IRF1 regulation of ZBP1 links mitochondrial DNA and chondrocyte damage in osteoarthritis.

BACKGROUND: Z-DNA binding protein 1 (ZBP1) is a nucleic acid sensor that is involved in multiple inflammatory diseases, but whether and how it contributes to osteoarthritis (OA) are unclear. METHODS: Cartilage tissues were harvested from patients with OA and a murine model of OA to evaluate ZBP1 expression. Subsequently, the functional role and mechanism of ZBP1 were examined in primary chondrocytes, and the role of ZBP1 in OA was explored in mouse models. RESULTS: We showed the upregulation of ZBP1 in articular cartilage originating from OA patients and mice with OA after destabilization of the medial meniscus (DMM) surgery. Specifically, knockdown of ZBP1 alleviated chondrocyte damage and protected mice from DMM-induced OA. Mechanistically, tumor necrosis factor alpha induced ZBP1 overexpression in an interferon regulatory factor 1 (IRF1)-dependent manner and elicited the activation of ZBP1 via mitochondrial DNA (mtDNA) release and ZBP1 binding. The upregulated and activated ZBP1 could interact with receptor-interacting protein kinase 1 and activate the transforming growth factor-beta-activated kinase 1-NF-κB signaling pathway, which led to chondrocyte inflammation and extracellular matrix degradation. Moreover, inhibition of the mtDNA-IRF1-ZBP1 axis with Cyclosporine A, a blocker of mtDNA release, could delay the progression of DMM-induced OA. CONCLUSIONS: Our data revealed the pathological role of the mtDNA-IRF1-ZBP1 axis in OA chondrocytes, suggesting that inhibition of this axis could be a viable therapeutic approach for OA.

HnRNPR strongly represses splicing of a critical exon associated with spinal muscular atrophy through binding to an exonic AU-rich element.

BACKGROUND: Spinal muscular atrophy (SMA) is a motor neuron disease caused by mutations of survival of motor neuron 1 (SMN1) gene, which encodes the SMN protein. SMN2, a nearly identical copy of SMN1, with several single-nucleotide substitutions leading to predominant skipping of its exon 7, is insufficient to compensate for loss of SMN1. Heterogeneous nuclear ribonucleoprotein R (hnRNPR) has been previously shown to interact with SMN in the 7SK complex in motoneuron axons and is implicated in the pathogenesis of SMA. Here, we show that hnRNPR also interacts with SMN1/2 pre-mRNAs and potently inhibits exon 7 inclusion. METHODS: In this study, to examine the mechanism that hnRNPR regulates SMN1/2 splicing, deletion analysis in an SMN2 minigene system, RNA-affinity chromatography, co-overexpression analysis and tethering assay were performed. We screened antisense oligonucleotides (ASOs) in a minigene system and identified a few that markedly promoted SMN2 exon 7 splicing. RESULTS: We pinpointed an AU-rich element located towards the 3' end of the exon that mediates splicing repression by hnRNPR. We uncovered that both hnRNPR and Sam68 bind to the element in a competitive manner, and the inhibitory effect of hnRNPR is much stronger than Sam68. Moreover, we found that, among the four hnRNPR splicing isoforms, the exon 5-skipped one has the minimal inhibitory effect, and ASOs inducing hnRNPR exon 5 skipping also promote SMN2 exon 7 inclusion. CONCLUSION: We identified a novel mechanism that contributes to mis-splicing of SMN2 exon 7.

Homeodomain protein Six4 prevents the generation of supernumerary Drosophila type II neuroblasts and premature differentiation of intermediate neural progenitors.

In order to boost the number and diversity of neurons generated from neural stem cells, intermediate neural progenitors (INPs) need to maintain their homeostasis by avoiding both dedifferentiation and premature differentiation. Elucidating how INPs maintain homeostasis is critical for understanding the generation of brain complexity and various neurological diseases resulting from defects in INP development. Here we report that Six4 expressed in Drosophila type II neuroblast (NB) lineages prevents the generation of supernumerary type II NBs and premature differentiation of INPs. We show that loss of Six4 leads to supernumerary type II NBs likely due to dedifferentiation of immature INPs (imINPs). We provide data to further demonstrate that Six4 inhibits the expression and activity of PntP1 in imINPs in part by forming a trimeric complex with Earmuff and PntP1. Furthermore, knockdown of Six4 exacerbates the loss of INPs resulting from the loss of PntP1 by enhancing ectopic Prospero expression in imINPs, suggesting that Six4 is also required for preventing premature differentiation of INPs. Taken together, our work identified a novel transcription factor that likely plays important roles in maintaining INP homeostasis.

Immunohistochemical Expression of Lymphoid Enhancer-binding Factor 1 in Low-grade Endometrial Stromal Tumors.

Endometrial stromal tumors (ESTs) are uncommon uterine mesenchymal lesions. Nuclear expression of ß-catenin, an indication of activated Wnt/ß-catenin signaling pathway, was described in 50% to 92% of low-grade ESTs, including endometrial stromal nodule and low-grade endometrial stromal sarcoma. Activation of the Wnt/ß-catenin signaling pathway leads to the translocation of ß-catenin into the nucleus and interaction with the T-cell factor/lymphoid enhancer-binding factor-1 (LEF1) family of transcription factors to regulate cell proliferation, differentiation, migration, and survival. Immunohistochemical analysis of ß-catenin and LEF1 was performed in 2 endometrial stromal nodules and 20 low-grade endometrial stromal sarcomas and demonstrated 90.9% and 81.8% positive rates for ß-catenin and LEF1, respectively. The sensitivity, specificity, positive predictive value, and negative predictive value of ß-catenin and LEF1 were 90.9% versus 81.8%, 81.0% versus 85.7%, 83.3% versus 85.7%, 89.5% versus 81.8%, respectively, in the diagnosis of low-grade ESTs. There is no statistical significance of the performance of ß-catenin and LEF1 in all ESTs (P = 0.664) or in primary or metastatic/recurrent settings (P = 0.515 and 0.999, respectively). Only 3 smooth muscle tumors showed focal and weak positivity for LEF1. Our results indicate LEF1 can be a useful marker in aiding a diagnosis of low-grade EST and differentiating from smooth muscle tumors alone or in combination with ß-catenin.

Enhanced Assembling of N-and-K-Riched Macroalgae as Carbon Adsorbent for CO2 Capture with Ni(NO3)2/KOH as Co-Catalysts.

Porous-activated carbons have drawn great attention due to their important role in CO2 capture. Ni(NO3)2/KOH, as co-catalysts under different temperatures, were studied to obtain porous graphitized carbon from Sargassum horneri feedstock. The results indicated that the properties of the porous graphitized carbon generated at 850 °C were greatly enhanced, showing a large specific surface area of 1486.38 cm3·g-1 with narrowly distributed micropores (~0.67 nm) and abundant functional groups, which endowed high CO2 uptake; moreover, the high CO2 uptake was mainly attributed to the synergistic effect of Ni(NO3)2 and KOH, both in chemical modification and pore formation. The fitted values of the four kinetic models showed that the double exponential model provided the best description of carbon adsorption, indicating both physical and chemical adsorption. It is worth noting that carbon could be reused four times in the adsorption/desorption procedure in this research with good stability. This work focuses on the high-value-added comprehensive utilization of macroalgae, which not only is important for high-performance adsorbent preparation but also has positive benefits for the development and utilization of macroalgae resources.

ADORA1-driven brain-sympathetic neuro-adipose connections control body weight and adipose lipid metabolism.

It is essential to elucidate brain-adipocyte interactions in order to tackle obesity and its comorbidities, as the precise control of brain-adipose tissue cross-talk is crucial for energy and glucose homeostasis. Recent studies show that in the peripheral adipose tissue, adenosine induces adipogenesis through peripheral adenosine A1 receptor (pADORA1) signaling; however, it remains unclear whether systemic and adipose tissue metabolism would also be under the control of central (c) ADORA1 signaling. Here, we use tissue-specific pharmacology and metabolic tools to clarify the roles of cADORA1 signaling in energy and adipocyte physiology. We found that cADORA1 signaling reduces body weight while also inducing adipose tissue lipolysis. cADORA1 signaling also increases adipose tissue sympathetic norepinephrine content. In contrast, pADORA1 signaling facilitates a high-fat diet-induced obesity (DIO). We propose here a novel mechanism in which cADORA1 and pADORA1 signaling hinder and aggravate DIO, respectively.

Update on prognostic and predictive biomarkers of breast cancer.

Breast cancer represents a heterogeneous group of human cancer at both histological and molecular levels. Estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) are the most commonly used biomarkers in clinical practice for making treatment plans for breast cancer patients by oncologists. Recently, PD-L1 testing plays an important role for immunotherapy for triple-negative breast cancer. With the increased understanding of the molecular characterization of breast cancer and the emergence of novel targeted therapies, more potential biomarkers are needed for the development of more personalized treatments. In this review, we summarized several main prognostic and predictive biomarkers in breast cancer at genomic, transcriptomic and proteomic levels, including hormone receptors, HER2, Ki67, multiple gene expression assays, PD-L1 testing, mismatch repair deficiency/microsatellite instability, tumor mutational burden, PIK3CA, ESR1 andNTRK and briefly introduced the roles of digital imaging analysis in breast biomarker evaluation.

Endometrial Polyp of the Placental Fetal Membranes: Report of a Case.

Endometrial polyps embedded in the fetal membranes have only rarely been described. A review of the English literature showed only one abstract describing this occurrence and to the best of our knowledge, there have been no other publications of this entity. Herein we present a case of a 37-yr-old woman with a history prior abortion and complicated pregnancy (type 2 diabetes mellitus and preeclampsia) who delivered by cesarean section. Although the placenta did not show hypertensive vasculopathic changes or other pathologic findings, an endometrial polyp embedded within the fetal membranes was present. Recognition of this rarely reported entity is important in order to avoid confusion with a significant neoplastic process.

The Ets protein Pointed prevents both premature differentiation and dedifferentiation of Drosophila intermediate neural progenitors.

Intermediate neural progenitors (INPs) need to avoid both dedifferentiation and differentiation during neurogenesis, but the underlying mechanisms are not well understood. In Drosophila, the Ets protein Pointed P1 (PntP1) is required to generate INPs from type II neuroblasts. Here, we investigated how PntP1 promotes INP generation. By generating pntP1-specific mutants and using RNAi knockdown, we show that the loss of PntP1 leads to both an increase in type II neuroblast number and the elimination of INPs. The elimination of INPs results from the premature differentiation of INPs due to ectopic Prospero expression in newly generated immature INPs (imINPs), whereas the increase in type II neuroblasts results from the dedifferentiation of imINPs due to loss of Earmuff at later stages of imINP development. Furthermore, reducing Buttonhead enhances the loss of INPs in pntP1 mutants, suggesting that PntP1 and Buttonhead act cooperatively to prevent premature INP differentiation. Our results demonstrate that PntP1 prevents both the premature differentiation and the dedifferentiation of INPs by regulating the expression of distinct target genes at different stages of imINP development.

PD-L1 expression and CD8-positive T cells are associated with favorable survival in HER2-positive invasive breast cancer.

Programmed cell death 1 (PD-1) and its ligand (PD-L1) are key physiologic suppressors of the cytotoxic immune reaction. However, to date, the combination of PD1/PD-L1 expression and tumor-infiltrating lymphocytes (TILs) and antigen-presenting cells has been only minimally reported in breast carcinoma, in particular in relation to HER2-positive cases. The goal of this study was to evaluate both cellular tumoral immune reaction and PD-L1/PD1 distribution in HER2-positive cases, as well as any associations with clinical outcome using conventional chemotherapy combined with HER2 blocking. Multicolor immunohistochemical multiplex assays simultaneously demonstrating PD1, PD-L1, and CD8 or PD-L1, CD3, and CD163 were performed on tissue microarrays (TMA) representing 216 pretreatment cases of HER2-positive invasive breast carcinoma. PD-L1 expression was identified in 38 cases (18%), including 12 cases (6%) with PD-L1 labeling of tumor cells and 26 cases (12%) with PD-L1 labeling of immune cells only. Ten of 12 cases with PD-L1 staining of tumor cells showed staining of associated immune cells as well. With this assay method, PD1 was detectable in many fewer cases (6 cases or 3%). PD-L1 expression was positively associated with high Nottingham grade, negative ER and PR, the absence of lymph node metastasis, and high levels of CD8+ cells. The overall survival by univariate analysis was positively associated with lower tumor stage, the absence of lymph node metastasis, PD-L1 expression, and high levels of CD8+ cells. Therefore, our data suggest cytotoxic immune reaction mediated by CD8-positive T cells and PD-L1 expression may predict a better outcome in patients with HER2-positive breast carcinoma managed with conventional chemotherapy and HER2-blocking therapy. These findings recommend clinical trials utilizing checkpoint blocking immunotherapy in some form for HER2-positive breast cancer.

HER2 intratumoral heterogeneity is independently associated with incomplete response to anti-HER2 neoadjuvant chemotherapy in HER2-positive breast carcinoma.

PURPOSE: Anti-HER2 neoadjuvant chemotherapy has been widely used in HER2-positive breast cancer patients; however, pathologic complete response (pCR) is achieved in only 40-50% of patients. The aim of this study was to investigate the association of HER2 intratumoral heterogeneity (ITH) with response to anti-HER2 neoadjuvant chemotherapy. METHODS: Assessment of HER2 ITH was performed on whole tissue sections of pre-treatment samples from a cohort of 64 invasive breast carcinoma cases originally considered positive for HER2 and treated with anti-HER2 neoadjuvant chemotherapy. Both HER2 gene signal and protein expression were simultaneously evaluated by means of a single-slide dual assay, designated as a HER2 gene-protein assay (GPA). HER2 GPA was carried out as well on surgical resection tissues from 25 cases with incomplete therapeutic response. RESULTS: Nineteen of 64 cases (30%) showed HER2 ITH. Significantly more cases with HER2 ITH were found in the incomplete response group (56%, 14/25) than in the pCR group (13%, 5/39). Patients without ITH detectable by GPA had a 76% pCR outcome (34/45), as compared to 26% (5/19) for those with detectable ITH. Multivariate analysis demonstrated HER2 ITH, progesterone receptor positivity, and relatively low HER2/chromosome 17 centromere ratio to be significantly associated with incomplete response. CONCLUSIONS: HER2 ITH analyses conducted with GPA method revealed that HER2 ITH is an independent factor predicting incomplete response to anti-HER2 neoadjuvant chemotherapy.

Utility of different immunostains for diagnosis of metastatic breast carcinomas in both surgical and cytological specimens.

OBJECTIVE: A panel of immunostains is usually performed to confirm a metastatic carcinoma origin. GATA3 is a transcription factor and has been proven to be a useful marker for breast carcinoma. Other immunostains including mammaglobin (MGB), gross cystic disease fluid protein 15 (GCDFP-15), estrogen receptor (ER) and progesterone receptor (PR) are also used in diagnosing metastatic breast cancer. In this study, we aimed to compare the performance of these immunostains in the work up of metastatic breast carcinoma in both surgical and cytological specimens. STUDY DESIGN: This study cohort was composed of 242 metastatic breast carcinomas (142 surgical and 100 cytological specimens) during a study period from October 2013 to December 2015. Immunostain results of GATA3, CK7, MGB, GCDFP-15, ER and PR and their correlations were examined. RESULTS: In surgical specimens, GATA3 and CK7 were highly expressed (88% and 87%), but MGB and GCDFP-15 showed much lower positivity rates (43% and 29%). In cytological specimens, GATA3, CK7 and MGB showed similar positivity rates to those in surgical specimens; but GCDFP-15, ER and PR showed significantly lower positivity rates than those in surgical specimens. All ER-positive cases were positive for GATA3 in both surgical and cytological specimens; however, GATA3 positivity showed a significantly stronger correlation with ER positivity in surgical specimens than in cytological specimens. CONCLUSIONS: GATA3 and CK7 performed better than other immunostains to detect metastatic breast carcinoma in both surgical and cytological specimens. GATA3 expression was positively correlated with ER expression, and the correlation was stronger in surgical specimens than in cytological specimens.

Surgical excision outcome after radial scar without atypical proliferative lesion on breast core needle biopsy: a single institutional analysis.

Radial scar (RS) has been recognized as a risk factor for developing breast cancer, and excision is recommended for patients with RS identified on core needle biopsy (CNB). However, recent literatures suggest that the increased risk may be caused by concurrent proliferative lesions on the biopsy, rather than radial scar itself. In this study, we investigated the follow-up excision (FUE) results for patients with RS on CNB with no history of a prior or a concurrent breast cancer or atypical proliferative lesions (APLs). A total of 113 RS cases including 32 cases with APLs or carcinoma and 81 cases without APLs on CNB were included in this study. Forty cases (49%) without APLs had FUE. No significant difference in radiologic and clinical findings was identified between cases with FUEs and cases without FUEs. Of the 40 cases with FUE, 9 cases (22.5%) were upgraded including 3 atypical ductal hyperplasias, 4 lobular neoplasias, 1 flat epithelial atypia, and 1 atypical apocrine adenosis. However, no case was upgraded to invasive carcinoma or ductal carcinoma in situ. All cases with mammotome CNBs were not upgraded. Our data suggest that conservative follow-up with imaging rather than surgical excisions may be more appropriate for patients with only RS on biopsy, especially for patients with mammotome CNBs.

Surgical follow-up results for apocrine adenosis and atypical apocrine adenosis diagnosed on breast core biopsy.

Apocrine adenosis (AA) and atypical apocrine adenosis (AAA) are uncommon findings in breast biopsies that may be misinterpreted as carcinoma. The clinical significance and risk implications of AAA diagnosed on core biopsy are not well established. This study aimed to determine the frequency of carcinoma on follow-up excision in patients with a diagnosis of AA or AAA on core biopsy. Forty-one breast core biopsies of AA (n=29) and AAA (n=12) were identified during a study period of 12 years. Of the 41 core biopsies with AA or AAA, 10 biopsies showed coexisting/concurrent atypical hyperplasia or carcinoma. In the absence of coexisting/concurrent atypical hyperplasia or carcinoma in core biopsy, none of the follow-up excision specimens after a diagnosis of AA or AAA showed ductal carcinoma in situ or invasive carcinoma. In conclusion, AA or AAA by itself is an uncommon core biopsy diagnosis that may not require surgical excision.

Zearalenone exposure affects mouse oocyte meiotic maturation and granulosa cell proliferation.

Zearalenone (ZEN) is a metabolite of Fusarium and is a common contaminant of grains and foodstuffs. ZEN acts as a xenoestrogen and is considered to be cytotoxic, tissue toxic, and genotoxic, which causes abortions and stillbirths in humans and animals. Since estrogens affect oocyte maturation during meiosis, in this study we investigated the effects of ZEN on mouse oocyte meiotic maturation and granulosa cell proliferation. Our results showed that ZEN-treated oocyte maturation rates were decreased, which might be due to the disrupted cytoskeletons: (1) ZEN treatment resulted in significantly more oocytes with abnormal spindle morphologies; (2) actin filament expression and distribution were also disrupted after ZEN treatment, which was confirmed by the aberrant distribution of actin regulatory proteins. In addition, cortical granule-free domains (CGFDs) were disrupted after ZEN treatment, which indicated that ZEN may affect mouse oocyte fertilization capability. ZEN reduced mouse granulosa cell proliferation in a dose-dependent manner as determined by MTT assay and TUNEL apoptosis analysis, which may be another cause for the decreased oocyte maturation. Thus, our results demonstrated that exposure to zearalenone affected oocyte meiotic maturation and granulosa cell proliferation in mouse.

[Study on estimation of deserts soil total phosphorus content from thermal-infrared emissivity].

Soil phosphorus provides nutrient elements for plants, is one of important parameters for evaluating soil quality. The traditional method for soil total phosphorus content (STPC) measurement is not effective and time-consuming. However, remote sensing (RS) enables us to determine STPC in a fast and efficient way. Studies on the estimation of STPC in near-infrared spectroscopy have been developed by scholars, but model accuracy is still poor due to the low absorption coefficient and unclear absorption peak of soil phosphorus in near-infrared. In order to solve the deficiency which thermal-infrared emissivity estimate desert soil total phosphorus content, and could improve precision of estimation deserts soil total phosphorus. In this paper, characteristics of soil thermal-infrared emissivity are analyzed on the basis of laboratory processing and spectral measurement of deserts soil samples from the eastern Junggar Basin. Furthermore, thermal-infrared emissivity based RS models for STPC estimation are established and accuracy assessed. Results show that: when STPC is higher than 0.200 g x kg(-1), the thermal-infrared emissivity increases with the increase of STPC on the wavelength between 8.00 microm and 13 microm, and the emissivity is more sensitive to STPC on the wavelength between 9.00 and 9.6 microm; the estimate mode based on multiple stepwise regression was could not to estimate deserts soil total phosphorus content from thermal-infrared emissivity because the estimation effects of them were poor. The estimation accuracy of model based on partial least squares regression is higher than the model based on multiple stepwise regression. However, the accuracy of second-order differential estimation model based on partial least square regression is higher than based on multiple stepwise regression; The first differential of continuous remove estimation model based on partial least squares regression is the best model with R2 of correction and verification are up to 0.97 and 0.82 respectively, and RMSE of correction and verification are only 0.0106 and 0.015 7 respectively, RPD is 2.62. Research results provide optimized models for remotely sensed analysis on deserts soil total phosphorus content and could realize timeliness and effective monitoring on the space-time dynamic of deserts soil total phosphorus content for future regional ecological restoration.

Zearalenone exposure affects epigenetic modifications of mouse eggs.

Zearalenone (ZEA) is a mycotoxin produced by various Fusarium fungi, which has been shown to cause several cases of mycotoxicosis in farm animals and humans. However, there is no evidence regarding the effect of ZEA on mouse egg developmental competence. In this study, we found that the activation rate of maturated oocytes was affected in mice by ZEA treatment, indicating that ZEA affects egg developmental competence. And we explored possible mechanisms of low mouse maturated oocyte developmental competence after ZEA treatment from an epigenetic modification perspective. The fluorescence intensity analysis showed that 5-methyl cytosine level increased after ZEA treatment, indicating that the general DNA methylation level increased in the treated eggs. Moreover, histone methylations were also altered: H3K4me2 as well as H3K9me3 and H4K20me1, me2, me3 levels decreased in eggs that were cultured in high-dose ZEA medium. Thus, our results indicated that ZEA decreased egg developmental competence by affecting the epigenetic modifications.

Effect of mycotoxin-containing diets on epigenetic modifications of mouse oocytes by fluorescence microscopy analysis.

Mycotoxins, such as aflatoxin (AF), fumonisin B1, zearalenone (ZEA), and deoxynivalenol (DON), are commonly found in many food commodities. Mycotoxins have been shown to increase DNA methylation levels in a human intestinal cell line. We previously showed that the developmental competence of oocytes was affected in mice that had been fed a mycotoxin-containing diet. In this study, we explored possible mechanisms of low mouse oocyte developmental competence after mycotoxin treatment in an epigenetic modification perspective. Mycotoxin-contaminated maize (DON at 3,875 µg/kg, ZEA at 1,897 µg/kg, and AF at 806 µg/kg) was included in diets at three different doses (mass percentage: 0, 15, and 30%) and fed to mice for 4 weeks. The fluorescence intensity analysis showed that the general DNA methylation levels increased in oocytes from high dose mycotoxin-fed mice. Mouse oocyte histone methylation was also altered. H3K9me3 and H4K20me3 level increased in oocytes from mycotoxin-fed mice, whereas H3K27me3 and H4K20me2 level decreased in oocytes from mycotoxin-fed mice. Thus, our results indicate that naturally occurring mycotoxins have effects on epigenetic modifications in mouse oocytes, which may be one of the reasons for reduced oocyte developmental competence.

Lactulose promotes equol production and changes the microbial community during in vitro fermentation of daidzein by fecal inocula of sows.

Equol has higher biological effects than other isoflavones. However, only about 30-50% of humans possess a microbiota capable of producing equol from dietary daidzein. In recent years, interest has grown in dietary applications to improve equol production in human and other animals. In this study, lactulose was used as a potential equol-promoting prebiotic in vitro. The effect of lactulose on transformation of daidzein into equol by sows' fecal microbiota was investigated. Results showed that lactulose treatment improved bacteria growth parameters, changing the kinetics of fermentation in vitro. Lactulose significantly increased total gas production, T1/2, Tmax, and Rmax. Furthermore, lactulose altered the microflora composition, increased equol production associated with a reduction in the population of methanogen and increased the sulfate-reducing bacteria population during 24 h of incubation. Here, we report for the first time that in a certain condition (sealing or high pressure), via a dihydrodaidzein (DHD) pathway equol might be able to reform to daidzein by further metabolism using lactulose as a substrate. This study proposes that "hydrogen-producing prebiotic" might be a novel way to promote equol production in vivo or in vitro.

Coupled InVEST-MGWR modeling to analyze the impacts of changing landscape patterns on habitat quality in the Fen River basin.

The present study employed remote sensing images of the Fen River Basin from 2005, 2010, 2015, and 2020 as the primary data source. The software ENVI, ArcGIS, and Fragstats 4.2 were utilized to measure the landscape pattern index of the Fen River Basin. A collinearity test was conducted to remove any redundant landscape pattern indices. Based on the selected landscape indices, the landscape pattern index values were ascertained as follows. Using the shifting window method, the landscape pattern index of the Fen River Basin was obtained. Second, the habitat quality in the Fen River Basin was assessed using the InVEST model, and the spatial autocorrelation approach was employed to confirm that the habitat quality was spatially autocorrelated. Finally, the spatial impacts of landscape pattern indices on habitat quality were examined using the MGWR model. The results show that (1) the Fen River Basin's overall habitat quality declined between 2005 and 2020; however, the deterioration slowed with time and had a typical "poor in the middle and high around the margins" spatial distribution. The habitat quality of the low-value area continued to increase, the habitat quality of the lower-value area decreased annually, the habitat quality of the middle-value area decreased and then increased, the habitat quality of the higher-quality area tended to increase, decrease, and then increase again, and the habitat quality of the high-quality area decreased annually. (2) The fit of the MGWR model was greater than those of the OLS and traditional GWR models, and it was able to more clearly illustrate the various roles that landscape pattern indices and habitat quality play in one another. (3) Changes in landscape patterns had a major impact on habitat quality; habitat quality was positively impacted by PD and AI, negatively impacted by MESH, and had positive and negative bidirectional effects from CONTAG and AI.