YTHDF2-Mediated m6A methylation inhibition by miR27a as a protective mechanism against hormonal osteonecrosis in BMSCs.

BACKGROUND: With the increasing incidence of steroid-induced necrosis of the femoral head (SNFH), numerous scholars have investigated its pathogenesis. Current evidence suggests that the imbalance between lipogenesis and osteoblast differentiation in bone marrow mesenchymal stem cells (BMSCs) is a key pathological feature of SNFH. MicroRNAs (miRNAs) have strong gene regulatory effects and can influence the direction of cell differentiation. N6-methyladenosine (m6A) is a prevalent epigenetic modification involved in diverse pathophysiological processes. However, knowledge of how miRNAs regulate m6A-related factors that affect BMSC differentiation is limited. OBJECTIVE: We aimed to investigate the role of miR27a in regulating the expression of YTHDF2 in BMSCs. METHODS: We compared miR27a, YTHDF2, and total m6A mRNA levels in SNFH-affected and control BMSCs. CCK-8 and TUNEL assays were used to assess BMSC proliferation and apoptosis. Western blotting and qRT‒PCR were used to measure the expression of osteogenic (ALP, RUNX2, and OCN) and lipogenic (PPARγ and C/EBPα) markers. Alizarin Red and Oil Red O staining were used to quantify osteogenic and lipogenic differentiation, respectively. miR27a was knocked down or overexpressed to evaluate its impact on BMSC differentiation and its relationship with YTHDF2. Bioinformatics analyses identified YTHDF2 as a differentially expressed gene in SNFH (ROC analysis) and revealed potential signaling pathways through GSEA. The effects of YTHDF2 silencing on the lipogenic and osteogenic functions of BMSCs were assessed. RESULTS: miR27a downregulation and YTHDF2 upregulation were observed in the SNFH BMSCs. miR27a knockdown/overexpression modulated YTHDF2 expression, impacting BMSC differentiation. miR27a silencing decreased m6A methylation and promoted osteogenic differentiation, while YTHDF2 silencing exerted similar effects. GSEA suggested potential signaling pathways associated with YTHDF2 in SNFH. CONCLUSION: miR27a regulates BMSC differentiation through YTHDF2, affecting m6A methylation and promoting osteogenesis. This finding suggests a potential therapeutic target for SNFH.

Exploring the Valence Diversity of Uranium by Flux Growth of Uranium Silicate under Inert Atmosphere.

The attributes of good solubility and the redox-neutral nature of molten salt fluxes enable them to be useful for the synthesis of novel crystalline actinide compounds. In this work, a flux growth method under an inert atmosphere is proposed to explore the valence diversity of uranium, and a series of five uranium silicate structures, [K3Cl][(UVIO2)(Si4O10)] (1), Cs3[(UVO2)(Si4O10)] (2), K2[UIV(Si2O7)] (3), K8[(UVIO2)(UVO2)2(Si8O22)] (4), and Cs6[UIV(UVO)2(Si12O32)] (5), were synthesized using different metal halide salt and feeding U/Si ratios. Crystal structure analysis reveals that the utilization of argon atmosphere that helps to avoid possible oxidation of low-valence uranium generates a variety of oxidation states of uranium including U(VI), U(V), U(IV), mixed-valence U(V) and U(VI), and mixed-valence U(IV) and U(V). Characterization of physicochemical properties of representative compounds shows that all these uranium silicate compounds have bandgaps among the range of 2.0-3.4 eV, and mixed-valence uranium silicate compounds have relatively narrower bandgaps. Density functional theory calculations on formation enthalpies, lattice energies, and bandgaps of all five compounds were also performed to provide more structural information about these uranium silicates. This work enriches the library of variable-valence uranium silicate compounds and provides a feasible way to produce novel actinide compounds with intriguing properties through the flux growth method that might show potential application in relevant fields such as storage media for nuclear waste.

[Multi-scale Driving Mechanism of Urbanization on PM2.5 Concentration in Urban Agglomeration in the Middle Reaches of the Yangtze River].

Exploring the nonlinear effect of urbanization on PM2.5 concentration and its driving mechanism is crucial for controlling urban air pollution. Based on remote sensing data and statistical data from 2002 to 2020, spatial autocorrelation, systematic dynamic panel regression, and spatio-temporal geographical weighted regression models were used to analyze the spatio-temporal evolution of PM2.5 concentration in the urban agglomeration of the middle reaches of the Yangtze River and explore the driving mechanism of urbanization on PM2.5 concentration at different spatial scales. The results showed that:① PM2.5 concentration in the middle reaches of the Yangtze River showed an overall decreasing trend from 2002 to 2020, with a spatial distribution pattern of "high in the north and low in the south." ② Hot spot cities expanded towards the western part of the urban agglomeration, whereas cold spot cities showed enhanced spatial correlation. ③ The relationship between PM2.5 concentration and economic, land, and population urbanization followed N-shaped, U-shaped, and U-shaped curves, respectively. Secondary industry and energy consumption significantly promoted the change in PM2.5 concentration, and precipitation and vegetation helped mitigate PM2.5 pollution. ④ The overall driving effects of all urbanization factors in local areas were transformed, and the main areas of influence were concentrated in the southeast, northwest, and southwest of the study area. Considering the current urban development status and regional characteristics of the urban agglomeration in the middle reaches of the Yangtze River, promoting green industrial transformation, rational planning of urban spatial distribution and population distribution, and enhancing infrastructure construction will facilitate the coordinated development between urbanization and environmental protection.

Learned associations serve as target proxies during difficult but not easy visual search.

The target template contains information in memory that is used to guide attention during visual search and is typically thought of as containing features of the actual target object. However, when targets are hard to find, it is advantageous to use other information in the visual environment that is predictive of the target's location to help guide attention. The purpose of these studies was to test if newly learned associations between face and scene category images lead observers to use scene information as a proxy for the face target. Our results showed that scene information was used as a proxy for the target to guide attention but only when the target face was difficult to discriminate from the distractor face; when the faces were easy to distinguish, attention was no longer guided by the scene unless the scene was presented earlier. The results suggest that attention is flexibly guided by both target features as well as features of objects that are predictive of the target location. The degree to which each contributes to guiding attention depends on the efficiency with which that information can be used to decode the location of the target in the current moment. The results contribute to the view that attentional guidance is highly flexible in its use of information to rapidly locate the target.

Genome- and transcriptome-wide identification of trehalose-6-phosphate phosphatases (TPP) gene family and their expression patterns under abiotic stress and exogenous trehalose in soybean.

BACKGROUND: Trehalose-6-phosphate phosphatase (TPP) is an essential enzyme catalyzing trehalose synthesis, an important regulatory factor for plant development and stress response in higher plants. However, the TPP gene family in soybean has not been reported. RESULTS: A comprehensive analysis of the TPP gene family identified 18 GmTPPs classified into eight groups based on the phylogenetic relationships and the conservation of protein in six monocot and eudicot plants. The closely linked subfamilies had similar motifs and intron/exon numbers. Segmental duplication was the main driving force of soybean GmTPPs expansion. In addition, analysis of the cis-regulatory elements and promoter regions of GmTPPs revealed that GmTPPs regulated the response to several abiotic stresses. Moreover, RNA-seq and qRT-PCR analysis of the tissue-specific GmTPPs under different abiotic stresses revealed that most GmTPPs were associated with response to different stresses, including cold, drought, saline-alkali, and exogenous trehalose. Notably, exogenous trehalose treatment up-regulated the expression of most TPP genes under saline-alkali conditions while increasing the carbohydrate and trehalose levels and reducing reactive oxygen species (ROS) accumulation in soybean sprouts, especially in the saline-alkali tolerant genotype. Furthermore, the interaction network and miRNA target prediction revealed that GmTPPs interacted with abiotic stress response-related transcription factors. CONCLUSIONS: The findings in this study lay a foundation for further functional studies on TPP-based breeding to improve soybean development and stress tolerance.

Th6-Based Multicomponent Heterometallic Metal-Organic Frameworks Featuring 6,12-Connected Topology for Iodine Adsorption.

Its high coordination number and tendency to cluster make Th4+ suitable for constructing metal-organic frameworks (MOFs) with novel topologies. In this work, two novel thorium-based heterometallic MOF isomers (IHEP-17 and IHEP-18) were assembled from a Th6 cluster, a multifunctional organic ligand [4-(1H-pyrazol-4-yl)benzoic acid (HPyba)], and Cu2+/Ni2+ cations via the one-pot solvothermal synthesis strategy. The framework features a 6,12-connected new topology net and contains two kinds of supramolecular cage structures, Th36M4 and Th24M2, suitable for guest exchange. Both MOF materials can efficiently adsorb I2. X-ray photoelectron spectroscopy, Raman spectroscopy, and single-crystal X-ray diffraction indicate that the adsorbed iodine is uniformly distributed within the Th36M4 cage but not the Th24M2 cage in the form of I3-.

Good-enough attentional guidance.

Theories of attention posit that attentional guidance operates on information held in a target template within memory. The template is often thought to contain veridical target features, akin to a photograph, and to guide attention to objects that match the exact target features. However, recent evidence suggests that attentional guidance is highly flexible and often guided by non-veridical features, a subset of features, or only associated features. We integrate these findings and propose that attentional guidance maximizes search efficiency based on a 'good-enough' principle to rapidly localize candidate target objects. Candidates are then serially interrogated to make target-match decisions using more precise information. We suggest that good-enough guidance optimizes the speed-accuracy-effort trade-offs inherent in each stage of visual search.

The potential effect of BMSCs with miR-27a in improving steroid-induced osteonecrosis of the femoral head.

Steroid induced osteonecrosis of the femoral head (ONFH) frequently leads to femoral head collapse and subsequent hip arthritis. This study aimed to investigate the potential therapeutic mechanism of miR-27a on steroid-induced ONFH. Levels of IL-6, TNF-α, miR-27a, Runx2, PPAR-γ and ApoA5 were first examined in bone marrow tissues from steroid-induced ONFH and controls. Subsequently, we overexpressed or knocked down miR-27a in bone marrow mesenchymal stem cells (BMSCs) and detected cell proliferation, osteogenic differentiation, adipogenic differentiation. In addition, miR-27a mimics and BMSCs were injected into the established steroid-induced ONFH rats, and the osteoprotective effects of both were evaluated. Dual luciferase reporter was used to test the targeting effect of miR-27a-3p and PPARG. miR-27a and Runx2 were lowly expressed in steroid-induced ONFH, PPAR-γ and ApoA5 were highly expressed. Overexpression of miR-27a in BMSCs promoted cell proliferation and osteogenic differentiation, inhibited adipogenic differentiation. Furthermore, increasing miR-27a and BMSCs obviously reduced bone loss in steroid induced ONFH rats. The expressions of Runx2 in BMSCs and steroid-induced ONFH rats was significantly up-regulated, while IL-6, TNF-α, PPAR-γ and ApoA5 were down-regulated with miR-27a overexpression. Additionally, PPARG was the target of miR-27a-3p. The results of the present study reveal a role for miR-27a in promoting osteogenesis and may have a synergistic effect with BMSCs.

Molecular mechanisms of flavonoid accumulation in germinating common bean (Phaseolus vulgaris) under salt stress.

Flavonoids are important secondary metabolites, active biomolecules in germinating beans, and have prominent applications in food and medicine due to their antioxidant effects. Rutin is a plant flavonoid with a wide biological activity range. In this study, flavonoid (rutin) accumulation and its related molecular mechanisms in germinating common bean (Phaseolus vulgaris) were observed at different time points (0-120 h) under salt stress (NaCl). The rutin content increased from germination onset until 96 h, after which a reducing trend was observed. Metabolome analysis showed that salt stress alters flavonoid content by regulating phenylpropanoid (ko00940) and flavonoid (ko00941) biosynthesis pathways, as well as their enzyme activities, including cinnamyl-alcohol dehydrogenase (CAD), peroxidase (POD), chalcone isomerase (CHI), and flavonol synthase (FLS). The RNA-seq and quantitative real-time PCR (qRT-PCR) analyses also showed that these two pathways were linked to changes in flavonoid content following salt treatment. These results reveal that salt stress effectively enhanced rutin content accumulation in germinating beans, hence it could be employed to enhance the functional quality of germinating common beans.

Genome-wide identification of the B3 gene family in soybean and the response to melatonin under cold stress.

Introduction: Melatonin is a multipotent molecule that exists widely in animals and plants and plays an active regulatory role in abiotic stresses. The B3 superfamily is a ubiquitous transcription factor with a B3 functional domain in plants, which can respond temporally to abiotic stresses by activating defense compounds and plant hormones. Despite the fact that the B3 genes have been studied in a variety of plants, their role in soybean is still unknown. Methods: The regulation of melatonin on cold resistance of soybean and the response of B3 genes to cold stress were investigated by measuring biochemical indexes of soybean. Meanwhile, the genome-wide identification of B3 gene family was conducted in soybean, and B3 genes were analyzed based on phylogeny, motifs, gene structure, collinearity, and cis-regulatory elements analysis. Results: We found that cold stress-induced oxidative stress in soybean by producing excessive reactive oxygen species. However, exogenous melatonin treatment could increase the content of endogenous melatonin and other hormones, including IAA and ABA, and enhance the antioxidative system, such as POD activity, CAT activity, and GSH/GSSG, to scavenge ROS. Furthermore, the present study first revealed that melatonin could alleviate the response of soybean to cold stress by inducing the expression of B3 genes. In addition, we first identified 145 B3 genes in soybean that were unevenly distributed on 20 chromosomes. The B3 gene family was divided into 4 subgroups based on the phylogeny tree constructed with protein sequence and a variety of plant hormones and stress response cis-elements were discovered in the promoter region of the B3 genes, indicating that the B3 genes were involved in several aspects of the soybean stress response. Transcriptome analysis and results of qRT-PCR revealed that most GmB3 genes could be induced by cold, the expression of which was also regulated by melatonin. We also found that B3 genes responded to cold stress in plants by interacting with other transcription factors. Discussion: We found that melatonin regulates the response of soybean to cold stress by regulating the expression of the transcription factor B3 gene, and we identified 145 B3 genes in soybean. These findings further elucidate the potential role of the B3 gene family in soybean to resist low-temperature stress and provide valuable information for soybean functional genomics study.

A software system for dispersive atomic fluorescence spectrometry based on UV digital micromirror device.

A dispersive atomic fluorescence spectrometer based on a UV digital micromirror device (UV-DMD-AFS) has been proposed by our team for attenuating spectral and scattering interferences. Software is nontrivial for the automation of component control and sample analysis in the new instrument. In this work, the software was developed using the C# programming language together with multi-threading and combined with the SQLite database, which consists of component control and data acquisition, database, wavelength initialization, and real-time interference reduction module. To realize the accurate analysis of the trace heavy metal concentration, the spectral interference was avoided by measuring the non-interference wavelength, and the scattering interference was eliminated by the real-time proportional coefficient method. The microsecond rotation speed of the DMD is the key to achieving real-time reduction. The concentration of arsenic in Water Quality (GSB 07-3171-2014) was detected to validate the practicability of the software with the concentration deviation of 0.02 ng/mL.

Joint low-rank prior and difference of Gaussian filter for magnetic resonance image denoising.

The low-rank matrix approximation (LRMA) is an efficient image denoising method to reduce additive Gaussian noise. However, the existing low-rank matrix approximation does not perform well in terms of Rician noise removal for magnetic resonance imaging (MRI). To this end, we propose a novel MR image denoising approach based on the extended difference of Gaussian (DoG) filter and nonlocal low-rank regularization. In the proposed method, a novel nonlocal self-similarity evaluation with the tight frame is exploited to improve the patch matching. To remove the Rician noise and preserve the edge details, the extended DoG filter is exploited to the nonlocal low-rank regularization model. The experimental results demonstrate that the proposed method can preserve more edge and fine structures while removing noise in MR image as compared with some of the existing methods.

Changes in visual cortical processing attenuate singleton distraction during visual search.

The ability to suppress distractions is essential to successful completion of goal-directed behaviors. Several behavioral studies have recently provided strong evidence that learned suppression may be particularly efficient in reducing distractor interference. Expectations about a distractor's repeated location, color, or even presence are rapidly learned and used to attenuate interference. In this study, we use a visual search paradigm in which a color singleton, which is known to capture attention, occurs within blocks with high or low frequency. The behavioral results show reduced singleton interference during the high compared to the low frequency block (Won et al., 2019). The fMRI results provide evidence that the attenuation of distractor interference is supported by changes in singleton, target, and non-salient distractor representations within retinotopic visual cortex. These changes in visual cortex are accompanied by findings that singleton-present trials compared to non-singleton trials produce greater activation in bilateral parietal cortex, indicative of attentional capture, in low frequency, but not high frequency blocks. Together, these results suggest that the readout of saliency signals associated with an expected color singleton from visual cortex is suppressed, resulting in less competition for attentional priority in frontoparietal attentional control regions.

LncRNA-ENST00000446135 is a novel biomarker of cadmium toxicity in 16HBE cells, rats, and Cd-exposed workers and regulates DNA damage and repair.

Cadmium (Cd) and its compounds are well-known human carcinogens, but the mechanisms underlying the carcinogenesis are not well understood. This study aimed to investigate whether long noncoding RNA (LncRNA)-ENST00000446135 could serve as a novel biomarker of Cd toxicity in cells, animals, and Cd-exposed workers and regulate DNA damage and repair. LncRNA-ENST00000446135 expression increased gradually in cadmium chloride-transformed 16HBE cells. Small interfering RNA-mediated knockdown of LncRNA-ENST00000446135 inhibited the growth of DNA-damaged cells and decreased the expressions of DNA damage-related genes (ATM, ATR, and ATRIP), whereas increased the expressions of DNA repair-related genes (DDB1, DDB2, OGG1, ERCC1, MSH2, XRCC1, and BARD1). Chromatin immunoprecipitation-sequencing showed that MSH2 is a direct transcriptional target of lncRNA-ENST00000446135. Cadmium increased lncRNA-ENST00000446135 expression in the lung of Cd-exposed rats in a dose-dependent manner. A significant positive correlation was observed between blood ENST00000446135 expression and urinary/blood Cd concentrations, and there were significant correlations of LncRNA-ENST00000446135 expression with the DNA damage cell and the expressions of target genes in the lung of Cd-exposed rats and the blood of Cd-exposed workers and significantly correlated with liver and renal function in Cd-exposed workers. These results indicate that the expression of LncRNA-ENST00000446135 is upregulated and may serve as a signature for DNA damage and repair related to the epigenetic mechanisms underlying the cadmium toxicity and become a novel biomarker of cadmium toxicity.

Functionally Separable Font-invariant and Font-sensitive Neural Populations in Occipitotemporal Cortex.

Reading relies on the rapid visual recognition of words viewed in a wide variety of fonts. We used fMRI to identify neural populations showing reduced fMRI responses to repeated words displayed in different fonts ("font-invariant" repetition suppression). We also identified neural populations showing greater fMRI responses to words repeated in a changing font as compared with words repeated in the same font ("font-sensitive" release from repetition suppression). We observed font-invariant repetition suppression in two anatomically distinct regions of the left occipitotemporal cortex (OT), a "visual word form area" in mid-fusiform cortex, and a more posterior region in the middle occipital gyrus. In contrast, bilateral shape-selective lateral occipital cortex and posterior fusiform showed considerable sensitivity to font changes during the viewing of repeated words. Although the visual word form area and the left middle occipital gyrus showed some evidence of font sensitivity, both regions showed a relatively greater degree of font invariance than font sensitivity. Our results show that the neural mechanisms in the left OT involved in font-invariant word recognition are anatomically distinct from those sensitive to font-related shape changes. We conclude that font-invariant representation of visual word form is instantiated at multiple levels by anatomically distinct neural mechanisms within the left OT.

Embedded word priming elicits enhanced fMRI responses in the visual word form area.

Lexical embedding is common in all languages and elicits mutual orthographic interference between an embedded word and its carrier. The neural basis of such interference remains unknown. We employed a novel fMRI prime-target embedded word paradigm to test for involvement of a visual word form area (VWFA) in left ventral occipitotemporal cortex in co-activation of embedded words and their carriers. Based on the results of related fMRI studies we predicted either enhancement or suppression of fMRI responses to embedded words initially viewed as primes, and repeated in the context of target carrier words. Our results clearly showed enhancement of fMRI responses in the VWFA to embedded-carrier word pairs as compared to unrelated prime-target pairs. In contrast to non-visual language-related areas (e.g., left inferior frontal gyrus), enhanced fMRI responses did not occur in the VWFA when embedded-carrier word pairs were restricted to the left visual hemifield. Our finding of fMRI enhancement in the VWFA is novel evidence of its involvement in representational rivalry between orthographically similar words, and the co-activation of embedded words and their carriers.

Anti-PD-1/PD-L1 therapy augments lenvatinib's efficacy by favorably altering the immune microenvironment of murine anaplastic thyroid cancer.

Patients with anaplastic thyroid cancer (ATC) have an extremely poor prognosis despite multimodal therapy with surgery and chemoradiation. Lenvatinib, a multi-targeted tyrosine kinase inhibitor, as well as checkpoint inhibitors targeting the programmed cell death pathway, have proven effective in some patients with advanced thyroid cancer. Combination of these therapies is a potential means to boost effectiveness and minimize treatment resistance in ATC. We utilized our novel immunocompetent murine model of orthotopic ATC to demonstrate that lenvatinib led to significant tumor shrinkage and increased survival, while combination therapy led to dramatic improvements in both. Lenvatinib monotherapy increased tumor-infiltrating macrophages, CD8+ T-cells, regulatory T-cells, and most notably, polymorphonuclear myeloid derived suppressor cells (PMN-MDSCs). While both combination therapies led to further increases in CD8+ T-cells, only the lenvatinib and anti-PD-1 combination decreased PMN-MDSCs. PMN-MDSC expansion was also seen in the blood of mice and one patient receiving lenvatinib therapy for ATC. RNA-Seq of the ATC cell line used in our mouse model demonstrated that lenvatinib has multifaceted effects on angiogenesis, response to hypoxia, the epithelial-to-mesenchymal transition, and on multiple pathways implicated in inflammation and host immunity. Combination of lenvatinib with anti-Gr-1 antibody ameliorated lenvatinib's expansion of MDSCs and significantly improved lenvatinib's anti-tumor effect. These data suggest that MDSCs play a negative role in ATC's response to lenvatinib and support future study of their role as a potential biomarker and treatment target.

Flexible TWDM-RoF system with good dispersion tolerance for downlink and uplink based on additional SCS.

A high-efficiency full-duplex radio-over-fiber (RoF) system incorporating time- and wavelength-division multiplexing technology is proposed in this paper, which is more flexible for the wavelength assignment based on an additional subcentral station (SCS). The periodic power fading effect resulting from a radio frequency signal transmitted over an optical fiber is effectively eliminated for the downlink and uplink. Colorless base stations are achieved by a centralized allocation strategy of upstream light sources. At the SCS, an optical cross-connect unit is employed to enhance the utilization of light sources and the flexibility of the proposed RoF system. Simultaneously, the requirements of high-bandwidth modulators and photodetectors are significantly reduced with a centralized optical carrier suppressed modulation and an all-optical frequency downconversion at the SCS. On the basis of the additional SCS, a 26 GHz full-duplex experiment system is demonstrated, and two 1.25 Gbps baseband data signals for downlink and uplink are successfully transmitted over a 40 km standard single-mode fiber.

Combinations of BRAF inhibitor and anti-PD-1/PD-L1 antibody improve survival and tumour immunity in an immunocompetent model of orthotopic murine anaplastic thyroid cancer.

BACKGROUND: Patients with anaplastic thyroid cancer (ATC) have an extremely poor prognosis despite aggressive multimodal therapy. ATC has a high prevalence of BRAFV600E mutations and is associated with an immunosuppressive microenvironment; we previously demonstrated that the combination of BRAF inhibitor and checkpoint inhibitor immunotherapy synergistically reduce tumour volume in an immunocompetent mouse model of orthotopic ATC. METHODS: We again utilised our mouse model of ATC to assess the combination of BRAFV600E inhibitor PLX4720 and anti-PD-L1 or anti-PD-1 antibody on survival, and performed immune cell profiling of lymphoid and myeloid-lineage cells during maximal treatment response and tumour regrowth. RESULTS: Combination therapy dramatically improved mouse survival. Maximal tumour reduction was associated with increases in the number and cytotoxicity of CD8+ T cells and NK cells, as well as increases in mostly M1-polarised tumour-associated macrophages (TAM) and decreases in myeloid-derived suppressor-like cells. Regrowth of tumour occurred after 2-3 weeks of ongoing combination therapy, and was most significantly associated with decreased TAMs and a dramatic increase in M2-polarisation. CONCLUSIONS: Combination of PLX4720 and anti-PD-L1/PD-1 antibody dramatically reduced tumour volume, prolonged survival and improved the anti-tumour immune profile in murine ATC. Tumour growth inevitably recurred and demonstrated re-emergence of an immunosuppressive tumour microenvironment.

Surface Instability of Bilayer Hydrogel Subjected to Both Compression and Solvent Absorption.

The bilayered structure of hard thin film on soft substrate can lose stability and form specific patterns, such as wrinkles or creases, on the surface, induced by external stimuli. For bilayer hydrogels, the surface morphology caused by the instability is usually controlled by the solvent-induced swelling/shrinking and mechanical force. Here, two important issues on the instability of bilayer hydrogels, which were not considered in the previous studies, are focused on in this study. First, the upper layer of a hydrogel is not necessarily too thin. Thus we investigated how the thickness of the upper layer can affect the surface morphology of bilayer hydrogels under compression through both finite element (FE) simulation and theoretical analysis. Second, a hydrogel can absorb water molecules before the mechanical compression. The effect of the pre-absorption of water before the mechanical compression was studied through FE simulations and theoretical analysis. Our results show that when the thickness of the upper layer is very large, surface wrinkles can exist without transforming into period doublings. The pre-absorption of the water can result in folds or unexpected hierarchical wrinkles, which can be realized in experiments through further efforts.