Deubiquitination of aryl hydrocarbon receptor (AhR) by USP21 negatively regulates Th17 cells differentiation.

Aryl hydrocarbon receptor (AhR) is a key transcription factor that modulates the differentiation of T helper 17 (Th17) cells. How AhR is regulated at the post-translational level in Th17 cells remains largely unclear. Here we identify USP21 as a newly defined deubiquitinase of AhR. We demonstrate that USP21 interacts with and stabilizes AhR by removing the K48-linked polyubiquitin chains from AhR. Interestingly, USP21 inhibits the transcriptional activity of AhR in a deubiquitinating-dependent manner. USP21 deubiquitinates AhR at the K432 residue, and the maintenance of ubiquitination on this site is required for the intact transcriptional activity of AhR. Moreover, the deficiency of USP21 promotes the differentiation of Th17 cells both in vitro and in vivo. Consistently, adoptive transfer of USP21 deficient naïve CD4+ T cells elicits more severe colitis in Rag1-/- recipients. Therefore, our study reveals a novel mechanism in which USP21 deubiquitinates AhR and negatively regulates the differentiation of Th17 cells.

Multiparametric MRI-based radiomic models for early prediction of response to neoadjuvant systemic therapy in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is often treated with neoadjuvant systemic therapy (NAST). We investigated if radiomic models based on multiparametric Magnetic Resonance Imaging (MRI) obtained early during NAST predict pathologic complete response (pCR). We included 163 patients with stage I-III TNBC with multiparametric MRI at baseline and after 2 (C2) and 4 cycles of NAST. Seventy-eight patients (48%) had pCR, and 85 (52%) had non-pCR. Thirty-six multivariate models combining radiomic features from dynamic contrast-enhanced MRI and diffusion-weighted imaging had an area under the receiver operating characteristics curve (AUC) > 0.7. The top-performing model combined 35 radiomic features of relative difference between C2 and baseline; had an AUC = 0.905 in the training and AUC = 0.802 in the testing set. There was high inter-reader agreement and very similar AUC values of the pCR prediction models for the 2 readers. Our data supports multiparametric MRI-based radiomic models for early prediction of NAST response in TNBC.

Spectrally Tunable Lead-Free Perovskite Rb2ZrCl6:Te for Information Encryption and X-ray Imaging.

A series of lead-free Rb2ZrCl6:xTe4+ (x = 0%, 0.1%, 0.5%, 1.0%, 2.0%, 3.0%, 5.0%, 10.0%) perovskite materials were synthesized through a hydrothermal method in this work. The substitution of Te4+ for Zr in Rb2ZrCl6 was investigated to examine the effect of Te4+ doping on the spectral properties of Rb2ZrCl6 and its potential applications. The incorporation of Te4+ induced yellow emission of triplet self-trapped emission (STE). Different luminescence wavelengths were regulated by Te4+ concentration and excitation wavelength, and under a low concentration of Te4+ doping (x ≤ 0.1%), different types of host STE emission and Te4+ triplet state emission could be achieved through various excitation energies. These luminescent properties made it suitable for applications in information encryption. When Te4+ was doped at high concentrations (x ≥ 1%), yellow triplet state emission of Te4+ predominated, resulting in intense yellow emission, which stemmed from strong exciton binding energy and intense electron-phonon coupling. In addition, a Rb2ZrCl6:2%Te4+@RTV scintillating film was fabricated and a spatial resolution of 3.7 lp/mm was achieved, demonstrating the potential applications of Rb2ZrCl6:xTe4+ in nondestructive detection and bioimaging.

Cannabinoid receptor 2 selective agonist alleviates systemic sclerosis by inhibiting Th2 differentiation through JAK/SOCS3 signaling.

Systemic sclerosis (SSc) poses a significant challenge in autoimmunology, characterized by the development of debilitating fibrosis of skin and internal organs. The pivotal role of dysregulated T cells, notably the skewed polarization toward Th2 cells, has been implicated in the vascular damage and progressive fibrosis observed in SSc. In this study, we explored the underlying mechanisms by which cannabinoid receptor 2 (CB2) highly selective agonist HU-308 restores the imbalance of T cells to alleviate SSc. Using a bleomycin-induced SSc (BLM-SSc) mouse model, we demonstrated that HU-308 effectively attenuates skin and lung fibrosis by specifically activating CB2 on CD4+ T cells to inhibit the polarization of Th2 cells in BLM-SSc mice, which was validated by Cnr2-specific-deficient mice. Different from classical signaling downstream of G protein-coupled receptors (GPCRs), HU-308 facilitates the expression of SOCS3 protein and subsequently impedes the IL2/STAT5 signaling pathway during Th2 differentiation. The deficiency of SOCS3 partially mitigated the impact of HU-308. Analysis of a cohort comprising 80 SSc patients and 82 healthy controls revealed an abnormal elevation in the Th2/Th1 ratio in SSc patients. The proportion of Th2 cells showed a significant positive correlation with mRSS score and positivity of anti-Scl-70. Administration of HU-308 to PBMCs and peripheral CD4+ T cells from SSc patients led to the upregulation of SOCS3, which effectively suppressed the aberrantly activated STAT5 signaling pathway and the proportion of CD4+IL4+ T cells. In conclusion, our findings unveil a novel mechanism by which the CB2 agonist HU-308 ameliorates fibrosis in SSc by targeting and reducing Th2 responses. These insights provide a foundation for future therapeutic approaches in SSc by modulating Th2 responses.

MUSTANG: Multi-sample spatial transcriptomics data analysis with cross-sample transcriptional similarity guidance.

Spatially resolved transcriptomics has revolutionized genome-scale transcriptomic profiling by providing high-resolution characterization of transcriptional patterns. Here, we present our spatial transcriptomics analysis framework, MUSTANG (MUlti-sample Spatial Transcriptomics data ANalysis with cross-sample transcriptional similarity Guidance), which is capable of performing multi-sample spatial transcriptomics spot cellular deconvolution by allowing both cross-sample expression-based similarity information sharing as well as spatial correlation in gene expression patterns within samples. Experiments on a semi-synthetic spatial transcriptomics dataset and three real-world spatial transcriptomics datasets demonstrate the effectiveness of MUSTANG in revealing biological insights inherent in the cellular characterization of tissue samples under study.

Unbiased metastatic niche-labeling identifies estrogen receptor-positive macrophages as a barrier of T cell infiltration during bone colonization.

Microenvironment niches determine cellular fates of metastatic cancer cells. However, robust and unbiased approaches to identify niche components and their molecular profiles are lacking. We established Sortase A-Based Microenvironment Niche Tagging (SAMENT), which selectively labels cells encountered by cancer cells during metastatic colonization. SAMENT was applied to multiple cancer models colonizing the same organ and the same cancer to different organs. Common metastatic niche features include macrophage enrichment and T cell depletion. Macrophage niches are phenotypically diverse between different organs. In bone, macrophages express the estrogen receptor alpha (ERα) and exhibit active ERα signaling in male and female hosts. Conditional knockout of Esr1 in macrophages significantly retarded bone colonization by allowing T cell infiltration. ERα expression was also discovered in human bone metastases of both genders. Collectively, we identified a unique population of ERα+ macrophages in the metastatic niche and functionally tied ERα signaling in macrophages to T cell exclusion during metastatic colonization. HIGHLIGHTS: SAMENT is a robust metastatic niche-labeling approach amenable to single-cell omics.Metastatic niches are typically enriched with macrophages and depleted of T cells.Direct interaction with cancer cells induces ERα expression in niche macrophages. Knockout of Esr1 in macrophages allows T cell infiltration and retards bone colonization.

GWAS unravels acid phosphatase ACP2 as a photosynthesis regulator under phosphate starvation conditions through modulating serine metabolism in rice.

Inorganic phosphorus (Pi) deficiency significantly impacts plant growth, development, and photosynthetic efficiency. This study evaluated 206 rice accessions from a MiniCore population under both Pi-sufficient (Pi+) and Pi-starvation (Pi-) conditions in the field to assess photosynthetic phosphorus use efficiency (PPUE), defined as the ratio of AsatPi- to AsatPi+. A genome-wide association study and differential gene expression analyses identified an acid phosphatase gene (ACP2) that responds strongly to phosphate availability. Overexpression and knockout of ACP2 led to a 67% increase and 32% decrease in PPUE, respectively, compared with wild type. Introduction of an elite allele A, by substituting the v5 SNP G with A, resulted in an 18% increase in PPUE in gene-edited ACP2 rice lines. The phosphate-responsive gene PHR2 was found to transcriptionally activate ACP2 in parallel with PHR2 overexpression, resulting in an 11% increase in PPUE. Biochemical assays indicated that ACP2 primarily catalyzes the hydrolysis of phosphoethanolamine and phospho-L-serine. In addition, serine levels increased significantly in the ACP2v8G-overexpression line, along with a concomitant decrease in the expression of all nine genes involved in the photorespiratory pathway. Application of serine enhanced PPUE and reduced photorespiration rates in ACP2 mutants under Pi-starvation conditions. We deduce that ACP2 plays a crucial role in promoting photosynthesis adaptation to Pi starvation by regulating serine metabolism in rice.

Survey data on livelihoods and inputs and outputs of crop production in Quzhou county on the North China Plain.

Farmers' decisions on crop choice, management practices, and livelihood strategies are essential to agricultural sustainability. This data article describes three datasets on crop production in Quzhou, a county in the central part of North China Plain. The three datasets cover different scales. The village dataset assembles basic data on all 342 villages of Quzhou county, including information on population, land area, crop grown, labour, irrigation and markets. Data was sourced from the yearbook data of 2017 and a village cadres survey in 2018. The village dataset was used to create a village typology from which 35 villages belonging to seven village types (five for each type) were selected for stratified random sampling to collect information on farm characteristics and cropping practices. We surveyed these 35 villages, interviewing fifteen farmer households per village (525 in total) in 2020. The interviewees represented two farm management models: smallholder farms and business farms. The resulting household dataset provides farm-level data, including demographic data of farming decision-makers and the number of household members, land use and machinery resources, crop production management practices, and government subsidies. The crop-level dataset was derived from the household survey and included input-output inventories for each crop grown during one year on each field greater than 1/30th ha (1/2 mu) on the 525 surveyed farms within a year. This dataset comprises information on cropping practices in 1352 fields. The three datasets provide a basis for analyses on cropping practices and sustainability attributes of farms and crops in a typical agricultural county on the North China Plain.

Siglec-15/sialic acid axis as a central glyco-immune checkpoint in breast cancer bone metastasis.

Immunotherapy is a promising approach for treating metastatic breast cancer (MBC), offering new possibilities for therapy. While checkpoint inhibitors have shown great progress in the treatment of metastatic breast cancer, their effectiveness in patients with bone metastases has been disappointing. This lack of efficacy seems to be specific to the bone environment, which exhibits immunosuppressive features. In this study, we elucidate the multiple roles of the sialic acid-binding Ig-like lectin (Siglec)-15/sialic acid glyco-immune checkpoint axis in the bone metastatic niche and explore potential therapeutic strategies targeting this glyco-immune checkpoint. Our research reveals that elevated levels of Siglec-15 in the bone metastatic niche can promote tumor-induced osteoclastogenesis as well as suppress antigen-specific T cell responses. Next, we demonstrate that antibody blockade of the Siglec-15/sialic acid glyco-immune checkpoint axis can act as a potential treatment for breast cancer bone metastasis. By targeting this pathway, we not only aim to treat bone metastasis but also inhibit the spread of metastatic cancer cells from bone lesions to other organs.

An integrated wearable sticker based on extended-gate AlGaN/GaN high electron mobility transistors for real-time cortisol detection in human sweat.

Cortisol hormone imbalances can be detected through non-invasive sweat monitoring using field-effect transistor (FET) biosensors, which provide rapid and sensitive detection. However, challenges like skin compatibility and integration with sweat collection have hindered FET biosensors as wearable sensing platforms. In this study, we present an integrated wearable sticker for real-time cortisol detection based on an extended-gate AlGaN/GaN high electron mobility transistor (HEMT) combined with a soft bottom substrate and flexible channel for sweat collection. The developed devices exhibit excellent linearity (R2 = 0.990) and a high sensitivity of 1.245 µA dec-1 for cortisol sensing from 1 nM to 100 µM in high-ionic-strength solution, with successful cortisol detection demonstrated using authentic human sweat samples. Additionally, the chip's microminiature design effectively reduces bending impact during the wearable process of traditional soft binding sweat sensors. The extendedgate structure design of the HEMT chip enhances both width-to-length ratio and active sensing area, resulting in an exceptionally low detection limit of 100 fM. Futhermore, due to GaN material's inherent stability, this device exhibits long-term stability with sustained performance within a certain attenuation range even after 60 days. These stickers possess small, lightweight, and portable features that enable real-time cortisol detection within 5 minutes through direct sweat collection. The application of this technology holds great potential in the field of personal health management, facilitating users to conveniently monitor their mental and physical conditions.

Diffusion Tensor Imaging for Characterizing Changes in Triple-Negative Breast Cancer During Neoadjuvant Systemic Therapy.

BACKGROUND: Assessment of treatment response in triple-negative breast cancer (TNBC) may guide individualized care for improved patient outcomes. Diffusion tensor imaging (DTI) measures tissue anisotropy and could be useful for characterizing changes in the tumors and adjacent fibroglandular tissue (FGT) of TNBC patients undergoing neoadjuvant systemic treatment (NAST). PURPOSE: To evaluate the potential of DTI parameters for prediction of treatment response in TNBC patients undergoing NAST. STUDY TYPE: Prospective. POPULATION: Eighty-six women (average age: 51 ± 11 years) with biopsy-proven clinical stage I-III TNBC who underwent NAST followed by definitive surgery. 47% of patients (40/86) had pathologic complete response (pCR). FIELD STRENGTH/SEQUENCE: 3.0 T/reduced field of view single-shot echo-planar DTI sequence. ASSESSMENT: Three MRI scans were acquired longitudinally (pre-treatment, after 2 cycles of NAST, and after 4 cycles of NAST). Eleven histogram features were extracted from DTI parameter maps of tumors, a peritumoral region (PTR), and FGT in the ipsilateral breast. DTI parameters included apparent diffusion coefficients and relative diffusion anisotropies. pCR status was determined at surgery. STATISTICAL TESTS: Longitudinal changes of DTI features were tested for discrimination of pCR using Mann-Whitney U test and area under the receiver operating characteristic curve (AUC). A P value <0.05 was considered statistically significant. RESULTS: 47% of patients (40/86) had pCR. DTI parameters assessed after 2 and 4 cycles of NAST were significantly different between pCR and non-pCR patients when compared between tumors, PTRs, and FGTs. The median surface/average anisotropy of the PTR, measured after 2 and 4 cycles of NAST, increased in pCR patients and decreased in non-pCR patients (AUC: 0.78; 0.027 ± 0.043 vs. -0.017 ± 0.042 mm2 /s). DATA CONCLUSION: Quantitative DTI features from breast tumors and the peritumoral tissue may be useful for predicting the response to NAST in TNBC. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 4.

Analysis of compression damage pattern and strength influencing factors in graphite-tailing-filled soilbags.

To realize the resourceful use of soilbags filled with graphite tailings, their load-bearing and deformation characteristics must be fully understood. In this study, the following results were obtained by performing geometric testing of water-filled sealing bags and uniaxial compression tests of soilbags filled with graphite tailings. The volume of the soilbag expressed in rectangular form was approximately 0.773 times the actual volume. The types of compression damage to soilbags can be defined as surface damage and overall damage. The surface damage load increases with decreasing filling density and decreases with decreasing soilbag size. Moreover, the higher the tensile capacity of the soilbag material and the lower the friction between the soilbags, the greater the surface damage load. The overall damage load increased with an increase in the tensile strength of the soilbag material and decreased with an increase in the degree of filling; the overall damage load was greater for large-sized soilbags at high degrees of filling. Thus, the existing theoretical calculation method cannot accurately calculate the damage load of soilbags filled with graphite tailings, and the test results deviate from the theoretical calculation results, with the latter showing an increasing damage load with a decreasing filling degree.