The insulator EACBE regulates V(D)J recombination of Tcrd gene by modulating chromatin organization.

T cell receptor (TCR) diversity, essential for the recognition of a wide array of antigens, is generated through V(D)J recombination. The and genes reside within a shared genomic locus, with rearrangement occurring first in the double-negative (DN) stage during thymocyte development. Elucidating the regulatory mechanisms governing rearrangement is therefore crucial for understanding the developmental coordination of both and rearrangements.

Coordination of transcription-coupled repair and repair-independent release of lesion-stalled RNA polymerase II.

Transcription-blocking lesions (TBLs) stall elongating RNA polymerase II (Pol II), which then initiates transcription-coupled repair (TCR) to remove TBLs and allow transcription recovery. In the absence of TCR, eviction of lesion-stalled Pol II is required for alternative pathways to address the damage, but the mechanism is unclear. Using Protein-Associated DNA Damage Sequencing (PADD-seq), this study reveals that the p97-proteasome pathway can evict lesion-stalled Pol II independently of repair.

Integration of ATAC-seq and RNA-seq identifies MX1-mediated AP-1 transcriptional regulation as a therapeutic target for Down syndrome.

Background: Growing evidence has suggested that Type I Interferon (I-IFN) plays a potential role in the pathogenesis of Down Syndrome (DS). This work investigates the underlying function of MX1, an effector gene of I-IFN, in DS-associated transcriptional regulation and phenotypic modulation.

Methods: We performed assay for transposase-accessible chromatin with high-throughout sequencing (ATAC-seq) to explore the difference of chromatin accessibility between DS derived amniocytes (DSACs) and controls.

Discovery of novel and potent InhA direct inhibitors by ensemble docking-based virtual screening and biological assays.

Multidrug-resistant tuberculosis (MDR-TB) continues to spread worldwide and remains one of the leading causes of death among infectious diseases. The enoyl-acyl carrier protein reductase (InhA) belongs to FAS-II family and is essential for the formation of the Mycobacterium tuberculosis cell wall. Recent years, InhA direct inhibitors have been extensively studied to overcome MDR-TB.

Three-way contact analysis characterizes the higher order organization of the Tcra locus.

The generation of highly diverse antigen receptors in T and B lymphocytes relies on V(D)J recombination. The enhancer Eα has been implicated in regulating the accessibility of Vα and Jα genes through long-range interactions during rearrangements of the T-cell antigen receptor gene Tcra. However, direct evidence for Eα physically mediating the interaction of Vα and Jα genes is still lacking.

Solubility and Valence Variation of Ce in Low-Alkali Borosilicate Glass and Glass Network Structure Analysis.

Low-alkali borosilicate glass was used as the immobilization substrate, and Ce was used to replicate the trivalent and tetravalent actinides, in order to create simulated waste glass through melt heat treatment. The valence of Ce and solubility of CeO in waste glass were studied as well as its network structure and thermal and chemical stability. The solubility of Ce in waste glass was examined by XRD and SEM.

Experiment and molecular dynamics simulations reveal proanthocyanidin B2 and B3 can inhibit prion aggregation by different mechanisms.

Prion diseases are a group of fatal neurodegenerative diseases caused by the misfolding and aggregation of prion protein (PrP), and the inhibition of PrP aggregation is one of the most effective therapeutic strategies. Proanthocyanidin B2 (PB2) and B3 (PB3), the effective natural antioxidants have been evaluated for the inhibition of amyloid-related protein aggregation. Since PrP has similar aggregation mechanism with other amyloid-related proteins, will PB2 and PB3 affect the aggregation of PrP? In this paper, experimental and molecular dynamics (MD) simulation methods were combined to investigate the influence of PB2 and PB3 on PrP aggregation.

Identification of CBPA as a New Inhibitor of PD-1/PD-L1 Interaction.

Targeting of the PD-1/PD-L1 immunologic checkpoint is believed to have provided a real breakthrough in the field of cancer therapy in recent years. Due to the intrinsic limitations of antibodies, the discovery of small-molecule inhibitors blocking PD-1/PD-L1 interaction has gradually opened valuable new avenues in the past decades. In an effort to discover new PD-L1 small molecular inhibitors, we carried out a structure-based virtual screening strategy to rapidly identify the candidate compounds.

Genome-wide mapping of protein-DNA damage interaction by PADD-seq.

Protein-DNA damage interactions are critical for understanding the mechanism of DNA repair and damage response. However, due to the relatively random distributions of UV-induced damage and other DNA bulky adducts, it is challenging to measure the interactions between proteins and these lesions across the genome. To address this issue, we developed a new method named Protein-Associated DNA Damage Sequencing (PADD-seq) that uses Damage-seq to detect damage distribution in chromatin immunoprecipitation-enriched DNA fragments.

Chromatin organizer SATB1 controls the cell identity of CD4 CD8 double-positive thymocytes by regulating the activity of super-enhancers.

CD4 and CD8 double-positive (DP) thymocytes play a crucial role in T cell development in the thymus. DP cells rearrange the T cell receptor gene Tcra to generate T cell receptors with TCRβ. DP cells differentiate into CD4 or CD8 single-positive (SP) thymocytes, regulatory T cells, or invariant nature kill T cells (iNKT) in response to TCR signaling.

Binding Thermodynamics and Dissociation Kinetics Analysis Uncover the Key Structural Motifs of Phenoxyphenol Derivatives as the Direct InhA Inhibitors and the Hotspot Residues of InhA.

Given the current epidemic of multidrug-resistant tuberculosis, there is an urgent need to develop new drugs to combat drug-resistant tuberculosis. Direct inhibitors of the InhA target do not require activation and thus can overcome drug resistance caused by mutations in drug-activating enzymes. In this work, the binding thermodynamic and kinetic information of InhA to its direct inhibitors, phenoxyphenol derivatives, were explored through multiple computer-aided drug design (CADD) strategies.

Effect of PO and NaO on the Solubility of Molybdenum and Structural Features in Borosilicate Glass.

In this paper, the effect of doping phosphorus in a borosilicate glass matrix to improve the solubility of Mo was investigated by X-ray diffraction (XRD), Raman, and solid-state nuclear magnetic resonance (NMR) spectroscopy, and the effectiveness of Na content on P species inhibiting the growth of the crystallization of Mo was assessed. The results indicate that phosphate-doped borosilicate glass can host 4 mol% of Mo, and that such a borosilicate glass matrix could only accommodate 1 mol% of Mo without phosphate doping. The effectiveness of phosphorus may be correlated with the Na content in borosilicate glass, and a high Na content borosilicate glass matrix requires more P doping to accommodate Mo.

Borosilicate Glass-Ceramics Containing Zirconolite and Powellite for RE- and Mo-Rich Nuclear Waste Immobilization.

In order to increase the loading of rare earth- and molybdenum-rich high-level waste in the waste forms, zirconolite- and powellite-based multi-phase borosilicate glass-ceramics were synthesized via an in-situ heat treatment method. The effects of the CTZ (CaO, TiO and ZrO) content on the crystallization, microstructure and aqueous durability of the multi-phase borosilicate glass-ceramics were studied. The results indicate that the increase of CTZ content can promote crystallization.

Study on Structure and Properties of LaO-Doped Basaltic Glasses for Immobilizing Simulated Lanthanides.

The LaO-doped basaltic glass simulated high-level waste form (HLW) was prepared by the solid-state melt method. The simulated waste LaO maximum loading and the doping effect on structure, thermal stability, leaching behavior, density, and hardness of basaltic glasses were studied. XRD and SEM results show that the simulated waste loading of LaO in basaltic glass can be up to ~46 wt.

Discovery of pentapeptide-inhibitor hits targeting FKBP51 by combining computational modeling and X-ray crystallography.

FKBP51 is well-known as a cochaperone of Hsp90 machinery and implicated in many human diseases including stress-related diseases, tau-mediated neurodegeneration and cancers, which makes FKBP51 an attractive drug target for the therapy of FKBP51-associated diseases. However, it has been reported that only nature product rapamycin, cyclosporine A, FK506 and its derivatives exhibit good binding affinities when bound to FKBP51 by now. Given the advantages of peptide-inhibitors, we designed and obtained 20 peptide-inhibitor hits through structure-based drug design.

Phase separation of Epstein-Barr virus EBNA2 protein reorganizes chromatin topology for epigenetic regulation.

Epstein-Barr virus nuclear antigen 2 (EBNA2) is a transactivator of viral and cellular gene expression, which plays a critical role in the Epstein-Barr virus-associated diseases. It was reported that EBNA2 regulates gene expression by reorganizing chromatin and manipulating epigenetics. Recent studies showed that liquid-liquid phase separation plays an essential role in epigenetic and transcriptional regulation.

Downregulation by CNNM2 of ATP5MD expression in the 10q24.32 schizophrenia-associated locus involved in impaired ATP production and neurodevelopment.

Genome-wide association studies (GWAS) have accelerated the discovery of numerous genetic variants associated with schizophrenia. However, most risk variants show a small effect size (odds ratio (OR) <1.2), suggesting that more functional risk variants remain to be identified.

A role of the CTCF binding site at enhancer Eα in the dynamic chromatin organization of the Tcra-Tcrd locus.

The regulation of T cell receptor Tcra gene rearrangement has been extensively studied. The enhancer Eα plays an essential role in Tcra rearrangement by establishing a recombination centre in the Jα array and a chromatin hub for interactions between Vα and Jα genes. But the mechanism of the Eα and its downstream CTCF binding site (here named EACBE) in dynamic chromatin regulation is unknown.

A linear-amplification VDJ-seq technique for quantification of immunoglobulin and T cell receptor diversity.

The V(D)J recombination is essential for generating a highly diverse repertoire of antigen receptors expressed on T and B lymphocytes. Here, we developed a linear-amplification VDJ-seq technique for quantifying V(D)J recombination of antigen receptor genes. This technique takes advantage of linear amplification using in vitro transcription and reverse transcription to avoid bias generated by the PCR amplification of low copy number of target DNA.

How graphene affects the misfolding of human prion protein: A combined experimental and molecular dynamics simulation study.

As the broad application of graphene in the biomedical field, it is urgent and important to evaluate how the graphene affects the structure and function of the proteins in our body, especially the amyloid-related proteins. Prion protein, as a typical amyloid protein, it misfolding and aggregation will lead to serious prion diseases. To explore if graphene promotes or inhibits the formation of amyloid, here, we combined the experimental and molecular dynamics (MD) simulation methods to study the influence of graphene on the globular domain of prion protein (PrP).

Carbon Nanoparticles Inhibit the Aggregation of Prion Protein as Revealed by Experiments and Atomistic Simulations.

The specific properties of carbon nanoparticles (NPs) have attracted great attention in applications in biotechnology and biomedicine, e.g., in the field of amyloidosis.

Discovery of small molecules binding to the normal conformation of prion by combining virtual screening and multiple biological activity evaluation methods.

Conformational conversion of the normal cellular prion protein, PrP, into the misfolded isoform, PrP, is considered to be a central event in the development of fatal neurodegenerative diseases. Stabilization of prion protein at the normal cellular form (PrP) with small molecules is a rational and efficient strategy for treatment of prion related diseases. However, few compounds have been identified as potent prion inhibitors by binding to the normal conformation of prion.

Experimental and Theoretical Insights into the Inhibition Mechanism of Prion Fibrillation by Resveratrol and its Derivatives.

Resveratrol and its derivatives have been shown to display beneficial effects to neurodegenerative diseases. However, the molecular mechanism of resveratrol and its derivatives on prion conformational conversion is poorly understood. In this work, the interaction mechanism between prion and resveratrol as well as its derivatives was investigated using steady-state fluorescence quenching, Thioflavin T binding assay, Western blotting, and molecular dynamics simulation.