Light-responsive transcription factors VvHYH and VvGATA24 mediate wax terpenoid biosynthesis in Vitis vinifera.

The cuticular wax that covers the surfaces of plants is the first barrier against environmental stresses and increasingly accumulates with light exposure. However, the molecular basis of light-responsive wax biosynthesis remains elusive. In grape (Vitis vinifera), light exposure resulted in higher wax terpenoid content and lower decay and abscission rates than controls kept in darkness. Assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and RNA-seq data were integrated to draw the chromatin accessibility and cis-elements regulatory map to identify the potential action sites. Terpenoid synthase 12 (VvTPS12) and 3-Hydroxy-3-methylglutaryl-CoA reductase 2 (VvHMGR2) were identified as grape wax biosynthesis targets, while VvHYH and VvGATA24 were identified as terpenoid biosynthesis activators, as more abundant wax crystals and higher wax terpenoid content were observed in transiently overexpressed grape berries and Nicotiana benthamiana leaves. The interaction between VvHYH and the open chromatin of VvTPS12 was confirmed qualitatively using a dual luciferase assay and quantitatively using surface plasma resonance, with an equilibrium dissociation constant of 2.81 nM identified via the latter approach. Molecular docking simulation implied the structural nature of this interaction, indicating that 24 amino acid residues of VvHYH, including Arg106A, could bind to the VvTPS12 G-box cis-element. VvGATA24 directly bound to the open chromatin of VvHMGR2, with an equilibrium dissociation constant of 8.59 nM. 12 amino acid residues of VvGATA24, including Pro218B, interacted with the VvHMGR2 GATA-box cis-element. Our work characterizes the mechanism underlying light-mediated wax terpenoid biosynthesis and provides gene targets for future molecular breeding.

Digital light processing printed hydrogel scaffolds with adjustable modulus.

Hydrogels are extensively explored as biomaterials for tissue scaffolds, and their controlled fabrication has been the subject of wide investigation. However, the tedious mechanical property adjusting process through formula control hindered their application for diverse tissue scaffolds. To overcome this limitation, we proposed a two-step process to realize simple adjustment of mechanical modulus over a broad range, by combining digital light processing (DLP) and post-processing steps. UV-curable hydrogels (polyacrylamide-alginate) are 3D printed via DLP, with the ability to create complex 3D patterns. Subsequent post-processing with Fe3+ ions bath induces secondary crosslinking of hydrogel scaffolds, tuning the modulus as required through soaking in solutions with different Fe3+ concentrations. This innovative two-step process offers high-precision (10 µm) and broad modulus adjusting capability (15.8-345 kPa), covering a broad range of tissues in the human body. As a practical demonstration, hydrogel scaffolds with tissue-mimicking patterns were printed for cultivating cardiac tissue and vascular scaffolds, which can effectively support tissue growth and induce tissue morphologies.

Architecture design and advanced manufacturing of heart-on-a-chip: scaffolds, stimulation and sensors.

Heart-on-a-chip (HoC) has emerged as a highly efficient, cost-effective device for the development of engineered cardiac tissue, facilitating high-throughput testing in drug development and clinical treatment. HoC is primarily used to create a biomimetic microphysiological environment conducive to fostering the maturation of cardiac tissue and to gather information regarding the real-time condition of cardiac tissue. The development of architectural design and advanced manufacturing for these "3S" components, scaffolds, stimulation, and sensors is essential for improving the maturity of cardiac tissue cultivated on-chip, as well as the precision and accuracy of tissue states. In this review, the typical structures and manufacturing technologies of the "3S" components are summarized. The design and manufacturing suggestions for each component are proposed. Furthermore, key challenges and future perspectives of HoC platforms with integrated "3S" components are discussed. Architecture design concepts of scaffolds, stimulation and sensors in chips.

Elucidating the molecular mechanisms behind the therapeutic impact of median nerve stimulation on cognitive dysfunction post-traumatic brain injury.

OBJECTIVE: Ferroptosis represents a form of regulated cellular death dependent upon iron and lipid peroxidation derivatives, holding considerable implications for cerebral and neurologic pathologies. In the present study, we endeavored to elucidate the molecular mechanisms governing ferroptosis and appraise the therapeutic value of electrical stimulation of median nerve in addressing cognitive impairments following traumatic brain injury (TBI), employing a rodent model. METHODS: In this study, we established a rat model to investigate the cognitive impairments resulting from TBI, followed by the application of median nerve stimulation (MNS). Initially, rats received an intraperitoneal injection of Erastin (2 mg/kg) prior to undergoing MNS. After 24 h of MNS treatment, the rats were subjected to an open field test to evaluate their cognitive and motor functions. Subsequently, we conducted biochemical assays to measure the serum levels of GSH, MDA and SOD. The structural integrity and cellular morphology of hippocampal tissue were examined through H&E staining, Nissl staining and transmission electron microscopy. Additionally, we assessed the expression levels of proteins crucial for neuronal health and function in the hippocampus, including VEGF, SLC7A11, GPX4, Nrf2, α-syn, NEUN and PSD95. RESULTS: Compared to the control group, rats in the stimulation group demonstrated enhanced mobility, reduced levels of tissue damage, a decrease in MDA concentration, and increased levels of GSH and SOD. Additionally, there was a significant upregulation in the expression of proteins critical for cellular defense and neuronal health, including GPX4, SLC7A11, Nrf2, VEGF, α-syn, NEUN, and PSD95 proteins. Conversely, rats in the Erastin group demonstrated decreased mobility, exacerbated pathological tissue damage, elevated MDA concentration, and decreased levels of GSH and SOD. There was also a notable decrease in the expression of GPX4, SLC7CA11, Nrf2, and VEGF proteins. The expression levels of α-syn, NEUN, and PSD95 were similarly diminished in the Erastin group. Each of these findings was statistically significant, indicating that MNS exerts neuroprotective effect in the hippocampal tissue of rats with TBI by inhibiting the ferroptosis pathway. CONCLUSION: (1) MNS may enhance the cognitive and behavioral performance of rats after TBI; (2) MNS can play a neuroprotective role by promoting the expression of nerve injury-related proteins, alleviating oxidative stress and ferroptosis process; (3) MNS may inhibit ferroptosis of neuronal cells by activating Nrf2/ GPX4 signaling pathway, thereby improving cognitive impairment in TBI rats.

The relationships between biological novel biomarkers Lp-PLA2 and CTRP-3 and CVD in patients with type 2 diabetes mellitus.

BACKGROUND: Cardiovascular disease (CVD) is recognized as a primary and severe comorbidity in patients with type 2 diabetes mellitus (T2DM) and is also identified as a leading cause of mortality within this population. Consequently, the identification of novel biomarkers for the risk stratification and progression of CVD in individuals with T2DM is of critical importance. METHODS: This retrospective cohort study encompassed 979 patients diagnosed with T2DM, of whom 116 experienced CVD events during the follow-up period. Clinical assessments and comprehensive blood laboratory analyses were conducted. Age- and sex-adjusted Cox proportional hazard regression analysis was utilized to evaluate the association between lipoprotein-associated phospholipase A2 (Lp-PLA2), C1q/tumor necrosis factor-related protein 3 (CTRP-3), and the incidence of CVD in T2DM. The diagnostic performance of these biomarkers was assessed through receiver operating characteristic (ROC) curve analysis and the computation of the area under the curve (AUC). RESULTS: Over a median follow-up of 84 months (interquartile range: 42 [32-54] months), both novel inflammatory markers, Lp-PLA2 and CTRP-3, and traditional lipid indices, such as low-density lipoprotein cholesterol and apolipoprotein B, exhibited aberrant expression in the CVD-afflicted subset of the T2DM cohort. Age- and sex-adjusted Cox regression analysis delineated that Lp-PLA2 (hazard ratio [HR] = 1.007 [95% confidence interval {CI}: 1.005-1.009], p < 0.001) and CTRP-3 (HR = 0.943 [95% CI: 0.935-0.954], p < 0.001) were independently associated with the manifestation of CVD in T2DM. ROC curve analysis indicated a substantial predictive capacity for Lp-PLA2 (AUC = 0.81 [95% CI: 0.77-0.85], p < 0.001) and CTRP-3 (AUC = 0.91 [95% CI: 0.89-0.93], p < 0.001) in forecasting CVD occurrence in T2DM. The combined biomarker approach yielded an AUC of 0.94 (95% CI: 0.93-0.96), p < 0.001, indicating enhanced diagnostic accuracy. CONCLUSIONS: The findings suggest that the biomarkers Lp-PLA2 and CTRP-3 are dysregulated in patients with T2DM who develop CVD and that each biomarker is independently associated with the occurrence of CVD. The combined assessment of Lp-PLA2 and CTRP-3 may significantly augment the diagnostic precision for CVD in the T2DM demographic.

New steroids from mangrove-associated fungus Trichoderma asperellum SCNU-F0048.

Chemical investigation of the fungus Trichoderma asperellum SCNU-F0048 led to the discovery of two new steroids, ergosta-4,6,8 (14),22-tetraen-3-(3'-methyl-4'-hydroxyl-γ-butenolide) (1) and camphosterol B (2), as well as two known compounds, i.e. stigmasta-4,6,8(14),22-tetraen-3-one (3) and 4-hydroxy-17- methylincisterol (4). Their structures were elucidated by extensive nuclear mangnetic resonance, spectrum analysis and single crystal X-ray diffraction analysis. Bioassay disclosed that compound 1 showed strong cytotoxicity to a panel of tumor cell lines. Moreover, compounds 1 and 2 showed excellent antifungal activity against Penicillium italicum with IC50 values of 0.016 and 0.022 µM, respectively.

A case report of intrahepatic bile duct dilatation caused by WDR19 gene mutation and presented as Caroli syndrome.

Background: Caroli syndrome or Caroli disease is characterized by focal dilation of the intrahepatic bile ducts, with or without congenital liver fibrosis. Mutations in the WDR19 gene can result in nephropathy, an autosomal recessive cystic kidney disease. However, this genetic mutation is clinically associated with Caroli syndrome or disease. We hypothesize that WDR19 gene mutations may contribute to extrarenal phenotypes such as Caroli disease or syndrome. Case Description: The outpatient department received a 1-year-old male patient with persistent dilated bile ducts for over four months. Subsequent ultrasound examination revealed liver cirrhosis, splenomegaly, and cystic dilatation of the intrahepatic bile duct. He was subsequently admitted for comprehensive diagnosis and treatment. Accordingly, we performed computed tomography (CT)-hepatic portal venography, magnetic resonance-cholangiography, and the plain liver scan, the results revealed liver cirrhosis, splenomegaly, cystic dilatation of the intrahepatic bile duct, as well as atypical hyperplasia nodules in the right posterior lobe of the liver and lymphatic hyperplasia and enlargement in the porta hepatis and the space between the liver and stomach. As the possibility of early small liver cancer could not be excluded due to the presence of nodules, surgical resection was performed followed by pathological examination and whole genome exome testing. The pathological findings revealed hepatocyte swelling, hydropic degeneration, and sporadic necrosis. Fibrous tissue hyperplasia was observed in the portal vein area, along with local pseudolobule formation. Also, numerous small bile duct hyperplasia was observed with lymphocyte infiltration, which is consistent with cirrhosis. Moreover, the hepatocytes of the small focal area showed atypical hyperplasia. Considering the above findings, Caroli syndrome was diagnosed. The genetic results showed two heterozygous mutations in the WDR19 gene, c.2290delC (p.Q764Nfs*29) and c.2401G>C (p.G801R). Therefore, the child's intrahepatic bile duct dilatation and cirrhosis were considered as the manifestations of Caroli syndrome caused by mutations in the WDR19 gene. Conclusions: Mutations in the WDR19 gene can manifest as Caroli disease or Caroli syndrome. For the definite diagnosis of liver diseases of unknown etiology, whole exome sequencing may be more conducive.

Penifuranone A: A Novel Alkaloid from the Mangrove Endophytic Fungus Penicillium crustosum SCNU-F0006.

One previously undescribed alkaloid, named penifuranone A (1), and three known compounds (2-4) were isolated from the mangrove endophytic fungus Penicillium crustosum SCNU-F0006. The structure of the new alkaloid (1) was elucidated based on extensive spectroscopic data analysis and single-crystal X-ray diffraction analysis. Four natural isolates and one new synthetic derivative of penifuranone A, compound 1a, were screened for their antimicrobial, antioxidant, and anti-inflammatory activities. Bioassays revealed that penifuranone A (1) exhibited strong anti-inflammatory activity in vitro by inhibiting nitric oxide (NO) production in lipopolysaccharide-activated RAW264.7 cells with an IC50 value of 42.2 µM. The docking study revealed that compound 1 exhibited an ideal fit within the active site of the murine inducible nitric oxide synthase (iNOS), establishing characteristic hydrogen bonds.

Variation and interrelationships in the growth, yield, and lodging of oat under different planting densities.

Background: Oat is a dual-purpose cereal used for grain and forage. The demand of oat has been increasing as the understanding of the nutritional, ecological, and economic values of oat increased. However, the frequent lodging during the growing period severely affect the high yielding potential and the quality of the grain and forage of oat. Methods: Therefore, we used the lodging-resistant variety LENA and the lodging-sensitive variety QY2 as materials, implementing four different planting densities: 2.25×106 plants/ha (D1), 4.5×106 plants/ha (D2), 6.75×106 plants/ha (D3), and 9×106 plants/ha (D4). At the appropriate growth and development stages, we assessed agronomic traits, mechanical characteristics, biochemical compositions, yield and its components. The study investigated the impact of planting density on the growth, lodging, and yield of oat, as well as their interrelationships. Additionally, we identified the optimal planting density to establish a robust crop structure. The research aims to contribute to the high-yield and high-quality cultivation of oat. Results: We observed that with increasing planting density, plant height, grass and grain yields of both varieties first increased and then decreased; root fresh weight, stem diameter, stem wall thickness, stem puncture strength, breaking strength, compressive strength, lignin and crude fiber contents, and yield components decreased; whereas the lodging rate and lodging coefficient increased. Planting density affects lodging by regulating plant height, height of center of gravity, stem wall thickness, internode length, and root fresh weight of oat. Additionally, it can impact stem mechanical strength by modulating the synthesis of lignin and crude fiber, which in turn affecting lodging resistance. Plant height, height of center of gravity, stem wall thickness, internode length, root fresh weight, breaking strength, compressive strength, lignin and crude fiber content, single-plant weight, grain yield and 1,000-grain weight can serve as important indicators for evaluating oat stem lodging resistance. We also noted that planting density affected grain yield both directly and indirectly (by affecting lodging); high density increased lodging rate and decreased grain yield, mainly by reducing 1,000-grain weight. Nonetheless, there was no significant relationship between lodging and grass yield. As appropriate planting density can increase the yield while maintaining good lodging resistance, in this study, 4.5×106 plants/ha (D2) was found to be the best planting density for oat in terms of lodging resistance and grass and grain yield. These findings can be used as a reference for oat planting.

Identification of Susceptibility Genes Underlying Bovine Respiratory Disease in Xinjiang Brown Cattle Based on DNA Methylation.

DNA methylation is a form of epigenetic regulation, having pivotal parts in controlling cellular expansion and expression levels within genes. Although blood DNA methylation has been studied in humans and other species, its prominence in cattle is largely unknown. This study aimed to methodically probe the genomic methylation map of Xinjiang brown (XJB) cattle suffering from bovine respiratory disease (BRD), consequently widening cattle blood methylome ranges. Genome-wide DNA methylation profiling of the XJB blood was investigated through whole-genome bisulfite sequencing (WGBS). Many differentially methylated regions (DMRs) obtained by comparing the cases and controls groups were found within the CG, CHG, and CHH (where H is A, T, or C) sequences (16,765, 7502, and 2656, respectively), encompassing 4334 differentially methylated genes (DMGs). Furthermore, GO/KEGG analyses showed that some DMGs were involved within immune response pathways. Combining WGBS-Seq data and existing RNA-Seq data, we identified 71 significantly differentially methylated (DMGs) and expressed (DEGs) genes (p < 0.05). Next, complementary analyses identified nine DMGs (LTA, STAT3, IKBKG, IRAK1, NOD2, TLR2, TNFRSF1A, and IKBKB) that might be involved in the immune response of XJB cattle infected with respiratory diseases. Although further investigations are needed to confirm their exact implication in the involved immune processes, these genes could potentially be used for a marker-assisted selection of animals resistant to BRD. This study also provides new knowledge regarding epigenetic control for the bovine respiratory immune process.

The etiology and differential diagnosis of "autoimmune hepatitis-like liver disease" in children: a single-center retrospective study.

Background: Children with autoimmune hepatitis (AIH) often present with symptoms similar to those of other liver diseases. This study consists of a comparison between the clinical and histological characteristics of AIH and those of other four AIH-like liver diseases [i.e., drug-induced liver injury (DILI), gene deficiency, infectious liver disease and other etiology of liver disease], as well as an evaluation of the AIH scoring system's diagnostic performance. Methods: All children with AIH-like liver disease at our center from January 2013 to December 2022 were included. The clinical and histological characteristics of the AIH group were retrospectively analyzed and compared with those of the other four groups. Results: A total of 208 children were included and divided into AIH group (18 patients), DILI group (38 patients), gene deficiency group (44 patients), infectious liver disease group (74 patients), and other etiology group (34 patients). The antinuclear antibodies (ANA) ≥ 1:320 rate was significantly higher in the AIH compared to the other four groups after multiple testing correction (p < 0.0125), while patients with positive antibodies to liver-kidney microsomal-1 (anti-LKM1, n = 3) and smooth muscle antibodies (SMA, n = 2) were only observed in the AIH group. The positive rates of antibodies to liver cytosol type1 (anti-LC1) and Ro52 were higher than those in the other four groups. The serum immunoglobulin G (IgG) and globulin levels, as well as the proportions of portal lymphoplasmacytic infiltration, lobular hepatitis with more than moderate interface hepatitis, and lobular hepatitis with lymphoplasmacytic infiltration, were significantly higher in the AIH group than in the other four groups after multiple testing correction (p < 0.0125). The cirrhosis rate in the AIH group was higher than that in the DILI and infectious liver disease groups (p < 0.0125). Both the simplified (AUC > 0.73) and the revised systems (AUC > 0.93) for AIH have good diagnostic performance, with the latter being superior (p < 0.05). Conclusion: Positive autoantibodies (ANA ≥ 1:320 or anti-LKM1 positive, or accompanied by SMA, anti-LC1 or Ro-52 positive) and elevated serum IgG or globulin levels contribute to early recognition of AIH. The presence of lobular hepatitis with more than moderate interface hepatitis and lymphoplasmacytic infiltration contribute to the diagnosis of AIH.

Symptom profiles in patients receiving maintenance hemodialysis and their association with quality of life: a longitudinal study.

PURPOSE: Many patients receiving maintenance hemodialysis experience one or multiple symptoms. Using a latent profile analysis to identify symptom profiles may provide insights for person-centered symptom management strategies. METHODS: This is a longitudinal study based on data from patients receiving maintenance hemodialysis at three hospitals in Shanghai, China. Of the 448 patients who completed the surveys at baseline (T1), 309 completed the 12-month follow-up survey (T2). Symptoms and quality of life were measured by the Chinese version of Kidney Disease Quality of Life 36 Short Form. The optimal classification of symptoms was identified using latent profile analysis. RESULTS: Five symptom profiles were identified: High (9.2%), Fatigue and Gastrointestinal (7.1%), Fatigue and Skin (10.7%), Skin (23.2%), and Low (49.8%). The high-symptom profile and the-fatigue-and-skin-symptom profile were associated with a lower level of physical functioning, a higher burden of kidney disease, and more negative effects of kidney disease than the low symptom profile at T1 and T2. Multivariate regression analysis showed that the high-symptom profile predicted a poorer physical functioning at T2, and the-fatigue-and-skin-symptom profile predicted a poorer physical functioning and higher burden of kidney disease at T2. CONCLUSION: Patients receiving maintenance hemodialysis reported unique symptom experiences which could be classified into different profiles. Patients reporting an overall high level of symptoms or a high level of fatigue and skin symptoms were more likely to have a poorer quality of life.

The pore-rhizosheath shapes maize root architecture by enhancing root distribution in macropores.

Pores and old root-channels are preferentially used by roots to allow them to penetrate hard soils. However, there are few studies that have accounted for the effects of pore-rhizosheath on root growth. In this study, we developed an approach by adding the synthetic root exudates using a porous stainless tube with 0.1-mm micropores through a peristaltic pump to reproduce the rhizosheath around the artificial pore, and investigated the effects of pores with and without rhizosheaths on maize root growth in a dense soil. The results indicated that the artificial rhizosheath was about 2.69 mm wide in the region surrounding the pores. The rhizosheath had a higher content of organic carbon, total nitrogen, and abundance of Actinobacteria than that of the bulk soil. Compared with the artificial macropores, the artificial root-pores with a rhizosheath increased the opportunities for root utilisation of the pores space, promoting steeper and deeper root growth. It is concluded that the pore-rhizosheath has a significant impact on root architecture by enhancing root distribution in macropores.

Prognostic Effect of Masked Morning Hypertension in Chinese Inpatients With Non-dialysis Chronic Kidney Disease: A Multicenter Retrospective Study.

BACKGROUND: This study aimed to elucidate the prognostic role of Masked Morning Hypertension (MMH) in non-dialysis-dependent chronic kidney disease (NDD-CKD). METHODS: 2,130 NDD-CKD patients of the inpatient department were categorized into four blood pressure (BP) groups: clinical normotension (CH-), clinical hypertension (CH+) with morning hypertension (MH+), and without MH+ (MH-) respectively. The correlation between these four BP types and the primary (all-cause mortality) and secondary endpoints (cardio-cerebrovascular disease [CVD] and end-stage kidney disease [ESKD]) was analyzed. RESULTS: The prevalence of MH and MMH were 47.4% and 14.98%, respectively. Morning hypertension independently increased the risk of all-cause mortality (P = 0.004) and CVD (P < 0.001) but not ESKD (P = 0.092). Masked morning hypertension was associated with heightened all-cause mortality (HR = 4.22, 95% CI = 1.31-13.59; P = 0.02) and CVD events (HR = 5.14, 95% CI = 1.37-19.23; P = 0.02), with no significant association with ESKD (HR = 1.18, 95% CI = 0.65-2.15; P = 0.60). When considering non-CVD deaths as a competing risk factor, a high cumulative incidence of CVD events was observed in the MMH group (HR = 5.16, 95% CI = 1.39-19.08). CONCLUSIONS: MMH is an independent risk factor for all-cause mortality and combined cardiovascular and cerebrovascular events in NDD-CKD patients, underscoring its prognostic significance. This highlights the need for comprehensive management of MH in this population.

The safety and tolerability of a one strength dose-escalation scheme for subcutaneous immunotherapy with a native house dust mite extract in Chinese children: A multicenter, randomized, open label clinical trial.

Background: Allergen immunotherapy (AIT) is still the only treatment that may affect the natural cause of allergic disease. This study is to investigate whether an accelerated up-dosing scheme for subcutaneous allergen immunotherapy (SCIT) using a native house dust mite (HDM) allergen extract is as safe as the standard 3-strengths dose-escalation scheme in children with moderate to severe allergic rhinitis or rhinoconjunctivitis with or without asthma in China. Methods: In this multicenter, open label, randomized controlled trial, the children aged 5-14 years were randomized 1:1 either to One Strength group or the Standard group. The dose escalation scheme for patients in the One Strength group included 6 injections of strength 3, whereas the Standard group comprised 14 injections using strength 1, 2, and 3. All treatment-emergent adverse events (TEAEs) were recorded and analyzed. The 5-point Likert scale was used to assess tolerability (ChiCTR2100050311). Results: Overall, 101 children were included in the Safety Set (One Strength group: 50 vs. Standard group: 51). A total of 26 TEAEs were reported for 15 children. TEAEs related to AIT occurred in 10 % of the children in the One Strength group and 11.8 % of the Standard group. The number of systemic adverse reactions was comparable in both groups (One Strength: 5 vs. Standard: 4). No serious TEAEs was recorded for either group. 90.0 % of patients in the One Strength group reached the maintenance dose without an interventional dose adjustment due to adverse events, compared to 78.4 % in the Standard group. All patients who completed the dose-escalation phase reached the recommended maintenance dose of 1.0 ml of strength 3.Investigators and patients rated the tolerability of the One Strength regimen slightly better than the Standard scheme. Conclusions: This exploratory study suggests that the accelerated One Strength dose-escalation scheme is comparable in safety and tolerability to the Standard regimen. However, due to the preliminary nature and small sample size, further research with larger sample sizes and robust study designs is necessary for confirmation.

Targeting FTO induces colorectal cancer ferroptotic cell death by decreasing SLC7A11/GPX4 expression.

Ferroptosis is a newly identified iron-dependent form of death that is becoming increasingly recognized as a promising avenue for cancer therapy. N6-methyladenosine (m6A) is the most abundant reversible methylation modification in mRNA contributing to tumorigenesis. However, the crucial role of m6A modification in regulating ferroptosis during colorectal cancer (CRC) tumorigenesis remains elusive. Herein, we find that m6A modification is increased during ferroptotic cell death and correlates with the decreased m6A demethylase fat mass and obesity-associated protein (FTO) expression. Functionally, we demonstrate that suppressing FTO significantly induces CRC ferroptotic cell death, as well as enhancing CRC cell sensitivity to ferroptosis inducer (Erastin and RSL3) treatment. Mechanistically, high FTO expression increased solute carrier family 7 member 11 (SLC7A11) or glutathione peroxidase 4 (GPX4) expressions in an m6A-YTHDF2 dependent manner, thereby counteracting ferroptotic cell death stress. In addition, we identify Mupirocin as a novel inhibitor of FTO, and Mupirocin induces CRC ferroptosis and inhibits tumor growth. Clinically, the levels of FTO, SLC7A11, and GPX4, are highly correlated expression in CRC tissues. Our findings reveal that FTO protects CRC from ferroptotic cell death in promoting CRC tumorigenesis through triggering SLC7A11/GPX4 expression.

Rituximab potentially improves clinical outcomes of CAR-T therapy for r/r B-ALL via sensitizing leukemia cells to CAR-T-mediated cytotoxicity and reducing CAR-T exhaustion.

PURPOSE: Despite chimeric antigen receptor (CAR) T-cell therapy has achieved great advances in recent year, approximately 50% of relapsed/refractory B cell acute lymphoblastic leukemia (r/r B-ALL) patients treated with CAR-T experience relapse 6 months post CAR-T treatment. CD20 express on 30 to 50% of B-ALL, which makes CD20 Monoclonal Antibody as one of the potential therapy strategies to decrease the tumor burden and improve the efficacy of CAR-T therapy. Adding Rituximab to chemotherapy protocol had been demonstrated to improve the outcome for CD20-positive ALL. However, rare study explored the influence of Rituximab combined with CAR-T therapy. METHODS: We retrospectively analyzed 20 r/r B-ALL patients who received CAR-T therapy, all of whom had failed multiple lines of therapy. Before CAR-T infusion, we administered Rituximab to 10 patients with high CD20 expression at a dose of 375 mg/m2 for 1 day. Meanwhile, we selected 10 patients with the comparable features who underwent CAR-T treatment without Rituximab in the same period as the control group. In vitro, the surface molecule expression and killing of CAR-T post Rituximab-treated B-ALL cells co-incubated with CAR-T cells were detected by flow cytometry. RESULTS: The median follow-up of Rituximab and Control groups were 29.27 and 9.83 months. We found that adding Rituximab may confer a favorable prognosis compared with Control group. The 2-year overall survival (OS) and leukemia-free survival (LFS) rates both were longer in the Rituximab group (90% vs. 26.7%, p = 0.0342; 41.7% vs. 25%, p = 0.308). In vitro, we observed that Rituximab-treated tumour cells are more sensitive to CAR-T killing and a broad range of cytokines and chemokines were produced when Rituximab-treated Nalm-6 cells co-cultured with 19-22CAR-T cells, such as interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2). To investigate whether Rituximab has an effect on CAR-T persistence, we stimulated CAR-T cells repeatedly in vitro with Rituximab-treated Nalm-6 to evaluate the changes in CAR-T surface exhaustion molecules at different times. We found that the expression of exhaustion molecules (LAG-3, PD-1, TIM-3) on CAR-T cells were significantly lower in the Rituximab group than in the Control group. CONCLUSION: Rituximab combined with CAR-T therapy is effective for improving the long-term prognosis of B-ALL patients who have failed multiple lines of therapy. In vitro, we observed that rituximab potentially improves CAR-T efficacy by sensitizing ALL to CART-mediated cytotoxicity and reducing CAR-T exhaustion.

Dissimilarity in radial growth and response to drought of Korshinsk peashrub (Caragana korshinskii Kom.) under different management practices in the western Loess Plateau.

Quantitative assessment of tree responses to the local environment can help provide scientific guidance for planted forest management. However, research on the climate-growth relationship of Korshinsk peashrub (Caragana korshinskii Kom.) under different land preparation and post-management (irrigation) conditions is still insufficient. In this study, we collected 223 tree-ring samples from Korshinsk peashrubs using dendroecological methods and systematically quantified the relationships between shrub growth and climatic factors under different management practices in the western Loess Plateau of China. Our findings demonstrated that drought stress caused by scarce precipitation from April to August was the primary factor limiting the growth of Korshinsk peashrubs in the northern and southern mountains of Lanzhou. The "climwin" climate model results showed a weak correlation between natural Korshinsk peashrub growth and drought stress, whereas planted Korshinsk peashrub under rain-fed conditions in the southern mountain was significantly (p<0.05) limited by drought stress from April to August. Moreover, planted Korshinsk peashrub growth under irrigated conditions in the northern mountain was limited only by drought stress in January. Drought model explained 28.9%, 38.3%, and 9.80% of the radial growth variation in Xiguoyuan (XGY), Shuibaozhan (SBZ), and Zhichagou (ZCG) sites, respectively. Artificial supplementary irrigation alleviated the limitation of drought on planted forest growth, which may be implemented for Korshinsk peashrubs planted on sunny slopes, while planted Korshinsk peashrubs under natural rain-fed conditions can be planted on shady slopes through rainwater harvesting and conservation measures such as horizontal ditches and planting holes.