Stepwise Progression of Dye-Induced In Situ Photoalignment and Subsequent Stabilization for Noncontact Alignment of Liquid Crystals.

Noncontact alignment of liquid crystals (LCs) is crucial for large-area and ultrahigh definition (UHD) display manufacturing. This research presents an innovative approach to the photoalignment of LCs, aiming to overcome challenges associated with uniformity and assembly in large-sized and UHD displays. Using homogeneously dissolved, nonionic azobenzene chromophores sensitive to both visible and UV light, we demonstrate an in situ stepwise progression of dye-induced LC alignment and subsequent stabilization using reactive mesogen (RM). Both dual-wavelength and single-wavelength approaches enable stepwise interfacial modifications for LC alignment and stabilization. The dye-induced LC alignment is rewritable, allowing for the creation of various patterns and gray-level alignments. The stability of the alignment is ensured through cross-linked RM layers, providing a robust and permanent solution for LC alignment without the need for delicate mechanical treatments. Importantly, this method addresses the challenges associated with conventional photoalignments, including various dye-induced approaches and high-energy photoalignment. The proposed method exhibits high-quality electro-optical switching, azimuthal anchoring strength, and stability against thermal, radiation, and ac-field stresses, making it a promising candidate for commercial mass production, especially in the fabrication of large-sized and UHD LC displays.

A remarkable genetic shift in a transmitted/founder virus broadens antibody responses against HIV-1.

A productive HIV-1 infection in humans is often established by transmission and propagation of a single transmitted/founder (T/F) virus, which then evolves into a complex mixture of variants during the lifetime of infection. An effective HIV-1 vaccine should elicit broad immune responses in order to block the entry of diverse T/F viruses. Currently, no such vaccine exists. An in-depth study of escape variants emerging under host immune pressure during very early stages of infection might provide insights into such a HIV-1 vaccine design. Here, in a rare longitudinal study involving HIV-1 infected individuals just days after infection in the absence of antiretroviral therapy, we discovered a remarkable genetic shift that resulted in near complete disappearance of the original T/F virus and appearance of a variant with H173Y mutation in the variable V2 domain of the HIV-1 envelope protein. This coincided with the disappearance of the first wave of strictly H173-specific antibodies and emergence of a second wave of Y173-specific antibodies with increased breadth. Structural analyses indicated conformational dynamism of the envelope protein which likely allowed selection of escape variants with a conformational switch in the V2 domain from an α-helix (H173) to a ß-strand (Y173) and induction of broadly reactive antibody responses. This differential breadth due to a single mutational change was also recapitulated in a mouse model. Rationally designed combinatorial libraries containing 54 conformational variants of V2 domain around position 173 further demonstrated increased breadth of antibody responses elicited to diverse HIV-1 envelope proteins. These results offer new insights into designing broadly effective HIV-1 vaccines.

PL-PatchSurfer3: Improved Structure-Based Virtual Screening for Structure Variation Using 3D Zernike Descriptors.

Structure-based virtual screening (SBVS) is a widely used method in silico drug discovery. It necessitates a receptor structure or binding site to predict the binding pose and fitness of a ligand. Therefore, the performance of the SBVS is affected by the protein conformation. The most frequently used method in SBVS is the protein-ligand docking program, which utilizes atomic distance-based scoring functions. Hence, they are highly prone to sensitivity towards variation in receptor structure, and it is reported that the conformational change significantly drops the performance of the docking program. To address the problem, we have introduced a novel program of SBVS, named PL-PatchSurfer. This program makes use of molecular surface patches and the Zernike descriptor. The surfaces of the pocket and ligand are segmented into several patches by the program. These patches are then mapped with physico-chemical properties such as shape and electrostatic potential before being converted into the Zernike descriptor, which is rotationally invariant. A complementarity between the protein and the ligand is assessed by comparing the descriptors and geometric distribution of the patches in the molecules. A benchmarking study showed that PL-PatchSurfer2 was able to screen active molecules regardless of the receptor structure change with fast speed. However, the program could not achieve high performance for the targets that the hydrogen bonding feature is important such as nuclear hormone receptors. In this paper, we present the newer version of PL-PatchSurfer, PL-PatchSurfer3, which incorporates two new features: a change in the definition of hydrogen bond complementarity and consideration of visibility that contains curvature information of a patch. Our evaluation demonstrates that the new program outperforms its predecessor and other SBVS methods while retaining its characteristic tolerance to receptor structure changes. Interested individuals can access the program at kiharalab.org/plps3.

Discovery of thiophen-2-ylmethylene bis-dimedone derivatives as novel WRN inhibitors for treating cancers with microsatellite instability.

Microsatellite instability (MSI) is a hypermutable condition caused by DNA mismatch repair system defects, contributing to the development of various cancer types. Recent research has identified Werner syndrome ATP-dependent helicase (WRN) as a promising synthetic lethal target for MSI cancers. Herein, we report the first discovery of thiophen-2-ylmethylene bis-dimedone derivatives as novel WRN inhibitors for MSI cancer therapy. Initial computational analysis and biological evaluation identified a new scaffold for a WRN inhibitor. Subsequent SAR study led to the discovery of a highly potent WRN inhibitor. Furthermore, we demonstrated that the optimal compound induced DNA damage and apoptotic cell death in MSI cancer cells by inhibiting WRN. This study provides a new pharmacophore for WRN inhibitors, emphasizing their therapeutic potential for MSI cancers.

The soil plastisphere.

Understanding the effects of plastic pollution in terrestrial ecosystems is a priority in environmental research. A central aspect of this suite of pollutants is that it entails particles, in addition to chemical compounds, and this makes plastic quite different from the vast majority of chemical environmental pollutants. Particles can be habitats for microbial communities, and plastics can be a source of chemical compounds that are released into the surrounding environment. In the aquatic literature, the term 'plastisphere' has been coined to refer to the microbial community colonizing plastic debris; here, we use a definition that also includes the immediate soil environment of these particles to align the definition with other concepts in soil microbiology. First, we highlight major differences in the plastisphere between aquatic and soil ecosystems, then we review what is currently known about the soil plastisphere, including the members of the microbial community that are enriched, and the possible mechanisms underpinning this selection. Then, we focus on outlining future prospects for research on the soil plastisphere.

Toxicity of Aged Paint Particles to Soil Ecosystems: Insights from Caenorhabditis elegans.

Despite the extensive global consumption of architectural paint, the toxicological effects of aged exterior paint particles on terrestrial biota remain largely uncharacterized. Herein, we assessed the toxic effect of aged paint particles on soil environments using the nematode Caenorhabditis elegans (C. elegans) as a test organism. Various types of paint particles were generated by fragmentation and sequential sieving (500-1000, 250-500, 100-250, 50-100, 20-50 µm) of paint coatings collected from two old residential areas. The paint particles exerted different levels of toxicity, as indicated by a reduction in the number of C. elegans offspring, depending on their size, color, and layer structure. These physical characteristics were found to be closely associated with the chemical heterogeneity of additives present in the paint particles. Since the paint particle sizes were larger than what C. elegans typically consume, we attributed the toxicity to leachable additives present in the paint particles. To assess the toxicity of these leachable additives, we performed sequential washings of the paint particles with distilled water and ethanol. Ethanol washing of the paint particles significantly reduced the soil toxicity of the hydrophobic additives, indicating their potential environmental risk. Liquid chromatography-mass spectrometry analysis of the ethanol leachate revealed the presence of alkyl amines, which exhibited a high correlation with the toxicity of the paint particles. Further toxicity testing using an alkyl amine standard demonstrated that a paint particle concentration of 1.2% in soil could significantly reduce the number of C. elegans offspring. Our findings provide insights into the potential hazards posed by aged paint particles and their leachable additives in the terrestrial environment.

Refractive Index-Adaptive Nanoporous Chiral Photonic Crystal Film for Chemical Detection Visualized via Selective Reflection.

Photonic crystals (PC) are of great importance in technology, especially in optics and photonics. In general, the structural color of PCs responds to external stimuli primarily by changing their periodicity. Herein, the authors report on refractive index (RI) adaptive PCs. Cross-linked cholesteric films with interconnected nanopores exhibit a very low RI without light scattering. Transparent PC films with maximum reflectance in the ultravoilet (UV) region respond to various chemicals by changing the reflective color of the PC. The authors demonstrate its unique colorimetric chemical detections of hazardous organic liquids. Loading various chemicals into nanopores significantly shifts the structural color into the visible range depending on the chemical's RI. These results are unique in that the structural color of photonic films is mediated by RI changes rather than periodicity changes. In principle, nanoporous photonic crystal films can detect the RI of a chemical substance by its unique color. In contrast to volumetric changes, this sensing mechanism offers several advantages, including durability, excellent sensitivity, fast response time, and wide detection range. These results provide useful insight into stimulus-responsive PCs. The structural color of PC films can be effectively tuned by adjusting average RIs instead of changing periodicity.

Quantitative comparison of protein-protein interaction interface using physicochemical feature-based descriptors of surface patches.

Driving mechanisms of many biological functions in a cell include physical interactions of proteins. As protein-protein interactions (PPIs) are also important in disease development, protein-protein interactions are highlighted in the pharmaceutical industry as possible therapeutic targets in recent years. To understand the variety of protein-protein interactions in a proteome, it is essential to establish a method that can identify similarity and dissimilarity between protein-protein interactions for inferring the binding of similar molecules, including drugs and other proteins. In this study, we developed a novel method, protein-protein interaction-Surfer, which compares and quantifies similarity of local surface regions of protein-protein interactions. protein-protein interaction-Surfer represents a protein-protein interaction surface with overlapping surface patches, each of which is described with a three-dimensional Zernike descriptor (3DZD), a compact mathematical representation of 3D function. 3DZD captures both the 3D shape and physicochemical properties of the protein surface. The performance of protein-protein interaction-Surfer was benchmarked on datasets of protein-protein interactions, where we were able to show that protein-protein interaction-Surfer finds similar potential drug binding regions that do not share sequence and structure similarity. protein-protein interaction-Surfer is available at https://kiharalab.org/ppi-surfer.

Soil Storage Conditions Alter the Effects of Tire Wear Particles on Microbial Activities in Laboratory Tests.

In this study, we focused on the fact that soil storage conditions in the laboratory have never been considered as a key factor potentially leading to high variation when measuring effects of microplastics on soil microbial activity. We stored field-collected soils under four different conditions [room-temperature storage, low-temperature storage (LS), air drying (AD), and heat drying] prior to the experiment. Each soil was treated with tire wear particles (TWPs), and soil microbial activities and water aggregate stability were investigated after soil incubation. As a result, microbial activities, including soil respiration and three enzyme activities (ß-glucosidase, N-acetyl-ß-glucosaminidase, and phosphatase), were shown to depend on soil storage conditions. Soil respiration rates increased with the addition of TWPs, and the differences from the control group (no TWPs added) were more pronounced in the AD TWP treatment than in soils stored under other conditions. In contrast, phosphatase activity followed an opposing trend after the addition of TWPs. The AD soil had higher phosphatase activity after the addition of TWPs, while the LS soil had a lower level than the control group. We suggest that microplastic effects in laboratory experiments can strongly depend on soil storage conditions.

Smoothing of inter-layer edge artifacts in depth-map computer-generated holograms.

In the depth-map computer-generated hologram (CGH), inter-layer edge artifacts are observed in the discontinuous edges of section-wise depth-map objects. CGH synthesis, utilizing the hybrid smoothing method of silhouette masking and edge-apodization, alleviates unwanted inter-layer edge artifacts. The proposed method achieves improved de-artifact filtering that generates holographic images closer to the ground truth image of the depth-map object unattainable by the conventional CGH synthesis method.

S-Pred: protein structural property prediction using MSA transformer.

Predicting the local structural features of a protein from its amino acid sequence helps its function prediction to be revealed and assists in three-dimensional structural modeling. As the sequence-structure gap increases, prediction methods have been developed to bridge this gap. Additionally, as the size of the structural database and computing power increase, the performance of these methods have also significantly improved. Herein, we present a powerful new tool called S-Pred, which can predict eight-state secondary structures (SS8), accessible surface areas (ASAs), and intrinsically disordered regions (IDRs) from a given sequence. For feature prediction, S-Pred uses multiple sequence alignment (MSA) of a query sequence as an input. The MSA input is converted to features by the MSA Transformer, which is a protein language model that uses an attention mechanism. A long short-term memory (LSTM) was employed to produce the final prediction. The performance of S-Pred was evaluated on several test sets, and the program consistently provided accurate predictions. The accuracy of the SS8 prediction was approximately 76%, and the Pearson's correlation between the experimental and predicted ASAs was 0.84. Additionally, an IDR could be accurately predicted with an F1-score of 0.514. The program is freely available at https://github.com/arontier/S_Pred_Paper and https://ad3.io as a code and a web server.

Synthesis of 4-substituted benzyl-2-triazole-linked-tryptamine-paeonol derivatives and evaluation of their selective inhibitions against butyrylcholinesterase and monoamine oxidase-B.

Cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors are being used and developed to treat Alzheimer's disease (AD), a major type of dementia patients. Fifteen 4-substituted benzyl-2-triazole-linked-tryptamine-paeonol derivatives were synthesized and evaluated for their inhibitory activities against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), monoamine oxidase-A (MAO-A), and B (MAO-B). Compound 896 was the most potent BChE inhibitor (IC50 = 0.13 µM) with the selectivity index (SI) value of >769.23 for BChE over AChE. Compound 897 was the most potent selective MAO-B inhibitor (IC50 = 0.73 µM; SI = 20.45 for MAO-B over MAO-A). The meta-CF3 substituent of 896 increased BChE inhibitory activity and the para-CF3 substituent of 897 increased MAO-B inhibitory activity. Compound 896 was a reversible noncompetitive BChE inhibitor (Ki = 0.171 µM) and 897 was a reversible competitive MAO-B inhibitor (Ki = 0.237 µM). Compound 896 had a lower binding energy (-13.75 kcal/mol) to BChE than 897 (-11.29 kcal/mol), and 897 had a lower binding energy to MAO-B (-11.31 kcal/mol) than that to MAO-A (-6.72 kcal/mol). Little cytotoxicity was observed for 896 and 897 to normal cells (MDCK) and human neuroblastoma cells (SH-SY5Y). This study suggested that 896 and 897 are therapeutic candidates for various neurodegenerative disorders such as AD.

Relationship between Social Distancing and Admissions for Cerebrovascular Accidents at a Tertiary Medical Center during the COVID-19 Pandemic: A Retrospective, Community-Based Study.

We evaluated the trend of admission of patients with acute cerebrovascular accidents (CVAs) during social distancing measures implemented during the coronavirus disease 2019 (COVID-19) era. The data of patients admitted with transient ischemic attack, ischemic stroke, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH) to the emergency department of the Hanyang University Seoul Hospital were retrospectively analyzed. The data were compared between the pre-COVID-19 and COVID-19 periods. Poisson regression analysis was performed to evaluate changes in admission rates as a function of the year, social distancing level, and the interaction between the year and social distancing level. The number of admissions for CVAs dropped from 674 in the pre-COVID-19 period to 582 in the COVID-19 period. The decline in the number of admissions for ICH during social distancing measures was statistically significant, while the declines in SAH and ischemic stroke admissions were not. When the social distancing level was raised, admissions for CVAs dropped by 19.8%. The correlation between social distancing and decreased admissions for CVAs is a paradoxical relationship that may be of interest to the field of public health.

Electrically Switchable Anisometric Carbon Quantum Dots Exhibiting Linearly Polarized Photoluminescence: Syntheses, Anisotropic Properties, and Facile Control of Uniaxial Orientation.

Carbon quantum dots (CQDs) have been extensively explored in diverse fields because of their exceptional features. The nanometric particles with photoluminescence (PL) benefit various optical and photonic applications. However, the majority of previous reports have mainly focused on either unpolarized or circular-polarized (CP) PL. Linearly polarized (LP) emission of CQDs is limited mainly because of their isometric shape and difficulties in macroscopic orientation control. Herein, we report syntheses of anisometric CQDs and facile control of the uniaxial orientation on a macroscopic scale, which results in linearly polarized photoluminescence (LP-PL). The anisometric CQDs are synthesized from rigid-rod-shaped precursors and evenly dispersed in the rod-like liquid crystal (LC) host. As-synthesized CQDs exhibit a PL quantum yield as high as 35% in chloroform. In addition to uniform alignment, facile directional switching of the elongated CQD is established by employing the electrical responsiveness of the CQD and host LC. Therefore, the dichroic photophysical properties of anisometric CQDs have been beneficially adopted for fabrications of polarization-sensitive and electrically switchable PL devices. Also, anisometric CQDs are embedded in polymer films with molecular orientational patterns and clearly recognized by LP-PL.

Species sensitivity distributions for ethylparaben to derive protective concentrations for soil ecosystems.

Ethylparaben is used as an antifungal preservative. Although some countries have implemented regulations for human exposure to parabens, environmental regulations for ethylparaben have not been established. This study provides new toxicological data for ethylparaben, for which data regarding soil organisms were previously lacking. Although ethylparaben toxicity has been reported in other species, we present herein the first comprehensive study of its toxicity in soil organisms. We used 12 test species (Lycopersicon esculentum, Vigna radiata, Hordeum vulgare, Oryza sativa, Eisenia andrei, Folsomia candida, Lobella sokamensis, Caenorhabiditis elegans, Chlamydomonas reinhardtii, Chlorococcum infusionum, Chlorella sorokiniana, Chlorella vulgaris) from eight taxonomic groups for acute bioassays and nine test species (L. esculentum, V. radiata, H. vulgare, O. sativa, C. reinhardtii, C. infusionum, C. sorokiniana, and C. vulgaris) from five taxonomic groups for chronic bioassays. A suite of acute and chronic toxicity tests, using 21 soil species, was conducted to estimate EC50 values, which facilitated the construction of species sensitivity distributions (SSDs) and the calculation of protective concentrations (PCs). Acute and chronic PC95 values (protective concentration for 95% of species) for ethylparaben were estimated to be 14 and 5 mg/kg dry soil, respectively. To the best of our knowledge, this is the first study to evaluate the toxicity of ethylparaben to soil species and derive PCs for soil ecosystems based on SSDs. Therefore, the data presented in this study can be used as a basis for further investigations of paraben toxicity to the soil environment.

Surface-based protein domains retrieval methods from a SHREC2021 challenge.

Proteins are essential to nearly all cellular mechanism and the effectors of the cells activities. As such, they often interact through their surface with other proteins or other cellular ligands such as ions or organic molecules. The evolution generates plenty of different proteins, with unique abilities, but also proteins with related functions hence similar 3D surface properties (shape, physico-chemical properties, …). The protein surfaces are therefore of primary importance for their activity. In the present work, we assess the ability of different methods to detect such similarities based on the geometry of the protein surfaces (described as 3D meshes), using either their shape only, or their shape and the electrostatic potential (a biologically relevant property of proteins surface). Five different groups participated in this contest using the shape-only dataset, and one group extended its pre-existing method to handle the electrostatic potential. Our comparative study reveals both the ability of the methods to detect related proteins and their difficulties to distinguish between highly related proteins. Our study allows also to analyze the putative influence of electrostatic information in addition to the one of protein shapes alone. Finally, the discussion permits to expose the results with respect to ones obtained in the previous contests for the extended method. The source codes of each presented method have been made available online.

Discovery of a Potent Candidate for RET-Specific Non-Small-Cell Lung Cancer-A Combined In Silico and In Vitro Strategy.

Rearranged during transfection (RET) is a tyrosine kinase oncogenic receptor, activated in several cancers including non-small-cell lung cancer (NSCLC). Multiple kinase inhibitors vandetanib and cabozantinib are commonly used in the treatment of RET-positive NSCLC. However, specificity, toxicity, and reduced efficacy limit the usage of multiple kinase inhibitors in targeting RET protein. Thus, in the present investigation, we aimed to figure out novel and potent candidates for the inhibition of RET protein using combined in silico and in vitro strategies. In the present study, screening of 11,808 compounds from the DrugBank repository was accomplished by different hypotheses such as pharmacophore, e-pharmacophore, and receptor cavity-based models in the initial stage. The results from the different hypotheses were then integrated to eliminate the false positive prediction. The inhibitory activities of the screened compounds were tested by the glide docking algorithm. Moreover, RF score, Tanimoto coefficient, prime-MM/GBSA, and density functional theory calculations were utilized to re-score the binding free energy of the docked complexes with high precision. This procedure resulted in three lead molecules, namely DB07194, DB03496, and DB11982, against the RET protein. The screened lead molecules together with reference compounds were then subjected to a long molecular dynamics simulation with a 200 ns time duration to validate the inhibitory activity. Further analysis of compounds using MM-PBSA and mutation studies resulted in the identification of potent compound DB07194. In essence, a cell viability assay with RET-specific lung cancer cell line LC-2/ad was also carried out to confirm the in vitro biological activity of the resultant compound, DB07194. Indeed, the results from our study conclude that DB07194 can be effectively translated for this new therapeutic purpose, in contrast to the properties for which it was originally designed and synthesized.

Exploring safe and potent bioactives for the treatment of non-small cell lung cancer.

Activating and suppressing mutations in the MAPK pathway receptors are the primary causes of NSCLC. Of note, MEK inhibition is considered a promising strategy because of the diverse structures and harmful effects of upstream receptors in MAPK pathway. Thus, we explore a total of 1574 plant-based bioactive compounds activity against MEK using an energy-based virtual screening strategy. Molecular docking, binding free energy, and drug-likeness analysis were performed through GLIDE, Prime MM-GBSA, and QikProp module, respectively. The findings indicate that 5-O-caffeoylshikimic acid has an increased binding affinity to MEK protein. Further, molecular dynamic simulations and MM-PBSA analysis were performed to explore the ligand activity in real-life situations. In essence, compounds inhibitory activity was validated across 77 lung cancer cell lines using multimodal attention-based neural network algorithm. Eventually, our analysis highlight that 5-O-caffeoylshikimic acid obtained from the bark of Rhizoma smilacis glabrae would be developed as a potential compound for treating NSCLC.

Microplastics disrupt accurate soil organic carbon measurement based on chemical oxidation method.

Microplastics are widespread contaminants in soils and terrestrial ecosystems in many areas worldwide. In this study, we measured soil organic carbon (SOC) and soil organic matter (SOM) in microplastic-treated soils to determine if the presence of microplastics could affect the accuracy of carbon-based soil quality indicator measurements. Six different sizes and types of microplastics were selected, and six soil samples were used to evaluate the impacts. Treating soil with polyethylene and low-density polyethylene significantly increased SOC (p < 0.05) when measured with the modified Walkley & Black method; microplastic addition (0.01%, v/v) increased SOC by >40% compared to control organic carbon-poor soil (<10.0 g kg-1). We conclude that the microplastics can disrupt the accurate measurement of SOC. Likely, the physicochemical treatment used in the SOC measurement process can cause the organic compounds and/or carbon complexes to be extracted from microplastics, and this can affect the results. Considering that SOC is a main indicator for assessing soil quality and the global carbon cycle, overestimations caused by microplastic contamination should be further discussed to identify appropriate ways to deal with microplastics as a new carbon source in the environment.