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Analogue series (AS) are generated during compound optimization in medicinal chemistry and are the major source of structure–activity relationship (SAR) information. Pairs of active AS consisting of compounds with corresponding substituents and comparable potency progression represent SAR transfer events for the same target or across different targets. We report a new computational approach to systematically search for SAR transfer series that combines an AS alignment algorithm with context-depending similarity assessment based on vector embeddings adapted from natural language processing. The methodology comprehensively accounts for substituent similarity, identifies non-classical bioisosteres, captures substituent-property relationships, and generates accurate AS alignments. Context-dependent similarity assessment is conceptually novel in computational medicinal chemistry and should also be of interest for other applications. Scientific contribution A method is reported to systematically search for and align analogue series with SAR transfer potential. Central to the approach is the assessment of context-dependent similarity for substituents, a new concept in cheminformatics, which is based upon vector embeddings and word pair relationships adapted from natural language processing. [ABSTRACT FROM AUTHOR]

Aim: Epithelial splicing regulatory protein 1 (ESRP1) regulates tumor progression and metastasis through the epithelial‒mesenchymal transition by interacting with zinc finger E‐box binding 1 (ZEB1) and CD44 in cancers. However, the role of ESRP1 in intrahepatic cholangiocarcinoma (iCCA) remains unclear. Methods: Three iCCA cell lines (HuCCT‐1, SSP‐25, and KKU‐100) were analyzed using small interfering RNA to investigate the molecular biological functions of ESRP1 and ZEB1. The association between clinicopathological features and the expression of ESRP1 and ZEB1 in iCCA tissues was analyzed immunohistochemically. Proteomic analysis was performed to identify molecules related to ESRP1 expression. Results: ESRP1 expression was upregulated in HuCCT‐1 and SSP‐25 cells. Cell migration and invasion were enhanced, and the expression of ZEB1 and CD44s (CD44 standard) isoforms were upregulated in the ESRP1 silencing cells. Moreover, ESRP1 silencing increased the expression of N‐cadherin and vimentin, indicating the presence of mesenchymal properties. Conversely, ZEB1 silencing increased the expression of ESRP1 and CD44v (CD44 variant) isoforms. Immunohistochemical analysis revealed that a lower ESRP1‐to‐ZEB1 expression ratio was associated with poor recurrence‐free survival in patients with iCCA. Flotillin 2, a lipid raft marker related to epithelial‒mesenchymal transition, was identified as a protein related to the interactive feedback loop in proteomic analysis. Conclusions: ESRP1 suppresses tumor progression in iCCA by interacting with ZEB1 and CD44 to regulate epithelial‒mesenchymal transition. [ABSTRACT FROM AUTHOR]

Carbon fiber reinforced plastic (CFRP) possesses numerous advantages, such as a light weight and high strength; however, its complex damage mechanisms make the evaluation of fatigue damage particularly challenging. Therefore, this study proposed and demonstrated an entropy-based damage evaluation model for CFRP that leverages the entropy derived from heat capacity measurements and does not require knowledge of the loading history. This entropy-based fatigue degradation model, though accurate, is computationally intensive and impractical for high-cycle analysis. To address this, we reduce computational cost through multi-timescale analysis, replacing cyclic loading with constant displacement loading. Characteristic variables are optimized using the machine learning model LightGBM and the response surface method (RSM), with LightGBM achieving a 75% lower root mean squared error than RSM by increasing features from 3 to 21. This approach cuts analysis time by over 90% while retaining predictive accuracy, showing that LightGBM outperforms RSM and that multi-timescale analysis effectively reduces computational demands. [ABSTRACT FROM AUTHOR]

Membrane targeting of the BECN1-containing class III PI 3-kinase (PI3KC3) complexes is pivotal to the regulation of autophagy. The interaction of PI3KC3 complex II and its ubiquitously expressed inhibitor, Rubicon, was mapped to the first β sheet of the BECN1 BARA domain and the UVRAG BARA2 domain by hydrogen-deuterium exchange and cryo-EM. These data suggest that the BARA β sheet 1 unfolds to directly engage the membrane. This mechanism was confirmed using protein engineering, giant unilamellar vesicle assays, and molecular simulations. Using this mechanism, a BECN1 β sheet-1 derived peptide activates both PI3KC3 complexes I and II, while HIV-1 Nef inhibits complex II. These data reveal how BECN1 switches on and off PI3KC3 binding to membranes. The observations explain how PI3KC3 inhibition by Rubicon, activation by autophagy-inducing BECN1 peptides, and inhibition by HIV-1 Nef are mediated by the switchable ability of the BECN1 BARA domain to partially unfold and insert into membranes.

Over the past two decades, the molecular machinery that underlies autophagic responses has been characterized with ever increasing precision in multiple model organisms. Moreover, it has become clear that autophagy and autophagy-related processes have profound implications for human pathophysiology. However, considerable confusion persists about the use of appropriate terms to indicate specific types of autophagy and some components of the autophagy machinery, which may have detrimental effects on the expansion of the field. Driven by the overt recognition of such a potential obstacle, a panel of leading experts in the field attempts here to define several autophagy-related terms based on specific biochemical features. The ultimate objective of this collaborative exchange is to formulate recommendations that facilitate the dissemination of knowledge within and outside the field of autophagy research.

We report the information support activities conducted by the Information Support Team (ISUT) in the heavy rain since July 1, 2021, after it was dispatched to Shizuoka Prefecture. During the activities, ISUT-SITE and other information were provided and utilized by the disaster response organizations. This study reports on the characteristics and future issues in this disaster response activity. [ABSTRACT FROM AUTHOR]

Horizontal and vertical moisture advection in the lower troposphere of the Arctic under progressing global warming is examined using a large‐scale ensemble model data set. Advection is decomposed into terms related to the basic state of the atmosphere and transient eddies and compared against a non‐warming experiment. During summer, horizontal moisture advection increases mainly by transient eddies advecting moisture from the lower latitudes. During winter, enhanced evaporation due to reduced sea ice becomes a source of moisture diminishing the role of transient eddies moistening the atmosphere. This effect intensifies under extreme global warming, turning the change in total horizontal advection in the lower troposphere negative. Diminished horizontal advection during winter is counteracted by vertical advection accompanied with enhanced evaporation and upper‐level horizontal advection maintaining the increase in column moisture. These results improve our understanding of how the water cycle in the Arctic responds via atmospheric processes under global warming. Plain Language Summary: This study uses a data set with a large number of members to investigate how the atmosphere is moistened in the Arctic (north of 70˚N) under various stages of global warming. The movement of moisture is summarized in terms of horizontal and vertical components of advection, a measure of how the atmosphere is moistened in a given specific humidity gradient and wind, which is decomposed into parts related to the average state of the atmosphere and parts related to high‐frequency phenomena, such as cyclones. It is found that (a) during summer, moisturization of the Arctic is mainly driven by horizontal movement of moisture from a remote source in the lower latitude, (b) during winter, this moisturization due to horizontal movement of moisture is suppressed and is driven more by vertical movement of moisture due to reduction of sea ice and increased evaporation. As global warming progresses, the role or horizontal movement of moisture is taken over by the local process of evaporation and vertical movement of moisture. This research helps us understand how the water cycle in the Arctic changes with severe global warming and improves our knowledge of the atmospheric processes that govern the climate system through various feedbacks. Key Points: Moisture advection in the Arctic under progressing global warming is examined using a large‐scale ensemble model simulation data setMoistening effect of horizontal advection in the lower troposphere is enhanced for summer and diminished for winter under extreme warmingEnhanced horizontal advection in the upper layer and surface evaporation are consistent with increased column moisture during winter [ABSTRACT FROM AUTHOR]