Q negatively regulates wheat salt tolerance through directly repressing the expression of TaSOS1 and reactive oxygen species scavenging genes.

The Q transcription factor plays important roles in improving multiple wheat domestication traits such as spike architecture, threshability and rachis fragility. However, whether and how it regulates abiotic stress adaptation remain unclear. We found that the transcriptional expression of Q can be induced by NaCl and abscisic acid treatments. Using the q mutants generated by CRISPR/Cas9 and Q overexpression transgenic lines, we showed that the domesticated Q gene causes a penalty in wheat salt tolerance. Then, we demonstrated that Q directly represses the transcription of TaSOS1-3B and reactive oxygen species (ROS) scavenging genes to regulate Na+ and ROS homeostasis in wheat. Furthermore, we showed that wheat salt tolerance protein TaWD40 interacts with Q to competitively interfere with the interaction between Q and the transcriptional co-repressor TaTPL. Taken together, our findings reveal that Q directly represses the expression of TaSOS1 and some ROS scavenging genes, thus causing a harmful effect on wheat salt tolerance.

Physical exercise in liver diseases.

Liver diseases contribute to ~2 million deaths each year and account for 4% of all deaths globally. Despite various treatment options, the management of liver diseases remains challenging. Physical exercise is a promising nonpharmacological approach to maintain and restore homeostasis and effectively prevent and mitigate liver diseases. In this review, we delve into the mechanisms of physical exercise in preventing and treating liver diseases, highlighting its effects on improving insulin sensitivity, regulating lipid homeostasis, and modulating immune function. In addition, we evaluate the impact of physical exercise on various liver diseases, including liver ischemia/reperfusion injury, cardiogenic liver disease, metabolic dysfunction-associated steatotic liver disease, portal hypertension, cirrhosis, and liver cancer. In conclusion, the review underscores the effectiveness of physical exercise as a beneficial intervention in combating liver diseases.

Small GTPase PvARFR2 interacts with Cytosolic ABA Receptor Kinase3 to enhance alkali tolerance in Switchgrass.

Soil alkalization has become a serious problem that limits plant growth through osmotic stress, ionic imbalance, and oxidative stress. Understanding how plants resist alkali stress has practical implications for alkaline-land utilization. In this study, we identified a small GTPase, PvARFR2 (ADP ribosylation factors related 2), that positively regulates alkali tolerance in switchgrass (Panicum virgatum) and uncovered its potential mode of action. Overexpressing PvARFR2 in switchgrass and Arabidopsis (Arabidopsis thaliana) conferred transformants tolerance to alkali stress, demonstrated by alleviated leaf wilting, less oxidative injury, and a lower Na+/K+ ratio under alkali conditions. Conversely, switchgrass PvARFR2-RNAi and its homolog mutant atgb1 in Arabidopsis displayed alkali sensitives. Transcriptome sequencing analysis showed that cytosolic ABA receptor kinase PvCARK3 transcript levels were higher in PvARFR2 overexpression lines compared to the controls and were strongly induced by alkali treatment in shoots and roots. Phenotyping analysis revealed that PvCARK3-OE×atgb1 lines were sensitive to alkali similar to the Arabidopsis atgb1 mutant, indicating that PvARFR2/AtGB1 functions in the same pathway as PvCARK3 under alkaline stress conditions. Application of ABA on PvARFR2-OE and PvCARK3-OE switchgrass transformants resulted in ABA sensitivity. Moreover, we determined that PvARFR2 physically interacts with PvCARK3 in vitro and in vivo. Our results indicate that a small GTPase, PvARFR2, positively responds to alkali stress by interacting with the cytosolic ABA receptor kinase PvCARK3, connecting the alkaline stress response to ABA signaling.

The Intermode Polariton Parametric Scattering Laser in a Strong Coupled Microcavity Via Two-Photon Absorption.

Exciton-polaritons, hybrid quasiparticles from the strong coupling of excitons and cavity photons in semiconductor microcavities, offer a platform for exploring quantum coherence and nonlinear optical properties. The unique polariton parametric scattering (PPS) laser is of interest for its potential in quantum technologies and nonlinear devices. However, direct resonant excitation of polaritons in strong-coupling microcavities is challenging. This study proposes an innovative two-photon absorption (TPA) pump mechanism to address this. We observe TPA-driven PPS lasing in a strongly coupled microcavity at room temperature. High K-value exciton injections promote coherent stimulated emission of polariton scattering through intermode channels. Angle-resolved spectra confirm a TPA process, showing evolution from pump-state to signal-state. Hanbury Brown-Twiss measurement of second-order correlation g2(τ) of signal state indicates a phase transition from a classical thermal state to a quantum coherent state. Theoretical modeling provides insights into the physical mechanisms of PPS. Our work advances nonlinear phenomena exploration in strongly coupled light-matter systems, contributing to quantum polaritonics and nonlinear optics.

Sequential activation of strigolactone and salicylate biosynthesis promotes leaf senescence.

Leaf senescence is a complex process strictly regulated by various external and endogenous factors. However, the key signaling pathway mediating leaf senescence remains unknown. Here, we show that Arabidopsis SPX1/2 negatively regulate leaf senescence genetically downstream of the strigolactone (SL) pathway. We demonstrate that the SL receptor AtD14 and MAX2 mediate the age-dependent degradation of SPX1/2. Intriguingly, we uncover an age-dependent accumulation of SLs in leaves via transcriptional activation of SL biosynthetic genes by the transcription factors (TFs) SPL9/15. Furthermore, we reveal that SPX1/2 interact with the WRKY75 subclade TFs to inhibit their DNA-binding ability and thus repress transcriptional activation of salicylic acid (SA) biosynthetic gene SA Induction-Deficient 2, gating the age-dependent SA accumulation in leaves at the leaf senescence onset stage. Collectively, our new findings reveal a signaling pathway mediating sequential activation of SL and salicylate biosynthesis for the onset of leaf senescence in Arabidopsis.

Hypoxia-induced miR-181a-5p up-regulation reduces epirubicin sensitivity in breast cancer cells through inhibiting EPDR1/TRPC1 to activate PI3K/AKT signaling pathway.

Breast carcinoma (BC) ranks as a predominant malignancy and constitutes the second principal cause of mortality among women globally. Epirubicin stands as the drug of choice for BC therapeutics. Nevertheless, the emergence of chemoresistance has significantly curtailed its therapeutic efficacy. The resistance mechanisms to Epirubicin remain not entirely elucidated, yet they are conjectured to stem from diminished tumor vascular perfusion and resultant hypoxia consequent to Epirubicin administration. In our investigation, we meticulously scrutinized the Gene Expression Omnibus database for EPDR1, a gene implicated in hypoxia and Epirubicin resistance in BC. Subsequently, we delineated the impact of EPDR1 on cellular proliferation, motility, invasive capabilities, and interstitial-related proteins in BC cells, employing methodologies such as the CCK-8 assay, Transwell assay, and western blot analysis. Our research further unveiled that hypoxia-induced miR-181a-5p orchestrates the regulation of BC cell duplication, migration, invasion, and interstitial-related protein expression via modulation of EPDR1. In addition, we identified TRPC1, a gene associated with EPDR1 expression in BC, and substantiated that EPDR1 influences BC cellular dynamics through TRPC1-mediated modulation of the PI3K/AKT signaling cascade. Our findings underscore the pivotal role of EPDR1 in the development of BC. EPDR1 was found to be expressed at subdued levels in BC tissues, Epirubicin-resistant BC cells, and hypoxic BC cells. The overexpression of EPDR1 curtailed BC cell proliferation, motility, invasiveness, and the expression of interstitial-related proteins. At a mechanistic level, the overexpression of hypoxia-induced miR-181a-5p was observed to inhibit the EPDR1/TRPC1 axis, thereby activating the PI3K/AKT signaling pathway and diminishing the sensitivity to Epirubicin in BC cells. In summation, our study demonstrates that the augmentation of hypoxia-induced miR-181a-5p diminishes Epirubicin sensitivity in BC cells by attenuating EPDR1/TRPC1 expression, thereby invigorating the PI3K/AKT signaling pathway. This exposition offers a theoretical foundation for the application of Epirubicin in BC therapy, marking a significant contribution to the existing body of oncological literature.

The STF/WOX1 MD is required for physical interaction with MtWOX9 and leaf blade outgrowth in Medicago truncatula.

Plant-specific WUSCHEL-related homeobox (WOX) family transcription factors play critical roles in maintaining meristems and lateral organ development. The WUS clade member STF/LAM1 physically interacts with the intermediate clade member WOX9. This interaction contributes to their antagonistical functions on leaf blade outgrowth by competing for the same cis-elements in the promoter of their common target in M. truncatula and N. sylvestris. Here, we identified the main interaction domains of STF and MtWOX9 in Medicago, shedding light on the mechanism of WOX gene function. The middle domain of STF and MtWOX9 are both critical for the interaction, while the conserved motif of STF in the C-terminal domain is also required. Deletion of the middle domain of STF partially rescued the leaf blade phenotypes of the stf null mutant, indicating that the middle domain plays an essential role during leaf blade expansion. This finding provides a new insight that the versatility of WOX function is not only caused by the conserved DNA binding and repression domains but also by the middle domain that recruits different partners.

Relationship between glycated hemoglobin levels at admission and chronic post-stroke fatigue in patients with acute ischemic stroke.

BACKGROUND: Chronic Post-Stroke Fatigue (PSF) is a common and persistent complications among ischemic stroke survivors. The serum glycated hemoglobin (HbA1c) level, as it is known has emerged as a critical risk factor for Acute Ischemic Stroke (AIS) and post-stroke cognitive and emotional impairment. However, no studies have been conducted on the link between HbA1c and PSF. Therefore, this study aims to estimate the relationship between HbA1c and PSF in the chronic phase. METHODS: A longitudinal study was conducted on 559 patients diagnosed with their first AIS episode and admitted to Suining Central Hospital within three days after onset. All patients were examined for serum HbA1c, blood glucose levels and routine blood biochemical indicators at admission. The Fatigue Severity Scale (FSS) was employed to assess fatigue symptoms at six months post-stroke. Multivariate logistic regression and smooth curve fitting were used to analyze the relationship between admission HbA1c, blood glucose levels, discharge blood glucose and PSF, and the predictive value of HbA1c on PSF was assessed using a segmented linear regression model. RESULTS: 189(33.8 %)of the 559 patients included in the study, reported PSF at six-month follow-up. Compared with the non-PSF group, the PSF group displayed significantly higher levels of HbA1c (7.8 ± 3.0 vs 6.5 ± 2.0 %, P < 0.001), admission blood glucose (7.8 ± 3.8 vs 7.1 ± 3.5 mmol/L, P = 0.041), and discharge blood glucose (6.3 ± 1.6 vs 5.8 ± 1.2 mmol/L, P < 0.001). The dose-response relationship among admission HbA1c, blood glucose, discharge blood glucose and PSF showed that HbA1c level is positively and non-linearly related to the risk of PSF. A linear positive correlation is noted between PSF and discharge blood glucose levels, while no significant correlation was observed for the blood glucose levels upon admission. CONCLUSIONS: Higher HbA1c levels at admission were independently associated with the risk of chronic PSF, the correlation between blood glucose and PSF showed significant variability, HbA1c may serve as a more stable risk factor in predicting the occurrence of chronic PSF and long-term active glycemic management may have a favorable impact on chronic PSF after AIS.

Nonlinear Relationship Between Homocysteine and Mild Cognitive Impairment in Early Parkinson's Disease: A Cross-Sectional Study.

Background: Cognitive impairment, a prevalent non-motor symptom in advanced Parkinson's disease (PD), has been associated with hyperhomocysteinemia, an important risk factor for PD progression and cognitive decline in PD. However, evidence regarding the association between homocysteine (Hcy) and cognitive function during early PD remains insufficient. Therefore, this study aims to examine the correlation between Hcy levels and cognitive function in the early stage of PD. Methods: The study included 218 individuals in the early stages of PD who were consecutively admitted to the Suining Central Hospital Neurology Department. All the individuals completed the Parkinson's Disease Cognitive Rating Scale (PD-CDR). The Unified Parkinson's Disease Rating Scale part III (UPDRS-III) was employed for measuring the severity of motor symptoms, while the Hoehn-Yahr scale was used to measure the clinical symptom stage. Fasting venous blood samples were also drawn to measure the Hcy concentration, red blood cell folate, and vitamin B12. Results: In this cross-sectional study, 47 (21.5%) patients with PD showed cognitive dysfunction. The serum Hcy levels were significantly higher in the cognitive impairment PD (PDCI) group compared with the cognitive normal PD group (P<0.001). The Generalized Additive Model (GAM) analysis revealed a nonlinear relationship between Hcy and the risk of PDCI. Multiple logistic regression analyses demonstrated a positive relationship between elevated Hcy and the risk of PDCI in the fully adjusted model ([OR]:3.1, 95% CI, 1.1-8.5, P=0.028). Segmented linear regression analysis showed that when Hcy levels were above 17.7 umol/l, the risk of PDCI increased by 1.6 times for every 1 unit elevated in Hcy (95% CI:1.1-2.2, P=0.008). Conclusion: This study revealed a nonlinear positive correlation between the risk of PDCI and elevated serum Hcy levels in early PD patients, suggesting hyperhomocysteinemia as one of the treatable factors for cognitive impairment in the early stages of PD.

The sonographic features of lymph node venous networks and flow patterns in patients with primary chronic venous disease.

BACKGROUND: Our study aims to enhance the understanding of lymph node venous networks (LNVNs) by summarising their anatomical, sonographic features, and reflux patterns. METHOD: We examined 241 legs from 141 patients with primary chronic venous disease (CVD) using duplex ultrasound. RESULTS: The findings indicated variations in the shape, size, vascularity, and echogenicity of LNVN. The superficial inguinal lymph node with reflux appeared slightly larger, exhibiting higher velocities in the hilar artery. Regarding connections, venous flow within LNVN was predominantly drained through the saphenofemoral junction (SFJ), anterior accessory great saphenous vein (AAGSV), and great saphenous vein (GSV). A significant number of LNVNs were observed to be associated with anterolateral thigh tributaries. The study also identified valve cusps within LNVN. CONCLUSION: This study revealed a 12% prevalence of primary LNVN. Understanding the anatomical and haemodynamic features of LNVN informs treatment strategies and potentially helps prevent the recurrence of varicose veins.

A study on the falls factors among the older adult with cognitive impairment based on large-sample data.

Introduction: This study explored the correlative factors of falls among the older adult with cognitive impairment, to provide distinct evidence for preventing falls in the older adult with cognitive impairment compared with the general older adult population. Methods: This study was based on a cross-sectional survey, with an older adult population of 124,124 was included. The data was sourced from the Elderly Care Unified Needs Assessment for Long-Term Care Insurance in Shanghai. Binary and multivariable logistic regression analyses were conducted sequentially on the correlative factors of falls. Multivariable logistic regression was performed on variables that were significant, stratified by cognitive function levels. Results: The incidence of fall in the past 90 days was 17.67% in this study. Specific variables such as gender (male), advanced age (≥80), residence with a elevator (or lift), mild or moderate disability, quality of sleep (acceptable/poor) were negatively correlated with falls, while higher education level, living alone, residence with indoor steps, unclean and untidy living environment, MCI or dementia, chronic diseases, restricted joints, impaired vision, and the use of diaper were positively correlative factors of falls. Comparing with older adult with normal cognitive functions, older adult with dementia faced a higher risk of falling due to accessibility barrier in the residence. For general older adults, less frequency of going outside and poor social interactions were positively correlated with falls, while for older adult with cognitive impairments, going outside moderately (sometimes) was found positively correlated with falls. Older adults with cognitive impairments have increased fall risks associated with chronic diseases, restricted joints, and the use of diaper. The risk of falling escalated with the greater number of chronic diseases. Discussion: For older adult with cognitive impairments, it is advisable to live with others. Additionally, creating an accessible living environment and maintaining the cleanness and tidiness can effectively reduce the risk of falls, particularly for those with MCI or dementia. Optimal outdoor activity plans should be developed separately based on the cognitive function of older adults. Older adult with dementia who have comorbidities should be paid special attention in fall prevention compared to the general older adult population.

Development of novel superconductivity with higherTcvia the suppression of magnetism in quasi-two-dimensional electrideY2Cunder high pressures.

Discovery of superconductivity in electride materials has been a topic of interest as their intrinsic electron-rich properties might suggest a considerable electron-phonon interaction. LayeredY2Cis a ferromagnetic quasi-two-dimensional electride with polarized anionic electrons confined in the interlayer space. In this theoretical study, we reportY2Cundergoes a series of structural phase transitions into two superconducting phases with estimatedTcof 9.2 and 21.0 K at 19 and 80 GPa, respectively, via the suppression of magnetism. Our extensive first-principles swarm structure searches identify that these two high-pressure superconducting phases possess an orthorhombicPnmaand a tetragonalI4/mstructures, respectively, where thePnmaphase is found to be a one-dimensional electride characterized by electron confinements in channel spaces of the crystal lattice, while the electride property inI4/mphase has been completely destroyed. We attribute the development of an unprecedentedly highTcsuperconductivity in Y-C system to the destructions of magnetism and the delocalization of interlayered anionic electrons under pressures. This work provides a unique example of pressure-induced collapse of magnetism at the onset of superconductivity in electride materials, along with the dramatic changes of electron-confinement topology in crystal lattices.

PvARL1 Increases Biomass Yield and Enhances Alkaline Tolerance in Switchgrass (Panicum virgatum L.).

Switchgrass is an important bioenergy crop valued for its biomass yield and abiotic tolerance. Alkali stress is a major abiotic stress that significantly impedes plant growth and yield due to high salinity and pH; however, the response mechanism of switchgrass to alkali stress remains limited. Here, we characterized PvARL1, an ARF-like gene, which was up-regulated in both the shoot and root tissues under alkali stress conditions. Overexpression of PvARL1 not only improved alkali tolerance but also promoted biomass yield with more tiller and higher plant height in switchgrass. Moreover, PvARL1 overexpression lines displayed higher capacities in the maintenance of water content and photosynthetic stability compared with the controls under alkali treatments. A significant reduction in the ratio of electrolyte leakage, MDA content, and reactive oxygen species (ROS) showed that PvARL1 plays a positive role in protecting cell membrane integrity. In addition, PvARL1 also negatively affected the K+ efflux or uptake in roots to alleviate ion toxicity under alkali treatments. Overall, our results suggest that PvARL1 functions as a positive regulator in plant growth as well as in the plant response to alkali stress, which could be used to improve switchgrass biomass yield and alkali tolerance genetically.

A large cross sectional study on diaper utilization and beneficial role in outdoor activity and emotions among incontinence elderly people.

This study was designed based on a cross-sectional investigation conducted Shanghai, China. Demographic characteristics, diaper utilization, Activities of Daily Living (ADL) and emotion were collected by Unified Needs Assessment Form for Elderly Care Questionnaire. Cognition function was assessed by Mini-mental State Examination (MMSE) scale. Multivariate logistic regression was used for statistical analysis. The diaper utilization rate was 31.2%. Female, higher level of education, poorer ADL and cognition, more severe incontinence and financial dependence on others were facilitating factors for diaper usage (P < 0.05). The possibility of using diaper differed according to the intimacy of caregivers. Among incontinent individuals with relatively good ADL and cognition level, diaper utilization can significantly decrease the risk of going out only once a month (OR: 2.63 vs 4.05), and going out less than once a month (OR: 5.32 vs 6.53). Incontinence people who going out at least once a week had a lower risk of some negative emotion. Significantly, diaper utilization further decreased this risk. In conclusion, for incontinence elderly people with relatively independent ability, proper use of diaper may improve the frequency of outdoor activity and emotion. Nevertheless, diaper utilization should be decided based on elderly people's own will.

N6-methyladenosine analysis unveils key mechanisms underlying long-term salt stress tolerance in switchgrass (Panicum virgatum).

N6-methyladenosine (m6A) RNA modification is critical for plant growth, development, and environmental stress response. While short-term stress impacts on m6A are well-documented, the consequences of prolonged stress remain underexplored. This study conducts a thorough transcriptome-wide analysis of m6A modifications following 28-day exposure to 200 mM NaCl. We detected 11,149 differentially expressed genes (DEGs) and 12,936 differentially methylated m6A peaks, along with a global decrease in m6A levels. Notably, about 62% of m6A-modified DEGs, including demethylase genes like PvALKBH6_N, PvALKBH9_K, and PvALKBH10_N, showed increased expression and reduced m6A peaks, suggesting that decreased m6A methylation may enhance gene expression under salt stress. Consistent expression and methylation patterns were observed in key genes related to ion homeostasis (e.g., H+-ATPase 1, High-affinity K+transporter 5), antioxidant defense (Catalase 1/2, Copper/zinc superoxide dismutase 2, Glutathione synthetase 1), and osmotic regulation (delta 1-pyrroline-5-carboxylate synthase 2, Pyrroline-5-carboxylate reductase). These findings provide insights into the adaptive mechanisms of switchgrass under long-term salt stress and highlight the potential of regulating m6A modifications as a novel approach for crop breeding strategies focused on stress resistance.

Effectiveness Assessment of Bispectral Index Monitoring Compared with Conventional Monitoring in General Anesthesia: A Systematic Review and Meta-Analysis.

Background and Objective. The Bispectral Index (BIS) is utilized to guide the depth of anesthesia monitoring during surgical procedures. However, conflicting results regarding the benefits of BIS for depth of anesthesia monitoring have been reported in numerous studies. The purpose of this meta-analysis and systematic review was to assess the effectiveness of BIS for depth of anesthesia monitoring. Search Methods. A systematic search of Ovid-MEDLINE, Cochrane, and PubMed was conducted from inception to April 20, 2023. Clinical trial registers and grey literature were also searched, and reference lists of included studies, as well as related review articles, were manually reviewed. Selection Criteria. The inclusion criteria were randomized controlled trials without gender or age restrictions. The control groups used conventional monitoring, while the intervention groups utilized BIS monitoring. The exclusion criteria included duplicates, reviews, animal studies, unclear outcomes, and incomplete data. Data Collection and Analysis. Two independent reviewers screened the literature, extracted data, and assessed methodological quality, with analyses conducted using R 4.0 software. Main Results. Forty studies were included. In comparison to the conventional depth of anesthesia monitoring, BIS monitoring reduced the postoperative cognitive dysfunction risk (RR = 0.85, 95% CI: 0.73∼0.99, P = 0.04), shortened the eye-opening time (MD = -1.34, 95% CI: -2.06∼-0.61, P < 0.01), orientation recovery time (MD = -1.99, 95% CI: -3.62∼-0.36, P = 0.02), extubation time (MD = -2.54, 95% CI: -3.50∼-1.58, P < 0.01), and postanesthesia care unit stay time (MD = -7.11, 95% CI: -12.67∼-1.55, P = 0.01) and lowered the anesthesia drug dosage (SMD = -0.39, 95% CI: -0.63∼-0.15, P < 0.01). Conclusion. BIS can be used to effectively monitor the depth of anesthesia. Its use in general anesthesia enhances the effectiveness of both patient care and surgical procedures.

Transcriptome-wide m6A methylation profile reveals tissue specific regulatory networks in switchgrass (Panicum virgatum L.) under cadmium stress.

The heavy metal cadmium (Cd), known for its high toxicity, poses a grave threat to human health through the food chain. N6-methyladenosine (m6A), the most abundant internal modification, regulates plant adaptation to various adversities, yet the panorama of m6A modifications in switchgrass under cadmium stress remains elusive. This study examines the physiological responses of switchgrass roots and shoots exposed to 50 µM CdCl2, alongside an overview of transcriptome-wide m6A methylation patterns. After cadmium treatment, methylation modifications are primarily enriched near stop codons and the 3'UTR region, with a negative correlation between m6A modification and gene expression levels. In shoots, approximately 58 % of DEGs with m6A modifications show upregulation in expression and decrease in m6A peaks, including zinc transporter 4-like (ZIP4). In roots, about 43 % of DEGs with m6A modifications exhibit downregulation in expression and increase in m6A peaks, such as the ABC transporter family member (ABCG25). We further validate the m6A enrichment, gene expression and mRNA stability of ZIP4 in response to Cd treatment. The results suggest that the negative correlation of m6A enrichment and gene expression is due to altered mRNA stability. Our study establishes an m6A regulatory network governing cadmium transport in switchgrass roots and shoots, offering new avenues for candidate gene manipulation in phytoremediation applications of heavy metal pollution.

Icariin protects against acute graft-versus-host disease while preserving graft-versus-leukemia activity after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Acute graft-versus-host disease (aGVHD), which is mainly mediated by allogeneic T cells, is a decisive factor in the success of allogeneic hematopoietic stem cell transplantation (allo-HCT). Prophylaxis for aGVHD in clinical patients is unsatisfactory, and there is still a huge unmet need for novel approaches. Icariin (ICA) shows potent anti-inflammatory activity and suppresses T cell-mediated immune responses. Thus, ICA is a potential drug for the prevention of aGVHD. However, there is no data assessing the impact of ICA on aGVHD after allo-HCT. PURPOSE: This study aimed to investigate the protective effect of ICA against aGVHD and its mechanisms. Moreover, the impact of ICA on the graft-versus-leukemia (GVL) effect and engraftment of donor hematopoietic and immune cells were assessed. METHODS: Different murine models of allo-HCT were developed to study the influence of the ICA on GVHD and GVL effect. Flow cytometry was used to analyze the growth of leukemia cells, alterations in different immune cells, and apoptosis. Cell proliferation was determined using a CCK-8 assay. RNA sequencing and quantitative proteomic analysis were performed to elucidate the underlying mechanisms, which were further verified by polymerase chain reaction or functional experiments. RESULTS: Different concentrations of ICA exhibited opposite effects: low-concentration ICA promoted, while high concentrations suppressed the proliferation and function of T cells. A high dose of ICA administration during days +3 to +5 post-allo-HCT can alleviate murine aGVHD but does not affect the course of chronic GVHD (cGVHD), the GVL effect against both acute myeloid and lymphoblastic leukemia, or the recovery of donor hematological and immune cells. ICA extensively represses the expansion, function, and infiltration of donor alloreactive T cells, while preserving regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSC). Quantitative proteomic analysis showed that downregulation of integrin-linked kinase (ILK) and lymphocyte cytosolic protein 2 (LCP2) expression was possibly associated with ICA-mediated aGVHD protective effects. Furthermore, an inhibitor of ILK, which can alleviate murine aGVHD administered early after allo-HCT. CONCLUSION: These findings suggest that the bioactivities of ICA are associated with its concentration and that ICA can effectively mitigate aGVHD without losing GVL activity or engraftment of donor hematopoietic and immune cells. Thus, ICA may be a promising drug for preventing aGVHD in clinical settings.

A chromosome-level genome assembly for Onobrychis viciifolia reveals gene copy number gain underlying enhanced proanthocyanidin biosynthesis.

Sainfoin (Onobrychis viciifolia), which belongs to subfamily Papilionoideae of Leguminosae, is a vital perennial forage known as "holy hay" due to its high contents of crude proteins and proanthocyanidins (PAs, also called condensed tannins) that have various pharmacological properties in animal feed, such as alleviating rumen tympanic disease in ruminants. In this study, we select an autotetraploid common sainfoin (2n = 4x = 28) and report its high-quality chromosome-level genome assembly with 28 pseudochromosomes and four haplotypes (~1950.14 Mb, contig N50 = 10.91 Mb). The copy numbers of genes involved in PA biosynthesis in sainfoin are significantly greater than those in four selected Fabales species, namely, autotetraploid Medicago sativa and three other diploid species, Lotus japonicus, Medicago truncatula, and Glycine max. Furthermore, gene expansion is confirmed to be the key contributor to the increased expression of these genes and subsequent PA enhancement in sainfoin. Transcriptomic analyses reveal that the expression of genes involved in the PA biosynthesis pathway is significantly increased in the lines with high PA content compared to the lines with medium and low PA content. The sainfoin genome assembly will improve our understanding of leguminous genome evolution and biosynthesis of secondary metabolites in sainfoin.

Bile acids attenuate hepatic inflammation during ischemia/reperfusion injury.

Background & Aims: Persistent cholestasis has been associated with poor prognosis after orthotopic liver transplantation. In this study, we aimed to investigate how the accumulation of tauro-beta-muricholic acid (TßMCA), resulting from the reprogramming of bile acid (BA) metabolism during liver ischemia/reperfusion (IR) stress, attenuates liver inflammation. Methods: Ingenuity Pathway Analysis was performed using transcriptome data from a murine hepatic IR model. Three different models of hepatic IR (liver warm IR, bile duct separation-IR, common bile duct ligation-IR) were employed. We generated adeno-associated virus-transfected mice and CD11b-DTR mice to assess the role of BAs in regulating the myeloid S1PR2-GSDMD axis. Hepatic BA levels were analyzed using targeted metabolomics. Finally, the correlation between the reprogramming of BA metabolism and hepatic S1PR2 levels was validated through RNA-seq of human liver transplant biopsies. Results: We found that BA metabolism underwent reprogramming in murine hepatocytes under IR stress, leading to increased synthesis of TßMCA, catalyzed by the enzyme CYP2C70. The levels of hepatic TßMCA were negatively correlated with the severity of hepatic inflammation, as indicated by the serum IL-1ß levels. Inhibition of hepatic CYP2C70 resulted in reduced TßMCA production, which subsequently increased serum IL-1ß levels and exacerbated IR injury. Moreover, our findings suggested that TßMCA could inhibit canonical inflammasome activation in macrophages and attenuate inflammatory responses in a myeloid-specific S1PR2-GSDMD-dependent manner. Additionally, Gly-ßMCA, a derivative of TßMCA, could effectively attenuate inflammatory injury in vivo and inhibit human macrophage pyroptosis in vitro. Conclusions: IR stress orchestrates hepatic BA metabolism to generate TßMCA, which attenuates hepatic inflammatory injury by inhibiting the myeloid S1PR2-GSDMD axis. Bile acids have immunomodulatory functions in liver reperfusion injury that may guide therapeutic strategies. Impact and implications: Our research reveals that liver ischemia-reperfusion stress triggers reprogramming of bile acid metabolism. This functions as an adaptive mechanism to mitigate inflammatory injury by regulating the S1PR2-GSDMD axis, thereby controlling the release of IL-1ß from macrophages. Our results highlight the crucial role of bile acids in regulating hepatocyte-immune cell crosstalk, which demonstrates an immunomodulatory function in liver reperfusion injury that may guide therapeutic strategies targeting bile acids and their receptors.