Novel Inhibitors for MDM2-MDM4 E3 Ligase Potently Induce p53-Indepedent Apoptosis in Drug-Resistant Leukemic Cells.

MDM2 and MDM4 are major negative regulators of tumor suppressor p53. Beyond regulating p53, MDM2 possesses p53-independent activity in promoting cell cycle progression and tumorigenesis via its RING domain ubiquitin E3 ligase activity. MDM2 and MDM4 form heterodimer polyubiquitin E3 ligases via their RING domain interaction.

Risk prediction for elderly cognitive impairment by radiomic and morphological quantification analysis based on a cerebral MRA imaging cohort.

Objective: To establish morphological and radiomic models for early prediction of cognitive impairment associated with cerebrovascular disease (CI-CVD) in an elderly cohort based on cerebral magnetic resonance angiography (MRA).

Methods: One-hundred four patients with CI-CVD and 107 control subjects were retrospectively recruited from the 14-year elderly MRA cohort, and 63 subjects were enrolled for external validation. Automated quantitative analysis was applied to analyse the morphological features, including the stenosis score, length, relative length, twisted angle, and maximum deviation of cerebral arteries.

Small-molecule MMRi36 induces apoptosis in p53-mutant lymphomas by targeting MDM2/MDM4/XIAP for degradation.

Rituximab combined with systemic chemotherapy significantly improves the rate of complete response in B-cell lymphomas. However, acquired rituximab resistance develops in most patients leading to relapse. The mechanisms underlying rituximab resistance are not well-understood.

Development and validation of intravoxel incoherent motion diffusion weighted imaging-based model for preoperative distinguishing nuclear grade and survival of clear cell renal cell carcinoma complicated with venous tumor thrombus.

Objective: To assess the utility of multiparametric MRI and clinical indicators in distinguishing nuclear grade and survival of clear cell renal cell carcinoma (ccRCC) complicated with venous tumor thrombus (VTT).

Materials And Methods: This study included 105 and 27 patients in the training and test sets, respectively. Preoperative MRI, including intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI), was performed.

Cell-based assay to detect small molecules restoring levels of let-7 miRNAs.

Blockage of miRNA biogenesis by LIN28, or other mechanisms, results in derepression of target genes, some of which are oncogenic (e.g., ) potentially contributing to tumor progression and drug resistance.

Association between serum albumin with geriatric nutritional risk index and osteopenia in Chinese elderly men: a nested case-control study.

Background And Objectives: Malnutrition is associated with a higher risk of osteoporosis. We aim to assess the relationship between serum albumin with geriatric nutritional risk index and osteopenia in Chinese elderly men.

Methods And Study Design: This is a nested case-control study from a prospective cohort enrolled 1109 individuals who were followed for seven years.

Imaging Transcriptomics of the Brain for Schizophrenia.

Schizophrenia is a severe mental disorder with a neurodevelopmental origin. Although schizophrenia results from changes in the brain, the underlying biological mechanisms are unknown. Transcriptomics studies quantitative expression changes or qualitative changes of all genes and isoforms, providing a more meaningful biological insight.

Designing semiconductor materials and devices in the post-Moore era by tackling computational challenges with data-driven strategies.

In the post-Moore's law era, the progress of electronics relies on discovering superior semiconductor materials and optimizing device fabrication. Computational methods, augmented by emerging data-driven strategies, offer a promising alternative to the traditional trial-and-error approach. In this Perspective, we highlight data-driven computational frameworks for enhancing semiconductor discovery and device development by elaborating on their advances in exploring the materials design space, predicting semiconductor properties and optimizing device fabrication, with a concluding discussion on the challenges and opportunities in these areas.

Age-adjusted Charlson comorbidity index is associated with the risk of osteoporosis in older fall-prone men: a retrospective cohort study.

Background: There is growing evidence linking the age-adjusted Charlson comorbidity index (aCCI), an assessment tool for multimorbidity, to fragility fracture and fracture-related postoperative complications. However, the role of multimorbidity in osteoporosis has not yet been thoroughly evaluated. We aimed to investigate the association between aCCI and the risk of osteoporosis in older adults at moderate to high risk of falling.

Second-harmonic generation in 2D moiré superlattices composed of bilayer transition metal dichalcogenides.

Moiré superlattices (MSLs) in twisted two-dimensional van der Waals materials feature twist-angle-dependent crystal symmetry and strong optical nonlinearities. By adjusting the twist angle in bilayer van der Waals materials, the second-harmonic generation (SHG) can be controlled. Here, we focus on exploring the electronic and SHG properties of MSLs in 2D bilayer transition metal dichalcogenides (TMDs) with different twist angles through first-principles calculations.

Environmental regulation and high-quality agricultural development.

Unlabelled: The key trend for future agricultural growth is efficient, green and sustainable high-quality development, and it is crucial to sort out the factors influencing high-quality agricultural development.

Objectives: The purpose of this study is to dissect whether environmental regulation has a catalytic effect on quality rural development, through which paths it is driven and whether there is a threshold effect to be further clarified.

Method: In this study, the panel data of 34 provinces in China from 2012 to 2018 are used, and 17 variables are used to construct an evaluation index system, covering four dimensions: agricultural endowment, agricultural output level, agricultural green degree and social sustainability.

Longitudinal real world correlation study of blood pressure and novel features of cerebral magnetic resonance angiography by artificial intelligence analysis on elderly cognitive impairment.

Objective: This study aims to investigate novel clinical risk factors for cognitive impairment (CI) in elderly.

Methods: A total of 3221 patients (259 patients with CI and 2,962 subjects without CI) were recruited into this nested case-control study who underwent cerebral magnetic resonance angiography (MRA) from 2007 to 2021. All of the clinical data with MRA imaging were recorded followed by standardization processing blindly.

Dual Targeting of MDM4 and FTH1 by MMRi71 for Induced Protein Degradation and p53-Independent Apoptosis in Leukemia Cells.

MDM2 and MDM4 are cancer drug targets validated in multiple models for p53-based cancer therapies. The RING domains of MDM2 and non-p53-binder MDM2 splice isoforms form RING domain heterodimer polyubiquitin E3 ligases with MDM4, which regulate p53 stability in vivo and promote tumorigenesis independent of p53. Despite the importance of the MDM2 RING domain in p53 regulation and cancer development, small molecule inhibitors targeting the E3 ligase activity of MDM2-MDM4 are poorly explored.

Design of Organic-Inorganic Hybrid Heterostructured Semiconductors via High-Throughput Materials Screening for Optoelectronic Applications.

Organic-inorganic hybrid semiconductors, of which organometal halide perovskites are representative examples, have drawn significant research interest as promising candidates for next-generation optoelectronic applications. This interest is mainly ascribed to the emergent optoelectronic properties of the hybrid semiconductors that are distinct from those of their purely inorganic and organic counterparts as well as different material fabrication strategies and the other material (e.g.

Small molecule MMRi62 targets MDM4 for degradation and induces leukemic cell apoptosis regardless of p53 status.

MDM2 and MDM4 proteins are key negative regulators of tumor suppressor p53. MDM2 and MDM4 interact their RING domains and form a heterodimer polyubiquitin E3 ligase essential for p53 degradation. MDM4 also forms heterodimer E3 ligases with MDM2 isoforms that lack p53-binding domains, which regulate p53 and MDM4 stability.

Electronic property modulation in two-dimensional lateral superlattices of monolayer transition metal dichalcogenides.

Fabricating lateral heterostructures (HSs) and superlattices (SLs) provides a unique degree of freedom for modulating the physical properties of two-dimensional (2D) materials by varying the chemical component, geometric size and interface structure in the ultra-thin atomic thickness limit. While a variety of 2D lateral HSs/SLs have been synthesized, especially for transition metal dichalcogenides (TMDs), how such structures affect quantitatively the physical properties of 2D materials has not yet been established. We herein explore electronic property modulation in 2D lateral SLs of monolayer TMDs through first-principles high-throughput calculations.

Correction: MDM2 E3 ligase activity is essential for p53 regulation and cell cycle integrity.

[This corrects the article DOI: 10.1371/journal.pgen.

Inorganic Crystal Structure Prototype Database Based on Unsupervised Learning of Local Atomic Environments.

Recognition of structure prototypes from tremendous known inorganic crystal structures has been an important subject beneficial for materials science research and new materials design. The existing databases of inorganic crystal structure prototypes were mostly constructed by classifying materials in terms of the crystallographic space group information. Herein, we employed a distinct strategy to construct the inorganic crystal structure prototype database, relying on the classification of materials in terms of local atomic environments (LAEs) accompanied by unsupervised machine learning method.

Thermal Shock Fabrication of Ion-Stabilized Perovskite and Solar Cells.

A highly crystalline tempered-glass-like perovskite grain structure with compressed surface lattice realized by a thermal-shocking fabrication is shown. The strained perovskite grain structure is stabilized by Cl -reinforcing surface lattice and shows enhanced bonding energy and ionic activation temperature, which contributes to hysteresis-free operation of perovskite solar cells (PSCs) at much higher temperature up to 363 K in thermal-shocking-processed MAPbCl I (T-MPI). The PSCs can be fabricated by a high-speed fully air process without post-annealing based on the scalable bar-coating technique.

Entropy-Driven Stabilization of Multielement Halide Double-Perovskite Alloys.

Currently, a major obstacle restricting the commercial application of halide perovskites is their low thermodynamic stability. Herein, inspired by the high-stability high-entropy alloys, we theoretically investigated a variety of multielement double-perovskite alloys. First-principles calculations show that the entropy contribution to Gibbs free energy, which offsets the positive enthalpy contribution by up to 35 meV/f.

MDM2 E3 ligase activity is essential for p53 regulation and cell cycle integrity.

MDM2 and MDM4 are key regulators of p53 and function as oncogenes when aberrantly expressed. MDM2 and MDM4 partner to suppress p53 transcriptional transactivation and polyubiquitinate p53 for degradation. The importance of MDM2 E3-ligase-mediated p53 regulation remains controversial.

Effect of long-term intensive cholesterol control on the plaque progression in elderly based on CTA cohort study.

Objectives: To investigate the long-term effects of intensive LDL cholesterol-lowering treatments on lumen stenosis severity, plaque calcification, spotty calcifications, percent calcified plaque volume (PCPV), and Agatston coronary artery calcium score (CACS) based on coronary computed tomography angiography (CCTA) in elderly patients.

Methods: A total of 240 patients over 60 years old (comprising 754 lesions) who underwent serial CCTA were retrospectively enrolled in this 5-year cohort study. Patients were divided into three groups: an intensive lipid-lowering group, a lipid-lowering group, and a control group.

Small-Molecule MMRi62 Induces Ferroptosis and Inhibits Metastasis in Pancreatic Cancer via Degradation of Ferritin Heavy Chain and Mutant p53.

High frequency of KRAS and TP53 mutations is a unique genetic feature of pancreatic ductal adenocarcinoma (PDAC). TP53 mutation not only renders PDAC resistance to chemotherapies but also drives PDAC invasiveness. Therapies targeting activating mutant KRAS are not available and the outcomes of current PDAC treatment are extremely poor.