes. Moreover, quantitative RNA-seq analysis revealed that the expression of target genes associated with enhancer-promoter loops was correlated with both the binding of LLPS proteins and the enrichment patterns of histone modifications within their ChIP-seq peaks at loop anchors.ConclusionsOur study suggests that LLPS proteins may cooperate with transcriptional repressors to facilitate chromatin looping. Furthermore, local enrichment of histone modifications at loop-associated peaks provides additional regulatory control over chromatin architecture and gene transcription.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13072-025-00632-3.

ABSTRACT Based on a critical analysis of existing models of coherent particle nucleation, growth and transition to the incoherent state, new models of these processes are developed within the framework of classical nucleation theory. It is shown that the growth mechanism of coherent particles with atomically smooth interfaces, controlled by a relatively slow process of nucleation of two-dimensional terraces on their faces, strongly suppresses the particle nucleation rate compared to the predictions of existing models. The new model for the transition to a semi-coherent state by the formation of misfit dislocation loops at the particle interface allows the quantification of the nucleation rate of misfit dislocation loops and facilitates the appropriate determination of the threshold radius of the particle, beyond which the transition to the semi-coherent state commences.

Loop formation between distant interior segments of a polymer is a fundamental process for biological functions such as gene regulation and protein folding. While prior studies predominantly focus on end-to-end looping, interior loop formation is more relevant in vivo. Using Langevin dynamics simulations, we investigate the kinetics of interior loop formation in confined flexible polymers with specific internal segments having attractive interactions, focusing on the effect of tail length (lt) and spatial confinement. The probability distribution function of the distance between attractive beads forming the interior loop, P(ra), and the corresponding free energy profile, F(ra), exhibit a bimodal structure due to the coexistence of two distinct conformational states: a compact folded state and an unlooped relaxed configuration. We observe a non-monotonic dependence of the looping probability (Pl) and looping time (Tl) on lt under strong confinement. We identify the optimal combination of the cavity size and the tail length that leads to maximizing the looping time Tl and minimizing the looping probability Pl. In addition, the interior loop dynamics for distinct loop lengths (ll) of a fixed polymer chain (L) showcase that Tl changes rapidly with the addition of the first few monomers and then plateaus as the tail grows, which is exactly verified with analytical results. The observed coexistence of looped and extended states is a hallmark of intermediate ɛ, disappearing for weak or strong attractions, highlighting the tunability of looping dynamics via interaction strength.

W and W-based high-entropy alloys are promising candidates for plasma-facing materials in fusion reactors. While irradiation studies on W have revealed a tendency for helium (He) bubble formation and radiation-induced defects, investigations of WTaCrV high-entropy alloy (HEA) have demonstrated superior radiation resistance, whether under He⁺ irradiation or heavy ion irradiation. To assess material performance under conditions relevant to fusion reactors—characterized by fast neutrons and gas production from transmutation reactions—complex irradiation environments need to be modeled. Using classical molecular dynamics simulations, we examined defect evolution in W and equimolar WTaCrV HEA with and without preexisting He atoms under overlapping displacement cascades up to 0.2 displacements per atom (dpa) at 300 K. In W, dislocation loops and large interstitial clusters formed readily, with increasing He content leading to higher dislocation densities and the formation of polygonal interstitial networks. In contrast, WTaCrV alloy exhibited strong resistance to formation of dislocation loops and large interstitial clusters but was more susceptible to bubble formation at higher He concentrations. Bubble growth was driven by helium trapping at vacancy sites and the coalescence of smaller bubbles. Larger bubbles remained stable against cascade overlap, limiting further growth by coalescence.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-19080-w.

Herein, we propose a versatile strategy for dynamic DNA self-assembly through a control loop embedded with responsive chemical groups. Responsive to a stimulus, the inserted chemical group will enable the formation or cleavage of the control loop, determining its intact or cleaved states. When the loop is intact, DNA self-assembly occurs; otherwise, the assembly process is prevented. The "Turn-On", "Turn-Off", and reversible "On-Off-On" systems have been achieved for two DNA assembly systems by incorporating different chemical groups, responding to various stimuli such as light irradiation, metal ions, and small molecules. The loop-controlled dynamic DNA self-assembly strategy holds excellent designability and versatility, enriching the existing regulation reservoir and bringing new opportunities for dynamic DNA nanotechnology.

Influence of patient-specific acute myocardial ischemia maps on arrhythmogenesis: A computational study.

Ureaplasma parvum SMC-ScpAB complex is capable of loop extrusion and demonstrates properties that distinguish it from Bacillus subtilis homologue.

To evaluate the efficacy and safety of the subclavian loop catheter technique for endovascular stenting of vertebral artery ostial stenosis (VAOS). We retrospectively reviewed all patients who underwent vertebral artery stenting between January 2022 and April 2025. The analysis included only those in whom standard transradial access (TRA) failed and the subclavian artery loop technique was used. Outcomes assessed included vascular access and surgical complications, postoperative modified Rankin Scale (mRS) scores, and in-stent restenosis on follow-up. Of 134 vertebral artery stenting procedures, 12 cases in which standard TRA failed were successfully completed using the subclavian loop catheter technique. Patients were aged 18-80 years, and VAOS was more frequent on the right side (n=11/12). Mean preoperative stenosis was 79%, reduced to 7.5% after stenting. No major periprocedural complications occurred. Median time from catheter loop formation to stent deployment was 33 min. Median follow-up was 3 months, during which 67% of patients were assessed and no in-stent restenosis was detected. The subclavian loop catheter technique via TRA was a safe, effective, and feasible option for VAOS stenting when conventional radial or transfemoral access was limited by vascular anatomy. The technique provided stable access, enabled precise stent deployment, and demonstrated a favorable safety profile in this series.

First Passage Time of Loop Formation in Chromatin Chains

Herniation, rotation, looping, and retraction of the midgut occur sequentially during midgut morphogenesis. Recent studies have demonstrated the importance of mechanical forces arising from the differential growth between the midgut and mesentery in the formation of small intestinal loops. However, the roles of mechanics and differential growth in the overall process remain unclear. In this study, we developed a computational model of midgut morphogenesis based on continuum mechanics. We showed that the protrusion, rotation, and retraction of the midgut can emerge sequentially because of temporal changes in differential growth. The midgut was modeled as a hyperelastic tube with a Gaussian shape. The differential growth of the midgut and mesentery was modeled by the spatial variation in spontaneous plastic deformation. The hyperelastic tube developed a protrusion by compression-induced deformation, suggesting that other external forces are not necessary for midgut herniation prior to rotation. Appropriate differential growth induced a rotation of the tube. A less-growing mesentery attempts to face inward to minimize the tensile forces, which causes tube twisting and results in midgut rotation. Excess differential growth may cause the retraction of the midgut before the formation of small intestinal loops. The results of this study will serve as reference in future studies on embryology and tissue engineering.

Purpose: The aim of this study was to elucidate the mechanisms underlying the formation and maintenance of drug resistance in cancer cells. Previously, we demonstrated that prolonged treatment of estrogen-dependent MCF-7 breast cancer cells with exosomes derived from estrogen-resistant MCF-7/T cells leads to a partial loss of estrogen sensitivity in MCF-7 cells. Moreover, repeated transfection with one of the exosomal microRNAs — microRNA-181a-2 — induced an irreversible decrease in hormonal sensitivity in the recipient cells. In the present work, to further investigate the possible mechanism of miR-181a-2-induced acquired resistance, we analyzed the effect of multiple miR-181a-2 transfections on the expression of cellular miR-181a-2 and related signaling proteins. Methods: MTT-assay, transient transfection, lentiviral infection, qRT-PCR, immunoblotting, and reporter assay. Results: We found that multiple transfections with miR-181a-2 resulted in a marked increase in cellular miR-181a-2 precursor levels, whereas single transfection had no such effect. Similarly, stable transfection with miR-181a-2 led to increased levels of cellular miR-181a-2 and its host gene, MIR181A2HG, which was associated with partial resistance to tamoxifen. Analysis of the genomic DNA encoding miR-181a-2 revealed no changes in copy number in transfected cells. Furthermore, we identified the transcription factor Snail as a key mediator of miR-181a-2–induced resistance and demonstrated its role in the formation of an autoregulatory loop of miR-181a-2 and the maintenance of cell resistance. Conclusion: Overall, these results reveal a novel mechanism of resistance-associated signaling pathway rearrangement based on the formation of a miR-181a-2 autoregulatory loop.

The active DNA demethylase Repressor of Silencing 1 (ROS1) regulates genomic DNA methylation patterns during plant development. ROS1 expression is promoted by DNA methylation within its promoter region. However, the mechanisms and biological significance of ROS1 regulation under abiotic stresses remain elusive. Here we show that heat stress reduces DNA methylation in the ROS1 promoter to suppress its expression. Under normal conditions, SUVH1 and SUVH3 bind methylated ROS1 promoter regions, inhibiting chromatin interactions around the ROS1 locus; heat stress triggers their dissociation, enabling chromatin loop formation to suppress ROS1 transcription. Transgenic plants with exogenous ROS1 maintain high expression levels during heat stress, causing transposable element hypomethylation and enhanced transcription and transgenerational transposition of the heat-activated retrotransposon ONSEN. We propose that heat-induced suppression of ROS1 transcription, which is conserved across plant species, serves as a brake system to limit transposable element activation, thereby safeguarding genome stability.