Analysis of gut microbiota-derived metabolites regulating pituitary neuroendocrine tumors through network pharmacology.

Pituitary neuroendocrine tumors (PitNETs) are a special class of tumors of the central nervous system that are closely related to metabolism, endocrine functions, and immunity. In this study, network pharmacology was used to explore the metabolites and pharmacological mechanisms of PitNET regulation by gut microbiota. The metabolites of the gut microbiota were obtained from the gutMGene database, and the targets related to the metabolites and PitNETs were determined using public databases. A total of 208 metabolites were mined from the gutMGene database; 1,192 metabolite targets were screened from the similarity ensemble approach database; and 2,303 PitNET-related targets were screened from the GeneCards database. From these, 392 overlapping targets were screened between the metabolite and PitNET-related targets, and the intersection between these overlapping and gutMGene database targets (223 targets) were obtained as the core targets (43 targets). Using the protein-protein interaction (PPI) network analysis, Kyoto encyclopedia of genes and genomes (KEGG) signaling pathway and metabolic pathway analysis, CXCL8 was obtained as a hub target, tryptophan metabolism was found to be a key metabolic pathway, and IL-17 signaling was screened as the key KEGG signaling pathway. In addition, molecular docking analysis of the active metabolites and target were performed, and the results showed that baicalin, baicalein, and compound K had good binding activities with CXCL8. We also describe the potential mechanisms for treating PitNETs using the information on the microbiota (Bifidobacterium adolescentis), signaling pathway (IL-17), target (CXCL8), and metabolites (baicalin, baicalein, and compound K); we expect that these will provide a scientific basis for further study.

Achieving a Balance of Good Quantum Efficiency and Thermal Stability in the Y2CaScAl3GeO12:Cr3+ Broadband Phosphor for Multiple NIR Spectroscopy Applications.

Near-infrared phosphor-converted light emitting diodes (NIR pc-LEDs) are considered as desirable NIR light sources to satisfy current needs owing to their numerous remarkable features. Nevertheless, as an essential component, previously reported NIR phosphors with broadband emission often suffer from inferior efficiency or thermal stability, therefore restricting their use and promotion. Herein, a novel Cr3+-doped garnet phosphor Y2CaScAl3GeO12:Cr3+ (YCSAG:Cr3+) is developed via regulating the near-neighbor coordination polyhedron. Under the excitation of blue light, it exhibits a broadband NIR emission peaking near 800 nm with a full width at half-maximum (fwhm) exceeding 150 nm, owing to the increased structural distortion of the octahedron. Particularly, due to the enhanced local structural rigidity induced by lattice shrinkage, the optimal sample achieves a balance of high internal quantum efficiency (IQE) of approximately 83% and thermal stability of approximately 90% at 393 K, facilitating its practical application as an NIR light source. Eventually, using the typical YCSAG:0.04Cr3+ phosphor and 450 nm blue LED chip, a high-performance NIR pc-LED device has been manufactured, demonstrating potential applications in anticounterfeiting and night vision.

Seedling dynamics differ between canopy species and understory species in a tropical seasonal rainforest, SW China.

We used 11 years of census data from 450 seedling quadrats established in a 20-ha forest dynamics plot to study seedling dynamics in tree species of a tropical seasonal rainforest in Xishuangbanna, southwestern China. We found that overall seedling recruitment rate and relative growth rate were higher in the rainy season than in the dry season. Both the recruitment rate of seedlings from canopy tree species (two species) and the relative growth rate of seedlings from understory species (nine species) were higher in the rainy season than in the dry season. However, in the rainy season, the recruitment rate of seedlings was higher for canopy tree species than for understory tree species. In addition, relative growth rate of seedlings was higher in the canopy species than in understory seedlings in the dry season. We also observed that, in both rainy and dry seasons, mortality rate of seedlings was higher for canopy species than for understory species. Overall, canopy tree species appear to have evolved a flexible strategy to adapt to the seasonal changes of a monsoon climate. In contrast, understory tree species seem to have adopted a conservative strategy. Specifically, these species mainly release seedlings in the rainy season and maintain relatively stable populations with a lower mortality rate and recruitment rate in both dry and rainy seasons. Our study suggests that canopy and understory seedling populations growing in forest understory may respond to future climate change scenarios with distinct regeneration strategies.

Dynamic change of lymphocytes associated with short-term prognosis in anti-MDA5-positive dermatomyositis with interstitial lung disease: a multicenter retrospective study.

Lymphopenia is a unique manifestation of anti-MDA5 positive dermatomyositis with interstitial lung disease (MDA5 + DM-ILD). This study aimed to investigate the relationship between dynamic changes in peripheral lymphocytes and short-term prognosis in patients of MDA5 + DM-ILD. Two hundred sixty-three MDA5 + DM-ILD patients were divided into different groups according to lymphocyte count and death or survival within 1 month, then the differences in clinical features and outcomes were compared. Associations between lymphocytes and risk of death within 1 month were also investigated in different lymphocyte groups using Cox proportional hazard models. A generalized additive mixed model (GAMM) was established to analyze the dynamic changes of lymphocytes in the death 1-month group. Lymphocytes of the patients who died within 1 month were significantly lower than survivors by different lymphocyte grouping methods, and the total lymphocytes showed a gradually decreasing trend in non-survivors. And the difference between survivors and non-survivors was more obvious over time. The lowest tertile of baseline lymphocytes as a reference, the hazard ratios for death within 1 month in the highest tertile were 0.497 (95% CI 0.26-0.949, P for trend = 0.033) after adjustment for potential confounders. GAMM analysis found a mean daily decrease of lymphocytes (0.034 × 10^9/L) after admission in death 1-month patients. Low baseline lymphocytes and gradually declined lymphocytes are both associated with a high risk of death within 1 month. However dynamic changes in lymphocytes can better reflect the disease status and better predict the short-term prognosis than baseline lymphocytes in MDA5 + DM-ILD patients. Key points •Low baseline lymphocytes and gradually decreased trend along time correlated with poor short-term prognosis in MDA5 + DM-ILD patients. •Dynamic changes of lymphocytes can better reflect the disease status and better predict the 1-month prognosis than baseline lymphocytes in MDA5 + DM-ILD patients. •Generalized additive mixed model (GAMM) analysis found that in 1-month non-survivors, peripheral blood lymphocytes decreased by 0.034 × 10^9/L per day, while the lymphocytes in survivors gradually increased.

Stabilization of dimeric PYR/PYL/RCAR family members relieves abscisic acid-induced inhibition of seed germination.

Abscisic acid (ABA) is the primary preventing factor of seed germination, which is crucial to plant survival and propagation. ABA-induced seed germination inhibition is mainly mediated by the dimeric PYR/PYL/RCAR (PYLs) family members. However, little is known about the relevance between dimeric stability of PYLs and seed germination. Here, we reveal that stabilization of PYL dimer can relieve ABA-induced inhibition of seed germination using chemical genetic approaches. Di-nitrobensulfamide (DBSA), a computationally designed chemical probe, yields around ten-fold improvement in receptor affinity relative to ABA. DBSA reverses ABA-induced inhibition of seed germination mainly through dimeric receptors and recovers the expression of ABA-responsive genes. DBSA maintains PYR1 in dimeric state during protein oligomeric state experiment. X-ray crystallography shows that DBSA targets a pocket in PYL dimer interface and may stabilize PYL dimer by forming hydrogen networks. Our results illustrate the potential of PYL dimer stabilization in preventing ABA-induced seed germination inhibition.

Trimetallic-doped carbon nitride achieves chondroitin sulfate degradation via a free radical degradation strategy.

Traditional Fenton principles for degrading polysaccharides, including chondroitin sulfate (CS), are fraught with limitations, such as strict pH-dependence, higher temperature requirements, desulfurization, and environmentally perilous. In this study, an effective Fenton-like system comprising trimetallic-doped carbon nitride material (tri-CN) with hydrogen-bonded melamine-cyanuric acid (MCA) supramolecular aggregates as its basic skeleton was engineered to overcome the challenges of traditional methods. Detailed material characterizations revealed that, compared to monometallic-doped or bimetallic-doped counterparts, tri-CN offered a larger surface area, higher porosity, and increased metal loading, thereby enhancing reactant accessibility and polysaccharide degradation efficiency. The characterization and activity assessment of the degraded polysaccharide revealed structurally intact products without significant desulfurization, indicating the effectiveness of the designed approach. Moreover, the degraded chondroitin sulfate CS3 catalyzed by tri-CN, exhibited promising antioxidant activity and anti-CRISPR potential. The results elucidated that the high-valent iron species in the material served as primary active sites, catalyzing the cleavage of hydrogen peroxide to generate hydroxyl radicals that subsequently attacked CS chains, leading to their fragmentation. Hence, the designed material can be efficiently applied to polysaccharide degradation, but not limited to photocatalysis, electrocatalysis, sensor, energy storage materials, and wastewater treatment.

Composite microneedles loaded with Astragalus membranaceus polysaccharide nanoparticles promote wound healing by curbing the ROS/NF-κB pathway to regulate macrophage polarization.

The healing of chronic diabetic wounds remains a formidable challenge in modern times. In this study, a novel traditional Chinese medicine microneedle patch was designed based on the physiological characteristics of wounds, with properties including hemostasis, anti-inflammatory, antioxidant, antimicrobial, and induction of angiogenesis. Initially, white peony polysaccharide (BSP) with hemostatic properties and carboxymethyl chitosan (CMCS) with antimicrobial capabilities were used as materials for microneedle fabrication. To endow it with antimicrobial, procoagulant, and adhesive properties. Among them, loaded with ROS-sensitive nanoparticles of Astragalus polysaccharides (APS) based on effective components baicalein (Bai) and berberine (Ber) from Scutellaria baicalensis (SB) and Coptis chinensis (CC) drugs (APB@Ber). Together, they are constructed into multifunctional traditional Chinese medicine composite microneedles (C/B@APB@Ber). Bai and Ber synergistically exert anti-inflammatory and antimicrobial effects. Microneedle patches loaded with BSP and APS exhibited significant effects on cell proliferation and angiogenesis induction. The combination of composite polysaccharides enabled the microneedles to adhere stably to wounds and provide sufficient strength to penetrate the biofilm and induce dispersion. The combination of composite polysaccharides enabled the microneedles to adhere stably to wounds and provide sufficient strength to penetrate the biofilm and induce dispersion. Therefore, traditional Chinese medicine multifunctional microneedle patches offer potential medical value in promoting the healing of diabetic wounds.

The value of metagenomic next-generation sequencing with different nucleic acid extracting methods of cell-free DNA or whole-cell DNA in the diagnosis of non-neutropenic pulmonary aspergillosis.

Purpose: Metagenomic next-generation sequencing(mNGS) is a novel molecular diagnostic technique. For nucleic acid extraction methods, both whole-cell DNA (wcDNA) and cell-free DNA (cfDNA) are widely applied with the sample of bronchoalveolar lavage fluid (BALF). We aim to evaluate the clinical value of mNGS with cfDNA and mNGS with wcDNA for the detection of BALF pathogens in non-neutropenic pulmonary aspergillosis. Methods: mNGS with BALF-cfDNA, BALF-wcDNA and conventional microbiological tests (CMTs) were performed in suspected non-neutropenic pulmonary aspergillosis. The diagnostic value of different assays for pulmonary aspergillosis was compared. Results: BALF-mNGS (cfDNA, wcDNA) outperformed CMTs in terms of microorganisms detection. Receiver operating characteristic (ROC) analysis indicated BALF-mNGS (cfDNA, wcDNA) was superior to culture and BALF-GM. Combination diagnosis of either positive for BALF-mNGS (cfDNA, wcDNA) or CMTs is more sensitive than CMTs alone in the diagnosis of pulmonary aspergillosis (BALF-cfDNA+CMTs/BALF-wcDNA+CMTs vs. CMTs: ROC analysis: 0.813 vs.0.66, P=0.0142/0.796 vs.0.66, P=0.0244; Sensitivity: 89.47% vs. 47.37%, P=0.008/84.21% vs. 47.37%, P=0.016). BALF-cfDNA showed a significantly greater reads per million (RPM) than BALF-wcDNA. The area under the ROC curve (AUC) for RPM of Aspergillus detected by BALF-cfDNA, used to predict "True positive" pulmonary aspergillosis patients, was 0.779, with a cut-off value greater than 4.5. Conclusion: We propose that the incorporation of BALF-mNGS (cfDNA, wcDNA) with CMTs improves diagnostic precision in the identification of non-neutropenic pulmonary aspergillosis when compared to CMTs alone. BALF-cfDNA outperforms BALF-wcDNA in clinical value.

Predominance of hyperprogression in mucosal melanoma during anti-PD-1 monotherapy treatment.

BACKGROUND: A minority subset of immunotherapy patients manifests hyperprogressive disease (HPD), with the disparity in melanoma subtypes yet to be reported. This study aimed to delineate the proportion and prognosis of HPD in patients receiving anti-PD-1 monotherapy and to identify patient with HPD clinical characteristics across melanoma subtypes to inform clinical decision making. METHODS: Utilizing 4 established HPD definitions, the incidence of HPD in patients with advanced melanoma on anti-PD-1 monotherapy was determined. The incidence rates and prognostic abilities of various HPD definitions were compared to elect the most effective one. This facilitated a comparative analysis of subtypes and clinical features between patients with HPD and traditional progression. RESULTS: A total of 262 patients with advanced melanoma treated with anti-PD-1 monotherapy from 5 prospectively registered clinical trials were included in the study. The objective response rate (ORR) and disease control rate (DCR) was 21% and 58%, respectively, with 42% showcasing progression disease. The HPD incidences by 4 definitions were 13.2%, 16.8%, 10.8%, and 28.2%. All definitions effectively segregated HPD patients, with significantly poorer outcome than other progressive patients. The Delta TGR > 100 definition was the most indicative of a reduced overall survival, corroborated by the highest hazard ratio and statistical significance. The number of metastatic organs over 2 is a risk factor for HPD (OR = 4.18, P = .0103). Mucosal melanoma was the HPD prevalent subtype (OR = 3.13, P = .0489) in multivariable analysis, which is also indicated by RECIST criteria (P = .005). CONCLUSION: A delta TGR exceeding 100 best identified HPD patients in the advanced melanoma population treated with anti-PD-1 monotherapy. Hyperprogression was notably prevalent in mucosal melanoma patients with multiple metastatic organs. Caution against HPD is warranted when applying anti-PD-1 monotherapy in mucosal subtype.

Bifunctional Bismuth-Based Layered Double Hydroxide Sonosensitizer for Magnetic Resonance Imaging-Guided Sonodynamic Cancer Therapy.

Novel inorganic sonosensitizers with excellent reactive oxygen species (ROS) generation activity and multifunctionality are appealing in sonodynamic therapy (SDT). Herein, amorphous bismuth (Bi)-doped CoFe-layered double hydroxide (a-CoBiFe-LDH) nanosheets are proposed via crystalline-to-amorphous phase transformation strategy as a new type of bifunctional sonosensitizer, which allows ultrasound (US) to trigger ROS generation for magnetic resonance imaging (MRI)-guided SDT. Importantly, a-CoBiFe-LDH nanosheets exhibit much higher ROS generation activity (≈6.9 times) than that of traditional TiO2 sonosensitizer under US irradiation, which can be attributed to the acid etching-induced narrow band gap, high electron (e-)/hole (h+) separation efficiency and inhibited e-/h+ recombination. In addition, the paramagnetic properties of Fe ion endow a-CoBiFe-LDH with excellent MRI contrast ability, making it a promising contrast agent for T2-weighted MRI. After modification with polyethylene glycol, a-CoBiFe-LDH nanosheets can function as a high-efficiency sonosensitizer to activate p53, MAPK, oxidative phosphorylation, and apoptosis-related signaling pathways, ultimately inducing cell apoptosis in vitro and tumor ablation in vivo under US irradiation, which shows great potential for clinical cancer treatment.

Exploring soil nitrogen and sulfur dynamics: implications for greenhouse gas emissions on the Qinghai-Tibet Plateau.

The Qinghai-Tibet Plateau is particularly vulnerable to the effects of climate change and disturbances caused by human activity. To better understand the interactions between soil nitrogen and sulfur cycles and human activities on the plateau, the distribution characteristics of soil nitrogen and sulfur density and their influencing factors for three soil layers in Machin County at depths of 0-20 cm, 0-100 cm, and 0-180 cm are discussed in this paper. The results indicated that at depths of 0-180 cm, soil nitrogen density in Machin County varied between 1.36 and 16.85 kg/m2, while sulfur density ranged from 0.37 to 4.61 kg/m2. The effects of three factors-geological background, land use status, and soil type-on soil nitrogen and sulfur density were all highly significant (p < 0.01). Specifically, natural factors such as soil type and geological background, along with anthropogenic factors including land use practices and grazing intensity, were identified as decisive in causing spatial variations in soil nitrogen and sulfur density. Machin County on the Tibetan Plateau exhibits natural nitrogen and sulfur sinks; However, it is crucial to monitor the emissions of N2O and SO2 into the atmosphere from areas with high external nitrogen and sulfur inputs and low fertility retention capacities, such as bare land. On this basis, changes in the spatial and temporal scales of the nitrogen and sulfur cycles in soils and their source-sink relationships remain the focus of future research.

Ants may buffer the Janzen-Connell effect in a tropical forest in Southwest China.

Mutualistic symbioses between ants and plants are widespread in nature. Ants can deter unwanted pests and provide protection for plants in return for food or housing rewards. Using a long-term demographic dataset in a tropical seasonal rain forest in Southwest China, we found that associations with ants positively influenced seedling survival and adult growth, and also, species with extrafloral nectaries experienced weaker conspecific negative density dependence compared with species without extrafloral nectaries. Furthermore, we found strong evidence suggesting that species in our forest experienced conspecific density dependence, which we interpreted as heavy pest pressure that may drive the development of anti-pest symbioses such as the plant-ant relationship. Our findings suggest that ants and conspecific neighbors play important but inverse roles on plant survival and growth and that ants can buffer tree neighborhood interactions in this tropical forest.

Drought tolerance and species abundance mediate dry season negative density dependence in a tropical forest.

Conspecific negative density dependence (CNDD) is thought to be a key process in maintaining plant diversity. However, the strength of CNDD is highly variable in space and time as well as among species, and correlates of this variation that might help to understand and explain it remain largely unquantified. Using Bayesian hierarchical models, we took advantage of 10-year seedling monitoring data that were collected annually in every dry and rainy season in a seasonal tropical forest. We quantified the interspecific variation in the strength of CNDD and its temporal variation. We also examined potential correlates of this interspecific and temporal variation, including species functional traits (such as drought-tolerant traits, defense-related traits, and recourse acquisition traits) and species abundances. In the dry season, we found a negative relationship between the density of neighboring conspecific seedlings on seedling survival, while in the rainy season, there was a negative relationship between the density of neighboring conspecific adults on seedling survival. In addition, we found that interspecific variation in CNDD was related to drought-tolerant traits in the dry season but not in the rainy season. Across years, we found that drought-intolerant species suffer less CNDD during the dry seasons that have higher rainfall, whereas drought-tolerant species suffer less CNDD when the dry season has lower rainfall. We also found that rare species suffered stronger CNDD in the dry season. Overall, our study highlights that CNDD is highly variable among species and through time, necessitating a deeper appreciation of the environmental and functional contexts of CNDD and their interactions.

Intraspecific variation in Janzen-Connell effect is mediated by stress and plant-soil feedbacks.

Janzen-Connell (JC) effects, hypothesized to be partially driven by negative plant-soil feedbacks (PSFs), are considered to be a key mechanism that regulates tropical forest plant diversity and coexistence. However, intraspecific variation in JC effects may weaken this mechanism, with the strength of PSFs being a potentially key variable process. We conducted a manipulated experiment with seedlings from two populations of Pometia pinnata (Sapindaceae), a tropical tree species in southwest China. We aimed to measure the intraspecific difference in PSF magnitude caused by inoculating the soil from different P. pinnata source populations and growing seedlings under differing light intensity and water availability treatments, and at varying plant densities. We found negative PSFs for both populations with the inoculum soil originating from the same sites, but PSFs differed significantly with the inoculum soil from different sites. PSF strength responded differently to biotic and abiotic drivers; PSF strength was weaker in low moisture and high light treatments than in high moisture and low light treatments. Our study documents intraspecific variation in JC effects: specifically, P. pinnata have less defenses to their natively-sourced soil, but are more defensive to the soil feedbacks from soil sourced from other populations. Our results imply that drought and light intensity tended to weaken JC effects, which may result in loss of species diversity with climate change.

Myeloid ectopic viral integration site 2 accelerates the progression of Alzheimer's disease.

Amyloid plaques, a major pathological hallmark of Alzheimer's disease (AD), are caused by an imbalance between the amyloidogenic and non-amyloidogenic pathways of amyloid precursor protein (APP). BACE1 cleavage of APP is the rate-limiting step for amyloid-ß production and plaque formation in AD. Although the alteration of BACE1 expression in AD has been investigated, the underlying mechanisms remain unknown. In this study, we determined MEIS2 was notably elevated in AD models and AD patients. Alterations in the expression of MEIS2 can modulate the levels of BACE1. MEIS2 downregulation improved the learning and memory retention of AD mice and decreased the number of amyloid plaques. MEIS2 binds to the BACE1 promoter, positively regulates BACE1 expression, and accelerates APP amyloid degradation in vitro. Therefore, our findings suggest that MEIS2 might be a critical transcription factor in AD, since it regulates BACE1 expression and accelerates BACE1-mediated APP amyloidogenic cleavage. MEIS2 is a promising early intervention target for AD treatment.

Network pharmacology analysis and molecular mechanism of paeoniflorin and its metabolite in prolactinoma cells.

Prolactinoma was the most common functional pituitary neuroendocrine tumor tissue type, which was caused by excessive proliferation of pituitary prolactin (PRL) cells. Drug therapy of dopamine receptor agonists was generally considered as the prior treatment for prolactinoma patients. However, there were still prolactinoma patients who were resistant to dopamine agonists. Studies have been reported that paeoniflorin can inhibit the secretion of PRL in prolactinoma cells lacking dopamine D2 receptor (D2R) expression, and paeoniflorin can be metabolized into albiflorin by intestinal flora in rats. The effect of albiflorin on prolactinoma has not been reported yet. In this study, network pharmacology was used to analyze the mechanism of paeoniflorin and its metabolite albiflorin as multi-target therapy for prolactinoma, and the experimental verification was carried out. In order to clarify the complex relationship among paeoniflorin, albiflorin and prolactinoma, we constructed a component-target-disease network, and further constructed interaction network, MMP9, EGFR, FGF2, FGFR1 and LGALS3 were screened as the core targets. Kyoto encyclopedia of genes and genomes (KEGG) analysis showed that paeoniflorin and albiflorin may be involved in various pathways in the treatment of prolactinoma, included relaxin signaling pathway and PI3K-Akt signaling pathway. Molecular docking analysis showed that paeoniflorin and albiflorin had good binding activity with MMP9. Western blotting results showed that paeoniflorin and albiflorin could significantly reduce the expression of MMP9, and ELISA results showed that paeoniflorin and albiflorin could significantly reduce the concentration of PRL in GH3 cells, and the reduce degree of albiflorin was stronger than paeoniflorin at 50 µM, which indicated that albiflorin might be a potential drug to treat prolactinoma, which can regulate prolactinoma through MMP9 and reduce the concentration of PRL. Our study provided a new therapeutic strategy for prolactinoma.

Physicochemical and Rheological Properties of Degraded Konjac Gum by Abalone (Haliotis discus hannai) Viscera Enzyme.

In the present study, a new degraded konjac glucomannan (DKGM) was prepared using a crude enzyme from abalone (Haliotis discus hannai) viscera, and its physicochemical properties were investigated. After enzymatic hydrolysis, the viscosity of KGM obviously decreased from 15,500 mPa·s to 398 mPa·s. The rheological properties analysis of KGM and DKGMs revealed that they were pseudoplastic fluids, and pseudoplasticity, viscoelasticity, melting temperature, and gelling temperature significantly decreased after enzymatic hydrolysis, especially for KGM-180 and KGM-240. In addition, the molecular weight of KGM decreased from 1.80 × 106 Da, to 0.45 × 106 Da and the polydispersity index increased from 1.17 to 1.83 after 240 min of degradation time. Compared with natural KGM, the smaller particle size distribution of DKGM further suggests enzyme hydrolysis reduces the aggregation of molecular chains with low molecular weight. FT-IR and FESEM analyses showed that the fragmented KMG chain did not affect the structural characteristics of molecular monomers; however, the dense three-dimensional network microstructure formed by intermolecular interaction changed to fragment microstructure after enzyme hydrolysis. These results revealed that the viscosity and rheological properties of KGM could be controlled and effectively changed using crude enzymes from abalone viscera. This work provides theoretical guidance for the promising application of DKGM in the food industry.

Natural variation of TBR confers plant zinc toxicity tolerance through root cell wall pectin methylesterification.

Zinc (Zn) is an essential micronutrient but can be cytotoxic when present in excess. Plants have evolved mechanisms to tolerate Zn toxicity. To identify genetic loci responsible for natural variation of plant tolerance to Zn toxicity, we conduct genome-wide association studies for root growth responses to high Zn and identify 21 significant associated loci. Among these loci, we identify Trichome Birefringence (TBR) allelic variation determining root growth variation in high Zn conditions. Natural alleles of TBR determine TBR transcript and protein levels which affect pectin methylesterification in root cell walls. Together with previously published data showing that pectin methylesterification increase goes along with decreased Zn binding to cell walls in TBR mutants, our findings lead to a model in which TBR allelic variation enables Zn tolerance through modulating root cell wall pectin methylesterification. The role of TBR in Zn tolerance is conserved across dicot and monocot plant species.