Corrigendum: Comprehensive transcriptomic analysis of critical RNA regulation associated with metabolism and prognosis in clear cell renal carcinoma.

[This corrects the article DOI: 10.3389/fcell.2021.709490.].

Supramolecular salicylic acid combined with niacinamide in chloasma: A randomized controlled trial.

BACKGROUND: No trial of supramolecular salicylic acid (SSA) for chloasma is available yet. OBJECTIVE: The purpose of this study was to assess the efficacy and safety of Bole DA 30% supramolecular salicylic acid (SSA) combined with 10% niacinamide in treating chloasma. METHODS: This multicenter (n=15), randomized, double-blind, parallel placebo-controlled trial randomized the subjects (1:1) to Bole DA 30% SSA or placebo. The primary endpoint was the effective rate after 16 weeks using the modified melasma area severity index (mMASI) [(pretreatment-posttreatment)/pretreatment×100%]. RESULTS: This study randomized 300 subjects (150/group in the full analysis set, 144 and 147 in the per-protocol set). The total mMASI score, overall Griffiths 10 score, left Griffiths 10 score, and right Griffiths 10 score were significantly lower in the Bole DA 30% SSA group than in the placebo group (all P<0.001). One study drug-related AE and one study drug-unrelated adverse events (AE) were reported in the Bole DA 30% SSA group. No AE was reported in the placebo group. CONCLUSION: Bole DA 30% SSA combined with 10% niacinamide is effective and safe for treating chloasma. CLINICAL TRIAL REGISTRATION NUMBER: ChiCTR2200065346.

Charting the cellular biogeography in colitis reveals fibroblast trajectories and coordinated spatial remodeling.

Gut inflammation involves contributions from immune and non-immune cells, whose interactions are shaped by the spatial organization of the healthy gut and its remodeling during inflammation. The crosstalk between fibroblasts and immune cells is an important axis in this process, but our understanding has been challenged by incomplete cell-type definition and biogeography. To address this challenge, we used multiplexed error-robust fluorescence in situ hybridization (MERFISH) to profile the expression of 940 genes in 1.35 million cells imaged across the onset and recovery from a mouse colitis model. We identified diverse cell populations, charted their spatial organization, and revealed their polarization or recruitment in inflammation. We found a staged progression of inflammation-associated tissue neighborhoods defined, in part, by multiple inflammation-associated fibroblasts, with unique expression profiles, spatial localization, cell-cell interactions, and healthy fibroblast origins. Similar signatures in ulcerative colitis suggest conserved human processes. Broadly, we provide a framework for understanding inflammation-induced remodeling in the gut and other tissues.

Facile fabrication of temperature/pH dual sensitive hydrogels based on cellulose and polysuccinimide through aqueous amino-succinimide reaction.

A temperature/pH dual sensitive hydrogel with a semi-interpenetrating network (semi-IPN) structure was synthesized through an aqueous amino-succinimide reaction between water-soluble polysuccinimide and polyethyleneimine in the presence of thermosensitive cellulose derivatives. Single-factor experiments were carried out to optimize the preparation conditions of the semi-IPN hydrogel. The swelling behavior and cytotoxicity assay of the hydrogel were tested. Finally, taking 5- fluorouracil (5-Fu) as a model drug, the release performance of the 5-Fu-loaded hydrogel was investigated. The results indicated that the swelling ratio (SR) first decreased and then increased when the pH of the solutions ascended from 2 to 10. The SR decreased with the increase in temperature. In addition, the swelling behavior of the hydrogel was reversible and reproducible under different pH values and temperatures. The prepared hydrogels had good cytocompatibility. The release behavior of 5-Fu was most consistent with the Korsmeyer-Peppas model and followed the case II diffusion. The acidic environment was beneficial for the release of 5-Fu. The preparation process of the semi-IPN hydrogel is simple and the reaction can proceed quickly in water. The strategy introduced here has great potential for application in the preparation of drug carriers.

Shear damage mechanisms of jointed rock mass: a macroscopic and mesoscopic study.

The joints are existing throughout the underground rock mass. It is of great significance to investigate the shear performance of the rock mass to maintain the stability of the underground structure. In this study, we conducted orthogonal tests to determine the proportion of rock-like materials, and used JRC curves to make specimen molds and then prepare the specimens. We conducted straight shear tests and uniaxial compression tests to determine the various mechanical parameters of the rock-like materials. Next, we carried out the compression and shear tests to investigate the shear characteristics of the specimens, and study the damage pattern and shear strength of the jointed rock mass under different confining pressures and roughness levels. The mesoscopic displacements in the shear process of joints were analyzed by using ABAQUS. The test results show that the effect of the confining pressure on the shear strength of the joint plane is relatively obvious, and a larger confining pressure indicates a larger shear strength. The effects of different joint plane roughness and shear rated on the shear characteristics of the joint plane are also significant. The mesoscopic displacement difference inside the joint plane with higher roughness is relatively large, and the stress concentration phenomenon is obvious and lasts longer, which leads to the faster destruction of the specimen with higher roughness and the higher destruction degree. Therefore, we suggest that the priority should be given to the reinforcement of jointed rock mass with high roughness during the construction to prevent sudden destabilization and failure.

Molecularly thin, two-dimensional all-organic perovskites.

Recently, the emergence of all-organic perovskites with three-dimensional (3D) structures has expanded the potential applications of perovskite materials. However, the synthesis and utilization of all-organic perovskites in 2D form remain largely unexplored because the design principle has not been developed. We present the successful synthesis of a metal-free 2D layered perovskite, denoted as the Choi-Loh van der Waals phase (CL-v phase), with the chemical formula A2B2X4, where A represents a larger-sized cation compared to B and X denotes an anion. The CL-v phase exhibits a van der Waals gap enabled by interlayer hydrogen bonding and can be exfoliated or grown as molecularly thin 2D organic crystals. The dielectric constants of the CL-v phase range from 4.8 to 5.5 and we demonstrate their potential as gate dielectrics for thin-film transistors.

Complement C1q-mediated microglial synaptic elimination by enhancing desialylation underlies sevoflurane-induced developmental neurotoxicity.

BACKGROUND: Repeated neonatal sevoflurane exposures led to neurocognitive disorders in young mice. We aimed to assess the role of microglia and complement C1q in sevoflurane-induced neurotoxicity and explore the underlying mechanisms. METHODS: Neonatal mice were treated with sevoflurane on postnatal days 6, 8, and 10, and the Morris water maze was performed to assess cognitive functions. For mechanistic explorations, mice were treated with minocycline, C1q-antibody ANX005, and sialidase-inhibitor N-acetyl-2,3-dehydro-2-deoxyneuraminic acid (NADNA) before sevoflurane exposures. Western blotting, RT-qPCR, Golgi staining, 3D reconstruction and engulfment analysis, immunofluorescence, and microglial morphology analysis were performed. In vitro experiments were conducted in microglial cell line BV2 cells. RESULTS: Repeated neonatal sevoflurane exposures resulted in deficiencies in learning and cognition of young mice, accompanied by microglial activation and synapse loss. Sevoflurane enhanced microglia-mediated synapse elimination through C1q binding to synapses. Inhibition of microglial activation and phagocytosis with minocycline significantly reduced the loss of synapses. We further revealed the involvement of neuronal sialic acids in this process. The enhanced activity of sialidase by sevoflurane led to the loss of sialic acids, which facilitated C1q binding to synapses. Inhibition of C1q with ANX005 or inhibition of sialidase with NADNA significantly rescued microglia-mediated synapse loss and improved neurocognitive function. Sevoflurane enhanced the engulfment of BV2 cells, which was reversed by ANX005. CONCLUSIONS: Our findings demonstrated that C1q-mediated microglial synaptic elimination by enhancing desialylation contributed to sevoflurane-induced developmental neurotoxicity. Inhibition of C1q or sialidase may be a potential therapeutic strategy for this neurotoxicity.

Biased virus transmission following sequential coinfection of Aedes aegypti with dengue and Zika viruses.

BACKGROUND: Mosquito-borne arboviruses are expanding their territory and elevating their infection prevalence due to the rapid climate change, urbanization, and increased international travel and global trade. Various significant arboviruses, including the dengue virus, Zika virus, Chikungunya virus, and yellow fever virus, are all reliant on the same primary vector, Aedes aegypti. Consequently, the occurrence of arbovirus coinfection in mosquitoes is anticipated. Arbovirus coinfection in mosquitoes has two patterns: simultaneous and sequential. Numerous studies have demonstrated that simultaneous coinfection of arboviruses in mosquitoes is unlikely to exert mutual developmental influence on these viruses. However, the viruses' interplay within a mosquito after the sequential coinfection seems intricated and not well understood. METHODOLOGY/PRINCIPAL FINDINGS: We conducted experiments aimed at examining the phenomenon of arbovirus sequential coinfection in both mosquito cell line (C6/36) and A. aegypti, specifically focusing on dengue virus (DENV, serotype 2) and Zika virus (ZIKV). We firstly observed that DENV and ZIKV can sequentially infect mosquito C6/36 cell line, but the replication level of the subsequently infected ZIKV was significantly suppressed. Similarly, A. aegypti mosquitoes can be sequentially coinfected by these two arboviruses, regardless of the order of virus exposure. However, the replication, dissemination, and the transmission potential of the secondary virus were significantly inhibited. We preliminarily explored the underlying mechanisms, revealing that arbovirus-infected mosquitoes exhibited activated innate immunity, disrupted lipid metabolism, and enhanced RNAi pathway, leading to reduced susceptibility to the secondary arbovirus infections. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that, in contrast to simultaneous arbovirus coinfection in mosquitoes that can promote the transmission and co-circulation of these viruses, sequential coinfection appears to have limited influence on arbovirus transmission dynamics. However, it is important to note that more experimental investigations are needed to refine and expand upon this conclusion.

Intercropping fruit trees in tea plantation improves soil properties and the formation of tea quality components.

Intercropping has been recommended as a beneficial cropping practice for improving soil characteristic and tea quality. However, there is limited research on the effects of intercropping fruit trees on soil chemical properties, soil aggregate structure, and tea quality components. In this study, intercropping fruit trees, specifically loquats and citrus, had a significant impact on the total available nutrients, AMN, and AP in soil. During spring and autumn seasons, the soil large-macroaggregates (>2 mm) proportion increased by 5.93% and 19.03%, as well as 29.23% and 19.14%, respectively, when intercropping loquats and citrus. Similarly, intercropping waxberry resulted in a highest small-macroaggregates (0.25 mm-2 mm) proportion at 54.89% and 77.32%. Soil aggregate stability parameters of the R0.25, MWD, and GMD were generally considered better soil aggregate stability indicators, and significantly improved in intercropping systems. Intercropping waxberry with higher values for those aggregate stability parameters and lower D values, showed a better soil aggregate distribution, while intercropping loquats and citrus at higher levels of AMN and AP in different soil aggregate sizes. As the soil aggregate sizes increased, the AMN and AP contents gradually decreased. Furthermore, the enhanced levels of amino acids were observed under loquat, waxberry, and citrus intercropping in spring, which increased by 27.98%, 27.35%, and 26.21%, respectively. The contents of tea polyphenol and caffeine were lower under loquat and citrus intercropping in spring. These findings indicated that intercropping fruit trees, specifically loquat and citrus, have immense potential in promoting the green and sustainable development of tea plantations.

Efficacy and safety of oral ibrexafungerp in Chinese patients with vulvovaginal candidiasis: a phase III, randomized, double-blind study.

PURPOSE: To evaluate the efficacy and safety of oral ibrexafungerp (HS-10366) versus placebo in Chinese patients with vulvovaginal candidiasis (VVC). METHODS: A double-blind, placebo-controlled, randomized, multicenter phase III study was conducted in symptomatic VVC patients. Patients received (2:1) twice-daily oral ibrexafungerp 300 mg or matching placebo for 1 day. The primary endpoint was clinical cure (vulvovaginal signs and symptoms [VSS] score = 0) at test-of-cure (TOC) on day 11 ± 3. The secondary endpoints included mycological eradication, overall response, and clinical improvement (VSS score ≤ 1) at TOC, and vulvovaginal symptom resolution at follow-up on day 25 ± 4. RESULTS: In total, 360 patients were included in the modified intention-to-treat set (defined as positive Candida cultured and receiving at least one study drug; 239 for ibrexafungerp, 121 for placebo). Compared with placebo, patients receiving ibrexafungerp had a significantly higher proportion of clinical cure (51.0% vs. 25.6%), mycological eradication (55.6% vs. 18.2%), overall response (33.9%, vs. 8.3%) at TOC and complete symptom resolution (74.5% vs. 39.7%, all P < 0.001) at follow-up. Subgroup analysis of clinical cure indicated that patients with C. albicans could benefit from ibrexafungerp over placebo. A similar benefit trend was also observed in those with non-albicans Candida by post-hoc analysis. Further analyses revealed similar efficacy of ibrexafungerp between patients with fluconazole non-susceptible C. albicans and fluconazole susceptible C. albicans regarding clinical cure and mycological eradication. Ibrexafungerp was generally well tolerated. Adverse events were primarily gastrointestinal and were mainly mild in severity. CONCLUSIONS: As a first-in-class antifungal agent, ibrexafungerp demonstrated promising efficacy and favorable safety for VVC treatment in Chinese patients. CHINADRUGTRIALS.ORG. CN REGISTRY NUMBER: CTR20220918.

Structure-guided functional suppression of AML-associated DNMT3A hotspot mutations.

DNA methyltransferases DNMT3A- and DNMT3B-mediated DNA methylation critically regulate epigenomic and transcriptomic patterning during development. The hotspot DNMT3A mutations at the site of Arg822 (R882) promote polymerization, leading to aberrant DNA methylation that may contribute to the pathogenesis of acute myeloid leukemia (AML). However, the molecular basis underlying the mutation-induced functional misregulation of DNMT3A remains unclear. Here, we report the crystal structures of the DNMT3A methyltransferase domain, revealing a molecular basis for its oligomerization behavior distinct to DNMT3B, and the enhanced intermolecular contacts caused by the R882H or R882C mutation. Our biochemical, cellular, and genomic DNA methylation analyses demonstrate that introducing the DNMT3B-converting mutations inhibits the R882H-/R882C-triggered DNMT3A polymerization and enhances substrate access, thereby eliminating the dominant-negative effect of the DNMT3A R882 mutations in cells. Together, this study provides mechanistic insights into DNMT3A R882 mutations-triggered aberrant oligomerization and DNA hypomethylation in AML, with important implications in cancer therapy.

Alignment error modeling and control of a double-sided microlens array during precision glass molding.

Double-sided microlens arrays (DSMLAs) include combinations of two single-sided MLAs to overcome positioning errors and greatly improve light transmissivity compared to other types of lenses. Precision glass molding (PGM) is used to fabricate DSMLAs, but controlling alignment errors during this process is challenging. In this paper, a mold assembly was manufactured with a novel combination of materials to improve the alignment accuracy of mold cores during PGM by using the nonlinear thermal expansion characteristics of the various materials to improve the DSMLA alignment accuracy. By establishing a mathematical model of the DSMLA alignment error and a thermal expansion model of the mold-sleeve pair, the relationship between the maximum alignment error of the DSMLA and the mold-sleeve gap was determined. This research provides a method to optimize the mold-sleeve gap and minimize the alignment error of the DSMLA. The measured DSMLA alignment error was 10.56 µm, which is similar to the predicted maximum alignment error. Optical measurements showed that the uniformity of the homogenized beam spot was 97.81%, and the effective homogeneous area accounted for 91.66% of the total area. This proposed method provides a novel strategy to improve the performance of DSMLAs.

Pontryagin's Minimum Principle-Guided RL for Minimum-Time Exploration of Spatiotemporal Fields.

This article studies the trajectory planning problem of an autonomous vehicle for exploring a spatiotemporal field subject to a constraint on cumulative information. Since the resulting problem depends on the signal strength distribution of the field, which is unknown in practice, we advocate the use of a model-free reinforcement learning (RL) method to find the solution. Given the vehicle's dynamical model, a critical (and open) question is how to judiciously merge the model-based optimality conditions into the model-free RL framework for improved efficiency and generalization, for which this work provides some positive results. Specifically, we discretize the continuous action space by leveraging analytic optimality conditions for the minimum-time optimization problem via Pontryagin's minimum principle (PMP). This allows us to develop a novel discrete PMP-based RL trajectory planning algorithm, which learns a planning policy faster than those based on a continuous action space. Simulation results: 1) validate the effectiveness of the PMP-based RL algorithm and 2) demonstrate its advantages, in terms of both learning efficiency and the vehicle's exploration time, over two baseline methods for continuous control inputs.

Recent advances in mesenchymal stem cell therapy for myocardial infarction.

Myocardial infarction refers to the ischemic necrosis of myocardium, characterized by a sharp reduction or interruption of blood flow in the coronary arteries due to the coronary artery occlusion, resulting in severe and prolonged ischemia in the corresponding myocardium and ultimately leading to ischemic necrosis of the myocardium. Given its high risk, it is considered as one of the most serious health threats today. In current clinical practice, multiple approaches have been explored to diminish myocardial oxygen consumption and alleviate symptoms, but notable success remains elusive. Accumulated clinical evidence has showed that the implantation of mesenchymal stem cell for treating myocardial infarction is both effective and safe. Nevertheless, there persists controversy and variability regarding the standardizing MSC transplantation protocols, optimizing dosage, and determining the most effective routes of administration. Addressing these remaining issues will pave the way of integration of MSCs as a feasible mainstream cardiac treatment.

Genetic parameter estimation and molecular foundation of chicken egg-laying trait.

The age of first egg (AFE) in chicken can affect early and even life-time egg production performance to some extent, and therefore is an important economic trait that affects production efficiency. To better understand the genetic patterns of AFE and other production traits including body weight at first egg (BWA), first egg weight (FEW), and total egg number from AFE to 58 wk of age (total-EN), we recorded the production performance of 2 widely used layer breeds, white leghorn (WL) and Rhode Island Red (RIR) and estimated genetic parameters based on pedigree and production data. The results showed that the heritability of AFE in both breeds ranged from 0.4 to 0.6, and AFE showed strong positive genetic and phenotypic correlations to BWA as well as FEW, while showing strong negative genetic and phenotypic correlations with total-EN. Furtherly, by genome-wide association analysis study (GWAS), we identified 12 and 26 significant SNPs to be related to AFE in the 2-layer breeds, respectively. A total of 18 genes were identified that could affect AFE based on the significant SNP annotations obtained, but there were no gene overlapped in the 2 breeds indicating the genetic foundation of AFE could differ from breed to breed. Our results provided a deeper understanding of genetic patterns and molecular basement of AFE in different breeds and could help in the selection of egg production traits.

An evolutionarily conserved ubiquitin ligase drives infection and transmission of flaviviruses.

Mosquito-borne flaviviruses such as dengue (DENV) and Zika (ZIKV) cause hundreds of millions of infections annually. The single-stranded RNA genome of flaviviruses is translated into a polyprotein, which is cleaved equally into individual functional proteins. While structural proteins are packaged into progeny virions and released, most of the nonstructural proteins remain intracellular and could become cytotoxic if accumulated over time. However, the mechanism by which nonstructural proteins are maintained at the levels optimal for cellular fitness and viral replication remains unknown. Here, we identified that the ubiquitin E3 ligase HRD1 is essential for flaviviruses infections in both mammalian hosts and mosquitoes. HRD1 directly interacts with flavivirus NS4A and ubiquitylates a conserved lysine residue for ER-associated degradation. This mechanism avoids excessive accumulation of NS4A, which otherwise interrupts the expression of processed flavivirus proteins in the ER. Furthermore, a small-molecule inhibitor of HRD1 named LS-102 effectively interrupts DENV2 infection in both mice and Aedes aegypti mosquitoes, and significantly disturbs DENV transmission from the infected hosts to mosquitoes owing to reduced viremia. Taken together, this study demonstrates that flaviviruses have evolved a sophisticated mechanism to exploit the ubiquitination system to balance the homeostasis of viral proteins for their own advantage and provides a potential therapeutic target to interrupt flavivirus infection and transmission.

In silico study on graphene quantum dots modified with various functional groups inhibiting α­synuclein dimerization.

HYPOTHESIS: Graphene quantum dots (GQDs) with various functional groups are hypothesized to inhibit the α-synuclein (αS) dimerization, a crucial step in Parkinson's disease pathogenesis. The potential of differently functionalized GQDs is systematically explored. EXPERIMENTS: All-atom replica-exchange molecular dynamics simulations (accumulating to 75.6 µs) in explicit water were performed to study the dimerization of the αS non-amyloid component region and the influence of GQDs modified with various functional groups. Conformation ensemble, binding behavior, and free energy analysis were conducted. FINDINGS: All studied GQDs inhibit ß-sheet and backbone hydrogen bond formation in αS dimers, leading to looser oligomeric conformations. Charged GQDs severely impede the growth of extended ß-sheets by providing extra contact surface. GQD binding primarily disrupts αS inter-peptide interactions through π-π stacking, CH-π interactions, and for charged GQDs, additionally through salt-bridge and hydrogen bonding interactions. GQD-COO- showed the most optimal inhibitory effect, binding mode, and intensity, which holds promise for the development of nanomedicines targeting amyloid aggregation in neurodegenerative diseases.