Conversion therapy with immunotherapy plus chemotherapy achieves a pathological complete response in stage IIIC NSCLC

As stage IIIC non-small cell lung cancer (NSCLC) is not recommended for surgical resection, the survival and prognosis for stage IIIC NSCLC remain poor. More powerful and individualized therapies are urgently needed to improve the prognosis of stage IIIC NSCLC. Recently, immunotherapeutics have been increasingly considered in the neoadjuvant therapy of NSCLC. This study presents a patient with stage IIIC NSCLC achieving a pathological complete response (pCR) following conversion therapy with immunotherapy plus chemotherapy. This case also presents a histologic transformation from squamous cell carcinoma to adenocarcinoma after prolonged progression-free survival (PFS) following surgery. Collectively, this case suggests that conversion immunotherapy with chemotherapy and subsequent surgery can be considered and benefits a subset of unresectable stage IIIC NSCLC

Effect of Water-Added Content on the Quality and Structural Characteristics of High-moisture Extruded SoybeanMeal-Based Meat Analogues

Soybean meal is a high quality plant protein resource. Exploring the possibility of using soybean meal instead of soybean protein isolate as raw material for high water extrusion plant protein meat processing is of great significance for production enterprises to control production cost and improve the economic value of soybean meal. In this study, the soybean meal was used as raw material to systemlly explore the effect of the water-added content (10.5, 11, 11.5, 12 kg/h) on the quality and structural characteristics of high-mositure extruded vegetable protein meat through determining the hardness, elasticity, chewiness, color and luster, water-holding capacity, oil-holding capacity, and chemical-crosslinking force and using Fourier infrared spectrum and scanning electron microscope. The results showed that the hardness, elasticity, and chewability of the vegetable protein meat were significantly decreased with the increasing water-added content during extrusion (P<0.05), while the brightness value, water-holding capacity, and oil-holding capacity showed a trend of increasing first and then decreasing. When the water-added content was 11.5 kg/h, the vegetable protein meat had better quality characteristics and appearance color, and the denser fibrous filaments were formed inside, and their layered structure became clear and neat, showing the fine directional structure. The results of Fourier infrared spectroscopy and chemical-crosslinking confirmed that the water-added content had a significant effect on the structure of vegetable protein meat, and the structure was maintained by the interaction of covalent bond and non-covalent bond

Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions

While germline copy-number variants (CNVs) contribute to schizophrenia (SCZ) risk, the contribution of somatic CNVs (sCNVs)—present in some but not all cells—remains unknown. We identified sCNVs using blood-derived genotype arrays from 12,834 SCZ cases and 11,648 controls, filtering sCNVs at loci recurrently mutated in clonal blood disorders. Likely early-developmental sCNVs were more common in cases (0.91%) than controls (0.51%, p = 2.68e−4), with recurrent somatic deletions of exons 1–5 of the NRXN1 gene in five SCZ cases. Hi-C maps revealed ectopic, allele-specific loops forming between a potential cryptic promoter and non-coding cis-regulatory elements upon 5′ deletions in NRXN1. We also observed recurrent intragenic deletions of ABCB11, encoding a transporter implicated in anti-psychotic response, in five treatment-resistant SCZ cases and showed that ABCB11 is specifically enriched in neurons forming mesocortical and mesolimbic dopaminergic projections. Our results indicate potential roles of sCNVs in SCZ risk

BRD4: New hope in the battle against glioblastoma

The BET family proteins, comprising BRD2, BRD3 and BRD4, represent epigenetic readers of acetylated histone marks that play pleiotropic roles in the tumorigenesis and growth of multiple human malignancies, including glioblastoma (GBM). A growing body of investigation has proven BET proteins as valuable therapeutic targets for cancer treatment. Recently, several BRD4 inhibitors and degraders have been reported to successfully suppress GBM in preclinical and clinical studies. However, the precise role and mechanism of BRD4 in the pathogenesis of GBM have not been fully elucidated or summarized. This review focuses on summarizing the roles and mechanisms of BRD4 in the context of the initiation and development of GBM. In addition, several BRD4 inhibitors have been evaluated for therapeutic purposes as monotherapy or in combination with chemotherapy, radiotherapy, and immune therapies. Here, we provide a critical appraisal of studies evaluating various BRD4 inhibitors and degraders as novel treatment strategies against GBM

The Relationship between Organizational Climate and Teaching Innovation among Preschool Teachers: The Mediating Effect of Teaching Efficacy

Preschool teachers’ teaching innovation is an important factor in enhancing teaching quality and improving children’s creativity. Based on ecological systems theory and self-determination theory, the purpose of this study was to investigate the relationship between kindergartens’ organizational climate and preschool teachers’ teaching innovation and the mediating role of teaching efficacy in it. In this study, an online questionnaire was distributed to 2092 preschool teachers from different provinces using an Organizational Climate Scale, Teaching Efficacy Scale, and Teaching Innovation Scale. The study used SPSS 25.0 software and the SPSS PROCESS macro program for data processing. The results showed that there was a positive correlation among kindergartens’ organizational climate, teaching efficacy, and teaching innovation, and that kindergartens’ organizational climate not only directly and positively predicted teaching innovation, but also indirectly predicted teaching innovation through the mediating role of teaching efficacy. The study explored the internal and external influences on preschool teachers’ teaching innovation and revealed their underlying mechanisms, providing theoretical support for research and educational practice on preschool teachers’ teaching innovation and children’s creativity

Local Scaffold Diversity-Contributed Generator for Discovering Potential NLRP3 Inhibitors

Deep generative models have become crucial tools in de novo drug design. In current models for multiobjective optimization in molecular generation, the scaffold diversity is limited when multiple constraints are introduced. To enhance scaffold diversity, we herein propose a local scaffold diversity-contributed generator (LSDC), which can be utilized to generate diverse lead compounds capable of satisfying multiple constraints. Compared to the state-of-the-art methods, molecules generated by LSDC exhibit greater diversity when applied to the generation of inhibitors targeting the NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3). We present 12 molecules, some of which feature previously unreported scaffolds, and demonstrate their reasonable docking binding modes. Consequently, the modification of selected scaffolds and subsequent bioactivity evaluation lead to the discovery of two potent NLRP3 inhibitors, A22 and A14, with IC50 values of 38.1 nM and 44.43 nM, respectively. And the oral bioavailability of compound A14 is very high (F is 83.09% in mice). This work contributes to the discovery of novel NLRP3 inhibitors and provides a reference for integrating AI-based generation with wet experiments

Local Scaffold Diversity-Contributed Generator for Discovering Potential NLRP3 Inhibitors

Deep generative models have become crucial tools in de novo drug design. In current models for multiobjective optimization in molecular generation, the scaffold diversity is limited when multiple constraints are introduced. To enhance scaffold diversity, we herein propose a local scaffold diversity-contributed generator (LSDC), which can be utilized to generate diverse lead compounds capable of satisfying multiple constraints. Compared to the state-of-the-art methods, molecules generated by LSDC exhibit greater diversity when applied to the generation of inhibitors targeting the NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3). We present 12 molecules, some of which feature previously unreported scaffolds, and demonstrate their reasonable docking binding modes. Consequently, the modification of selected scaffolds and subsequent bioactivity evaluation lead to the discovery of two potent NLRP3 inhibitors, A22 and A14, with IC50 values of 38.1 nM and 44.43 nM, respectively. And the oral bioavailability of compound A14 is very high (F is 83.09% in mice). This work contributes to the discovery of novel NLRP3 inhibitors and provides a reference for integrating AI-based generation with wet experiments

Local Scaffold Diversity-Contributed Generator for Discovering Potential NLRP3 Inhibitors

Deep generative models have become crucial tools in de novo drug design. In current models for multiobjective optimization in molecular generation, the scaffold diversity is limited when multiple constraints are introduced. To enhance scaffold diversity, we herein propose a local scaffold diversity-contributed generator (LSDC), which can be utilized to generate diverse lead compounds capable of satisfying multiple constraints. Compared to the state-of-the-art methods, molecules generated by LSDC exhibit greater diversity when applied to the generation of inhibitors targeting the NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3). We present 12 molecules, some of which feature previously unreported scaffolds, and demonstrate their reasonable docking binding modes. Consequently, the modification of selected scaffolds and subsequent bioactivity evaluation lead to the discovery of two potent NLRP3 inhibitors, A22 and A14, with IC50 values of 38.1 nM and 44.43 nM, respectively. And the oral bioavailability of compound A14 is very high (F is 83.09% in mice). This work contributes to the discovery of novel NLRP3 inhibitors and provides a reference for integrating AI-based generation with wet experiments

Local Scaffold Diversity-Contributed Generator for Discovering Potential NLRP3 Inhibitors

Deep generative models have become crucial tools in de novo drug design. In current models for multiobjective optimization in molecular generation, the scaffold diversity is limited when multiple constraints are introduced. To enhance scaffold diversity, we herein propose a local scaffold diversity-contributed generator (LSDC), which can be utilized to generate diverse lead compounds capable of satisfying multiple constraints. Compared to the state-of-the-art methods, molecules generated by LSDC exhibit greater diversity when applied to the generation of inhibitors targeting the NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3). We present 12 molecules, some of which feature previously unreported scaffolds, and demonstrate their reasonable docking binding modes. Consequently, the modification of selected scaffolds and subsequent bioactivity evaluation lead to the discovery of two potent NLRP3 inhibitors, A22 and A14, with IC50 values of 38.1 nM and 44.43 nM, respectively. And the oral bioavailability of compound A14 is very high (F is 83.09% in mice). This work contributes to the discovery of novel NLRP3 inhibitors and provides a reference for integrating AI-based generation with wet experiments