Search Results (122)

Cancer-associated fibroblasts (CAFs) restructure collagen hydrogels via actomyosin-driven fibril bundling and crosslinking, increasing polymer density to generate mechanical stress that accelerates tumor proliferation. Conventional hydrogel models lack spatial heterogeneity, thus obscuring how localized stiffness gradients regulate cell cycle progression. To address this, we developed a collagen hydrogel-based microtissue platform integrated with programmable microstrings (single/double tethering), enabling real-time quantification of gel densification mechanics and force transmission efficiency. Using this system combined with FUCCI cell cycle biosensors and molecular perturbations, we demonstrate that CAF-polarized contraction increases hydrogel stiffness (350 → 775 Pa) and reduces pore diameter (5.0 → 1.9 μm), activating YAP/TAZ nuclear translocation via collagen–integrin–actomyosin cascades. This drives a 2.4-fold proliferation increase and accelerates G1/S transition in breast cancer cells. Pharmacological inhibition of YAP (verteporfin), actomyosin (blebbistatin), or collagen disruption (collagenase) reversed mechanotransduction and proliferation. Partial rescue upon CYR61 knockdown revealed compensatory effector networks. Our work establishes CAF-remodeled hydrogels as biomechanical regulators of tumor growth and positions gel-based mechanotherapeutics as promising anti-cancer strategies. Full article

Background/Objectives: Colorectal cancer (CRC) remains a leading cause of cancer-related mortality globally, highlighting the urgent need for novel therapeutic strategies. This study aimed to investigate the anticancer potential of sodium pentaborate pentahydrate (NaB) in CRC by evaluating its effects on human colorectal cancer cell lines and elucidating underlying molecular mechanisms. Methods: The cytotoxic and molecular effects of NaB were assessed in three human CRC cell lines (HCT-116, HT-29, and COLO-205) and one normal colon epithelial cell line (CCD-18CO). Cell viability assays were conducted to determine time- and dose-dependent responses. Apoptosis, cell cycle progression, colony formation, and migration capacity were evaluated. Gene and protein expression analyses were performed to examine apoptosis-related, DNA damage response, cell cycle, and Hippo signaling pathway components. Results: NaB significantly reduced cancer cell viability in a time- and dose-dependent manner, with minimal cytotoxicity to normal colon cells. It induced marked apoptosis, especially in HCT-116 and COLO-205 cells, and caused G2/M cell cycle arrest. In HCT-116 cells, NaB suppressed proliferation by downregulating PCNA and MKI-67 and reduced colony formation and migration. Molecular analyses revealed upregulation of pro-apoptotic BAX and downregulation of BCL-2, ATM, ATR, and cell cycle–related genes. NaB also inhibited oncogenic Hippo signaling by enhancing YAP1 phosphorylation and decreasing CTGF and CYR61 expression. Conclusions: These findings demonstrate that sodium pentaborate pentahydrate exerts selective anticancer effects on colorectal cancer cells through the induction of apoptosis, cell cycle arrest, and suppression of key oncogenic pathways. NaB represents a promising candidate for further development as a therapeutic agent in CRC treatment. Full article

Wheat stripe rust (Puccinia striiformis f. sp. tritici, Pst) resistance and agronomic traits are crucial determinants of wheat yield. Elucidating the quantitative trait loci (QTLs) associated with these essential traits can furnish valuable genetic resources for improving both the yield potential and disease resistance in wheat. Lantian 31 is an excellent Chinese winter wheat cultivar; multi-environment phenotyping across three ecological regions (2022–2024) confirmed stable adult-plant resistance (IT 1–2; DS < 30%) against predominant Chinese Pst races (CYR31–CYR34), alongside superior thousand-kernel weight (TKW) and kernel morphology. Here, we dissected the genetic architecture of these traits using a total of 234 recombinant inbred lines (RILs) derived from a cross between Lantian 31 and the susceptible cultivar Avocet S (AvS). Genotyping with a 15K SNP array, complemented by 660K SNP-derived KASP and SSR markers, identified four stable QTLs for stripe rust resistance (QYrlt.swust-1B, -1D, -2D, -6B) and eight QTLs governing plant height (PH), spike length (SL), and kernel traits. Notably, QYrlt.swust-1B (1BL; 29.9% phenotypic variance) likely represents the pleiotropic Yr29/Lr46 locus, while QYrlt.swust-1D (1DL; 22.9% variance) is the first reported APR locus on chromosome 1DL. A pleiotropic cluster on 1B (670.4–689.9 Mb) concurrently enhanced the TKW and the kernel width and area, demonstrating Lantian 31’s dual utility as a resistance and yield donor. The integrated genotyping pipeline—combining 15K SNP discovery, 660K SNP fine-mapping, and KASP validation—precisely delimited QYrlt.swust-1B to a 1.5 Mb interval, offering a cost-effective model for QTL resolution in common wheat. This work provides breeder-friendly markers and a genetic roadmap for pyramiding durable resistance and yield traits in wheat breeding programs. Full article

Stripe rust, caused by Puccinia striiformis f. sp. tritici (Pst), threatens global wheat production. Breeding resistant varieties is a key to disease control. In this study, 198 modern wheat varieties were phenotyped with the prevalent Pst races CYR33 and CYR34 at the seedling stage and with mixed Pst races at the adult-plant stage. Seven stable resistance varieties with infection type (IT) ≤ 2 and disease severity (DS) ≤ 20% were found, including five Chinese accessions (Zhengpinmai8, Zhengmai1860, Zhoumai36, Lantian36, and Chuanmai32), one USA accession (GA081628-13E16), and one Pakistani accession (Pa12). The genotyping applied a 55K wheat single-nucleotide polymorphism (SNP) array. A genome-wide association study (GWAS) identified 14 QTL using a significance threshold of p ≤ 0.001, which distributed on chromosomes 1B (4), 1D (2), 2B (4), 6B, 6D, 7B, and 7D (4 for CYR33, 7 for CYR34, 3 for mixed Pst races), explaining 6.04% to 18.32% of the phenotypic variance. Nine of these QTL were potentially novel, as they did not overlap with the previously reported Yr or QTL loci within a ±5.0 Mb interval (consistent with genome-wide LD decay). The haplotypes and resistance effects were evaluated to identify the favorable haplotype for each QTL. Candidate genes within the QTL regions were inferred based on their transcription levels following the stripe rust inoculation. These resistant varieties, QTL haplotypes, and favorable alleles will aid in wheat breeding for stripe rust resistance. Full article

Wheat (Triticum aestivum L.) is the world’s most indispensable staple crop and a vital source of food for human diet. Wheat stripe rust, caused by Puccinia striiformis f. sp. tritici (Pst), constitutes a severe threat to wheat production and in severe cases, the crop fails completely. Anmai1350 (AM1350) is moderately resistant to leaf rust and powdery mildew, and highly susceptible to sheath blight and fusarium head blight. We found that the length and area of mycelium in AM1350 cells varied at different time points of Pst infection. To investigate the molecular mechanism of AM1350 resistance to Pst, we performed transcriptome sequencing (RNA-seq). In this study, we analyzed the transcriptomic changes of the seedling leaves of AM1350 at different stages of Pst infection at 0 h post-infection (hpi), 6 hpi, 24 hpi, 48 hpi, 72 hpi, and 120 hpi through RNA-seq. Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) was used to validate RNA-seq data. It was determined that there were differences in the differentially expressed genes (DEGs) of AM1350, and the upregulation and downregulation of the DEGs changed with the time of infection. At different time points, there were varying degrees of enrichment in the response pathways of AM1350, such as the ”MAPK signaling pathway–plant”, the “plant–pathogen interaction” pathway and other pathways. After Pst infected AM1350, the reactive oxygen species (ROS) content gradually increases. The ROS is toxic to Pst, promotes the synthesis of phytoalexins, and inhibits the spread of Pst. As a result, AM1350 shows resistance to Pst race CYR34. The main objective of this study is to provide a better understanding for resistance mechanisms of wheat in response to Pst infections and to avoid production loss. Full article

Myeloproliferative neoplasms (MPNs) are a group of rare blood cancers characterized by the excessive production of blood cells in the bone marrow. These disorders arise from acquired genetic driver mutations, with or without underlying genetic predispositions, resulting in the uncontrolled production of red blood cells, white blood cells, or platelets. The excessive cell production and abnormal signaling from driver mutations cause chronic inflammation and a higher risk of blood clots and vascular complications. The primary goals of MPN treatment are to induce remission, improve quality of life and survival, as well as to reduce the risk of complications such as thrombosis, vascular events, and leukemic transformation. This review provides a comprehensive update on the diagnosis and therapeutic advancements in major MPN subtypes, including chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, and primary myelofibrosis. It examines these complex diseases from a molecular and evolutionary perspective, highlighting key clinical trials’ long-term follow-up and therapies targeting driver mutations that have transformed treatment strategies. Additionally, several important advancements in addressing challenges such as anemia in myelofibrosis, along with promising emerging therapies, are also discussed. Full article

Background/Objectives: Oxidative stress plays a pivotal role in skin aging and carcinogenesis. Phytochemicals such as sulforaphane (SF, from broccoli sprouts or seeds) or curcumin (CUR, from turmeric) can be highly protective against this stress. They each induce a suite of cytoprotective and antioxidant enzymes that are coordinately transcribed via the Keap1-Nrf2-ARE pathway in mammals, such as the prototypical cytoprotective enzyme NAD(P)H dehydrogenase 1 (NQO1). Methods: Eighteen healthy human volunteers (9 males, 9 females, aged 18–69. were randomized to receive daily glucoraphanin (GR), which is converted to SF upon ingestion (450 mg; 1 mmol), CUR (1000 mg; 2.7 mmol), or both (450 mg GR + 1000 mg CUR), as oral supplements. After 8 days of a diet low in both compounds, blood and urine were collected for compliance and biomarker measurements. Randomized spots on the buttock’s skin were exposed to 2 x M.E.D. of UVB, and punch biopsies were obtained 1 and 3 days later for biomarker and histological measurement. Erythema was measured with a chromameter daily for 3 consecutive days following UVB. The process was repeated after receiving oral supplements, both with and without UVB exposure. Results: Compared to baseline, each treatment (n = 6 for each) induced NQO1 mRNA levels in skin biopsies: 3.1-fold with GR, 3.3-fold with CUR, and 3.6-fold with the combination of GR and CUR. Across all treatments (n = 18), expression of the pro-inflammatory cytokines IL-1β and TNF-α were reduced, as were IL-6, IL-17, STING, and CYR61, though less robustly. Modulation of these biomarkers persisted, but was less pronounced, in biopsies taken following UV exposure. The presence of SF and its metabolites in the skin post-treatment was confirmed by examining 6 of 12 subjects who ingested GR. Supplement effects on erythema following UV exposure were not significant, and no significant changes were measured in the same biomarkers in blood cells (PBMC), or by counting dyskeratotic keratinocytes. Supplements were well tolerated and compliance was excellent. Conclusions: Oral GR and CUR are well tolerated and have for the first time been shown to result in increased expression of cytoprotective genes and reduced expression of inflammatory cytokine genes in human skin in vivo. This mechanism-based clinical study suggests that an antioxidant, anti-inflammatory, and cytoprotective benefit from these oral supplements is delivered to the skin in humans. Full article

Cysteine-rich protein 61 (CYR61) is a matricellular protein in the CCN family that is involved in cellular adhesion, migration, proliferation, and angiogenesis. CYR61 interacts with integrins α6β1, αvβ3, αvβ5, and αIIbβ3 to modulate tumor progression and metastasis while modifying the tumor microenvironment. CYR61 exhibits context-dependent roles in cancer, acting as both a tumor promoter and suppressor. Increased CYR61 expression is linked to extracellular matrix remodeling, immune modulation, and integrin-mediated signaling, making it a potential prognostic biomarker and therapeutic target. Emerging research highlights the utility of CYR61 in liquid biopsies for cancer detection and monitoring. Integrin-targeted therapies, including CYR61-blocking antibodies and CAR-T approaches, offer novel treatment strategies. However, therapy-induced toxicity and resistance remain challenges with these strategies. The further elucidation of the molecular mechanisms of CYR61 may enhance targeted therapeutic interventions and improve patient outcomes. Full article

Increasing antifungal resistance and side effects of existing drugs demand alternative approaches for treating Candida (C.) infections. This study aimed to comprehensively evaluate the antifungal efficacy of myricetin (MYR), a natural flavonoid, against both fluconazole (FLC)-resistant and susceptible clinical Candida strains, with a particular focus on its inhibitory effects on C. albicans biofilms. Antifungal susceptibility was evaluated on Candida spp. by the broth microdilution method, and the impact of myricetin on C. albicans biofilms was determined using the Cell Counting Kit-8 (CCK-8) assay. To understand the molecular mechanisms underlying the antibiofilm properties of myricetin, expression analysis of genes in the RAS1/cAMP/EFG1 pathway (ALS3, HWP1, ECE1, UME6, HGC1) and cAMP-dependent protein kinase regulation (RAS1, CYR1, EFG1) involved in the transition from yeast to hyphae was performed. Field emission scanning electron microscopy (FESEM) was used to study the ultrastructural changes and morphological dynamics of Candida biofilms after exposure to MYR and FLC. The in vivo toxicity of myricetin was evaluated by survival analysis using the Galleria mellonella model. Myricetin significantly suppressed key genes related to hyphae development (RAS1, CYR1, EFG1, UME6, and HGC1) and adhesion (ALS3 and HWP1) in both clinical and reference Candida strains at a concentration of 640 µg/mL. FESEM analysis revealed that myricetin inhibited hyphae growth and elongation in C. albicans. This study highlights the promising antibiofilm potential of myricetin through a significant inhibition of biofilm formation and hyphal morphogenesis. Full article

Background: The thymus is the central hub of T-cell differentiation, where epithelial cells guide the process of their maturation. Objective: Our goal was to identify and describe progenitor cells within the human thymus that can differentiate into epithelial cells. Methods: When we plated enriched thymic cells in 3D culture conditions, rare individual cells capable of self-renewal and differentiation formed spheroids. Results: Both neonatal and adult thymuses produced similar numbers of spheroids, suggesting that progenitor potential remains consistent across age groups. Some cells within the spheres express genes typical of mature epithelial cells, while others express genes associated with the immature compartment active during thymic organogenesis. However, there were also cells expressing PDGFRβ. We treated the tissues with 2-deoxyguanosine before digestion, which improved the yield of progenitor cells. We also cultured the enriched stromal thymocytes with Cyr61 and Interleukin-22, which affected the spheroid size. Conclusions: Our efforts towards thymic reconstitution are ongoing, but our research uncovers previously unknown characteristics of the elusive epithelial progenitor population. Full article

Brain arteriovenous malformations (bAVMs) are complex vascular lesions with significant clinical risks. The Hippo signaling pathway, particularly its downstream effector YAP, plays a crucial role in angiogenesis and vascular remodeling. This study investigates the role of YAP and related molecular markers in bAVMs, focusing on the effects of embolization. Immunohistochemical analysis was conducted on tissue samples from bAVM patients (n = 127), as well as on healthy blood vessels (n = 17). YAP, HIF-1α, FGFR1, CTGF, and CYR61 expression were quantified and correlated with clinical parameters. Results: In healthy vessels, YAP exhibited nuclear localization in (sub)endothelial cells and the tunica media, while CTGF and CYR61 were detected in the cytoplasm and extracellular matrix. The expression of YAP, CTGF, and CYR61 was significantly lower in bAVM tissues. Embolized bAVMs exhibited significantly higher expression of YAP, CTGF, and CYR61 compared to non-embolized tissues, suggesting a link between embolization and pro-angiogenic signaling. Additionally, FGFR1 was upregulated in embolized tissues. These results suggest that upregulation of YAP expression via the Hippo pathway might play a key role in bAVM pathophysiology. Embolization may further promote vascular remodeling. Dysregulation of YAP and related molecules in bAVMs warrants further studies to explore potential therapeutic strategies targeting the Hippo pathway. Full article

We investigated the transcription of circadian clock genes in publicly available datasets of gene expression in medulloblastoma (MB) tissues using the R2 Genomics Analysis and Visualization Platform. Differential expression of the core clock genes among the four consensus subgroups of MB (defined in 2012 as Group 3, Group 4, the SHH group, and the WNT group) included the core clock genes (CLOCK, NPAS2, PER1, PER2, CRY1, CRY2, BMAL1, BMAL2, NR1D1, and TIMELESS) and genes which encode proteins that regulate the transcription of clock genes (CIPC, FBXL21, and USP2). The over-expression of several clock genes, including CIPC, was found in individuals with the isochromosome 17q chromosomal aberration in MB Group 3 and Group 4. The most significant biological pathways associated with clock gene expression were ribosome subunits, phototransduction, GABAergic synapse, WNT signaling pathway, and the Fanconi anemia pathway. Survival analysis of clock genes was examined using the Kaplan–Meier method and the Cox proportional hazards regression model through the R2 Genomics Platform. Two clock genes most significantly related to survival were CRY1 and USP2. The data suggest that several clock proteins, including CRY1 and USP2, be investigated as potential therapeutic targets in MB. Full article

Accurately assessing the carbon sink intensity of China’s ecosystem is crucial for achieving carbon neutrality. However, existing ecosystem process models have significant uncertainties in net ecosystem productivity (NEP) estimates due to the lack of or insufficient description of phenological regulation. Although plant developmental factors have been proven to significantly influence autumn phenology, they have not been systematically incorporated into autumn phenology models. In this study, we modified the autumn phenology model (cold-degree-day, CDD) by incorporating the growing-season gross primary productivity (GPP) and the start of growing season (SOS) and used it as a constraint to improve the CASA model for quantifying NEP across China from 2003 to 2021. Validation results showed that the CDD model incorporating developmental factors significantly improved the simulation accuracy at the end of the growing season (EOS). More importantly, compared with flux tower observations, the NEP derived from the improved CASA model based on the above phenology model showed a 15.34% reduction in root mean square error and a 74% increase in the coefficient of determination relative to the original model. During the study period, China’s multiyear average total NEP was 489.67 ± 38.27 Tg C/yr, with the highest found in evergreen broadleaf forests and the lowest detected in shrublands. Temporally, China’s NEP demonstrated an overall increasing trend with an average rate of 1.75 g C/m²/yr². However, the growth rate of NEP remained far below concurrent carbon emissions from fossil fuel combustion totally, especially for eastern China, while the northeastern regions performed relatively better. The improved regional carbon flux estimation framework proposed in this study will provide important support for developing future climate change mitigation strategies. Full article

Stripe rust, induced by Puccinia striiformis f. sp. tritici (Pst), is one of the most destructive fungal diseases of wheat worldwide. Thinopyrum ponticum, a significant wild relative for wheat improvement, exhibits innate immunity to this disease. To transfer the stripe rust resistance gene from Th. ponticum to wheat, two translocation lines, SN21171 and SN52684, were produced through distant hybridization techniques. Disease evaluation results showed that these two lines were immune to Pst species CYR32 at the adult plant stage. Molecular cytogenetic analyses and specific intron-targeting markers amplification results revealed that SN21171 and SN52684 harbor several T3E^b-3DS·3DL and T1E^b-1BS·1BL translocation chromosomes. Furthermore, the comparison of the chromosome karyotype from two translocation lines and their recurrent parent YN15, revealed that structural variation occurred in chromosomes 2A, 5A, 2B, 4B, 5B, and 6B in SN21171 and chromosomes 5A, 3B, 4B, 5B, 6B, and 7B in SN52684. Agronomic trait assessments uncovered advantageous properties in both lines, with SN21171 matching the recurrent parent and SN52684 exhibiting elevated higher grain number per main spike and increased thousand grain weight. These two translocation lines and specific markers may apply to wheat stripe rust-resistance breeding. Full article

Basic inventory is required for proper understanding and utilization of Earth’s natural resources, especially with increasing soil degradation and species loss. Soil carbon is newly refined at >30,000 Gt C (gigatonnes C), ten times above prior totals. Soil organic carbon (SOC) is up to 24,000 Gt C, plus plant stocks at ~2400 Gt C, both above- and below-ground, hold >99% of Earth’s biomass. On a topographic surface area of 25 Gha with mean 21 m depth, Soil has more organic carbon than all trees, seas, fossil fuels, or the Atmosphere combined. Soils are both the greatest biotic carbon store and the most active CO₂ source. Values are raised considerably. Disparity is due to lack of full soil depth survey, neglect of terrain, and other omissions. Herein, totals for mineral soils, Permafrost, and Peat (of all forms and ages), are determined to full depth (easily doubling shallow values), then raised for terrain that is ignored in all terrestrial models (doubling most values again), plus SOC in recalcitrant glomalin (+25%) and friable saprock (+26%). Additional factors include soil inorganic carbon (SIC some of biotic origin), aquatic sediments (SeOC), and dissolved fractions (DIC/DOC). Soil biota (e.g., forests, fungi, bacteria, and earthworms) are similarly upgraded. Primary productivity is confirmed at >220 Gt C/yr on land supported by Barrow’s “bounce” flux, C/O isotopes, glomalin, and Rubisco. Priority issues of species extinction, humic topsoil loss, and atmospheric CO₂ are remedied by SOC restoration and biomass recycling via (vermi-)compost for 100% organic husbandry under Permaculture principals, based upon the Scientific observation of Nature. Full article