Elevated lactate/albumin ratio is associated with poor prognosis in sepsis patients: A systematic review and meta-analysis.

Background: The aim of this study was to explore the association between lactate/albumin ratio and the prognosis of sepsis patients. Methods: A computerized search was performed in Pubmed, EMbase, Ovid, Medline, and Google Scholar to collate relevant studies. The results were compared using standardized mean differences (SMD)/odds ratio (OR) and 95% confidence intervals (CI). Prospective and retrospective cohort studies were both included in this study.

Tissue Culture Response and In Vitro Plant Regeneration of Malus 'Baiyun' (a New Cultivar of Ornamental Crabapple).

Malus 'Baiyun' (registration no. 20210210), a new crabapple cultivar, was registered in 2021 by the Nanjing Forestry Unversity. However, the difficult rooting has greatly limited the production of high-quality M. 'Baiyun' in industrialization development. There is thus a pressing need to develop an organogenesis protocol for the in vitro propagation of M. 'Baiyun' to alleviate a shortage of high-quality M. 'Baiyun' seedlings. The results showed that choosing the apical bud in mid-March was an excellent explant material. To promote proliferation, the highest proliferation (6.27) of apical shoots was cultured on Murashige and Skoog (MS) medium supplemented with 0.5 mg·L-1 6-benzylaminopurine(6-BA) + 0.05 mg·L-1 indole-3-butyric acid (IBA). Subsequently, a 100% rooting rate, average number of roots per shoot of 6.2 and maximum length of roots of 4.96 cm were obtained on half-strength Murashige and Skoog (1/2 MS) medium with the application of 0.5 mg·L-1 naphthaleneacetic acid (NAA) or 0.6 mg·L-1 NAA + 0.7 mg·L-1 IBA. Additionally, thick and lateral roots were obtained with 0.6 mg·L-1 NAA + 0.7 mg·L-1 IBA. Our study is the first to establish an effective organogenesis protocol for new crabapple cultivars using stem segments.

Selective production of high-value fuel via catalytic upgrading of bio-oil over nitrogen-doped carbon-alumina hybrid supported cobalt catalysts.

Bio-oil derived from biomass fast pyrolysis can be upgraded to gasoline and diesel alternatives by catalytic hydrodeoxygenation (HDO). Here, the novel nitrogen-doped carbon-alumina hybrid supported cobalt (Co/NCAn, n = 1, 2.5, 5) catalyst is established by a coagulation bath technique. The optimized Co/NCA2.5 catalyst presented 100 % conversion of guaiacol, high selectivity to cyclohexane (93.6 %), and extremely high deoxygenation degree (97.3 %), respectively. Therein, the formation of cyclohexanol was facilitated by stronger binding energy and greater charge transfer between Co and NC which was unraveled by density functional theory calculations. In addition, the appropriate amount of Lewis acid sites enhanced the cleavage of the C-O bond in cyclohexanol, finally resulting in a remarkable selectivity for cyclohexane. Finally, the Co/NCA2.5 catalyst also exhibited excellent selectivity (93.1 %) for high heating value hydrocarbon fuel in crude bio-oil HDO. This work provides a theoretical basis on N dopants collaborating alumina hybrid catalysts for efficient HDO reaction.

Valence-Change MnO2-Coated Arsenene Nanosheets as a Pin1 Inhibitor for Hepatocellular Carcinoma Treatment.

The heterogeneity of hepatocellular carcinoma (HCC) can prevent effective treatment, emphasizing the need for more effective therapies. Herein, we employed arsenene nanosheets coated with manganese dioxide and polyethylene glycol (AMPNs) for the degradation of Pin1, which is universally overexpressed in HCC. By employing an "AND gate", AMPNs exhibited responsiveness toward excessive glutathione and hydrogen peroxide within the tumor microenvironment, thereby selectively releasing AsxOy to mitigate potential side effects of As2O3. Notably, AMPNs induced the suppressing Pin1 expression while simultaneously upregulation PD-L1, thereby eliciting a robust antitumor immune response and enhancing the efficacy of anti-PD-1/anti-PD-L1 therapy. The combination of AMPNs and anti-PD-1 synergistically enhanced tumor suppression and effectively induced long-lasting immune memory. This approach did not reveal As2O3-associated toxicity, indicating that arsenene-based nanotherapeutic could be employed to amplify the response rate of anti-PD-1/anti-PD-L1 therapy to improve the clinical outcomes of HCC patients and potentially other solid tumors (e.g., breast cancer) that are refractory to anti-PD-1/anti-PD-L1 therapy.

Study on the recovery of bladder function in patients with cervical cancer after operation by portable ultrasound combined.

BACKGROUND: Postoperative urination dysfunction is a common complication after surgery in patients with cervical cancer. Portable bladder ultrasound are commonly utilized in clinical practice for measuring residual urine volume. This study aimed to the effect of bladder function training combined with portable ultrasound monitoring on bladder function recovery in patients with cervical cancer after training. METHODS: A total of 40 postoperative patients with cervical cancer were randomly divided into a control group (A) and an experimental group (B) of 20 cases each. Group A was given routine postoperative care, while group B was given bladder function training. Urgent urine bladder volume were taken twice daily after removal of the urinary catheter and monitored for five consecutive days. The difference of urgent urine bladder volume and bladder filling rate were compared by t-test and chi-square test respectively. The 36-item Short Form Health Survey (SF-36) was used to evaluate the quality of life of patients before and after intervention, and compared by Mann-Whitney U test. RESULTS: There was no significant difference in preoperative urgent urine volume between the two groups. After catheter removal, the bladder volume of patients in the B increased, while the bladder volume of patients in the A increased less and fluctuated greatly. The bladder filling rate in the A was significantly lower than that in the B (5/15 vs 17/18, p < 0.05). After intervention, the quality of life of the experimental group was better than that of the control group, including scores of general health, mental health, vitality, and physical role (p < 0.05). CONCLUSION: Postoperative cervical cancer patients trained to hold urine by portable ultrasound monitoring are able to recover bladder function.

Accelerating 3D genomics data analysis with Microcket.

The three-dimensional (3D) organization of genome is fundamental to cell biology. To explore 3D genome, emerging high-throughput approaches have produced billions of sequencing reads, which is challenging and time-consuming to analyze. Here we present Microcket, a package for mapping and extracting interacting pairs from 3D genomics data, including Hi-C, Micro-C, and derivant protocols. Microcket utilizes a unique read-stitch strategy that takes advantage of the long read cycles in modern DNA sequencers; benchmark evaluations reveal that Microcket runs much faster than the current tools along with improved mapping efficiency, and thus shows high potential in accelerating and enhancing the biological investigations into 3D genome. Microcket is freely available at https://github.com/hellosunking/Microcket .

Silk fibroin promotes H3K9me3 expression and chromatin reorganization to regulate endothelial cell proliferation.

Silk fibroin (SF), which is extensively utilized in tissue engineering and vascular grafts for enhancing vascular regeneration, has not been thoroughly investigated for its epigenetic effects on endothelial cells (EC). This study employed RNA sequencing analysis to evaluate the activation of histone modification regulatory genes in EC treated with SF. Subsequent investigations revealed elevated H3K9me3 levels in SF-treated EC, as evidenced by immunofluorescence and western blot analysis. The study utilized H2B-eGFP endothelial cells to demonstrate that SF treatment results in the accumulation of H2B-marked chromatin in the nuclear inner cavities of EC. Inhibition of H3K9me3 levels by a histone deacetylase inhibitor TSA decreased cell proliferation. Furthermore, the activation of the MAPK signaling pathway using chromium picolinate decreased the proliferative activity and H3K9me3 level in SF-treated EC. SF also appeared to enhance cell growth and proliferation by modulating the H3K9me3 level and reorganizing chromatin, particularly after oxidative stress induced by H2O2 treatment. In summary, these findings indicate that SF promotes EC proliferation by increasing the H3K9me3 level even under stress conditions.

Magnetic Resonance Elastography of Anterior Mediastinal Tumors.

BACKGROUND: Preoperative differentiation of the types of mediastinal tumors is essential. Magnetic resonance (MR) elastography potentially provides a noninvasive method to assess the classification of mediastinal tumor subtypes. PURPOSE: To evaluate the use of MR elastography in anterior mediastinal masses and to characterize the mechanical properties of tumors of different subtypes. STUDY TYPE: Prospective. SUBJECTS: 189 patients with anterior mediastinal tumors (AMTs) confirmed by histopathology (62 thymomas, 53 thymic carcinomas, 57 lymphomas, and 17 germ cell tumors). FIELD STRENGTH/SEQUENCE: A gradient echo-based 2D MR elastography sequence and a diffusion-weighted imaging (DWI) sequence at 3.0 T. ASSESSMENT: Stiffness and apparent diffusion coefficients (ADC) were measured in AMTs using MR elastography-derived elastograms and DWI-derived ADC maps, respectively. The aim of this study is to identify whether MR elastography can differentiate between the histological subtypes of ATMs. STATISTICAL TESTS: One-way analysis of variance (ANOVA), two-way ANOVA, Pearson's linear correlation coefficient (r), receiver operating characteristic (ROC) curve analysis; P < 0.05 was considered significant. RESULTS: Lymphomas had significantly lower stiffness than other AMTs (4.0 ± 0.63 kPa vs. 4.8 ± 1.39 kPa). The mean stiffness of thymic carcinomas was significantly higher than that of other AMTs (5.6 ± 1.41 kPa vs. 4.2 ± 0.94 kPa). Using a cutoff value of 5.0 kPa, ROC analysis showed that lymphomas could be differentiated from other AMTs with an accuracy of 59%, sensitivity of 97%, and specificity of 38%. Using a cutoff value of 5.1 kPa, thymic carcinomas could be differentiated from other AMTs with an accuracy of 84%, sensitivity of 67%, and specificity of 90%. However, there was an overlap in the stiffness values of individual thymomas (4.2 ± 0.71; 3.9-4.5), thymic carcinomas (5.6 ± 1.41; 5.0-6.1), lymphomas (4.0 ± 0.63; 3.8-4.2), and germ cell tumors (4.5 ± 1.79; 3.3-5.6). DATA CONCLUSION: MR elastography-derived stiffness may be used to evaluate AMTs of various histologies. TECHNICAL EFFICACY: Stage 2.

Remediation effect of walnut shell biochar on Cu and Pb co-contaminated soils in different utilization types.

Biochar, with its dual roles of soil remediation and carbon sequestration, is gradually demonstrating great potential for sustainability in agricultural and ecological aspects. In this study, a porous biochar derived from walnut shell wastes was prepared via a facile pyrolysis coupling with in-situ alkali etching method. An incubation study was conducted to investigate its performance in stabilizing copper (Cu) and lead (Pb) co-contaminated soils under different utilization types. The biochar effectively decreased the bioavailable Cu (8.5-91.68%) and Pb (5.03-88.54%), while increasing the pH, CEC, and SOM contents in both soils. Additionally, the results of sequential extraction confirmed that biochar promoted the transformation of the labile fraction of Cu and Pb to stable fractions. The mechanisms of Cu and Pb stabilization were found to be greatly dependent on the soil types. For tea plantation yellow soil, the main approach for stabilization was the complexation of heavy metals with abundant organic functional groups and deprotonation structure. Surface electrostatic adsorption and cation exchange contributed to the immobilization of Cu and Pb in vegetable-cultivated purple soil. This research provides valuable information for the stabilization of Cu and Pb co-contaminated soils for different utilization types using environmentally-friendly biochar.

High resistance risk of Phytophthora colocasiae to azoxystrobin in southeastern of China.

Quinone outside inhibitor (QoI) has been applied to manage taro leaf blight caused by Phytophthora colocasiae in southeastern of China for many years. The risk of P. colocasiae to QoI and the potential resistant mechanism remain unknown. In this study, the 74 P. colocasiae strains were sampled from southeastern of China. Sequence analysis of the QoI target Cytb showed one nucleotide variant in the fragment of this gene in this population, producing two haplotypes. The nucleotide variant leads to codon change at 142 (GGT to GCT) producing A142 (alanine) and G142 (glycine) in Hap_1 and Hap_2 strains, respectively. The sensitivity differentiation to azoxystrobin of two haplotypes were observed in vitro. The Hap_1 and Hap_2 strains were confirmed resistant and sensitive by control efficacy of label rate fungicide application, which was 3.0% and 88.8% treated with 500 µg/mL azoxystrobin, respectively. In addition, 10.0 µg/mL azoxystrobin plus 50 µg/mL salicylhydroxamic acid (SHAM) supplemented in PDA medium was identified as a discriminatory dose for differentiation of these two phenotype strains. The azoxystrobin resistant frequency reached 86.5%, indicating prevalence of QoI resistance in the field. Further fitness related features showed that no significant difference in temperature sensitivity, mycelial growth rate, sporangia production, zoospore release and aggressiveness between azoxystrobin-resistant and sensitive strains indicating no potential fitness cost for azoxystrobin resistance. Taken together, azoxystrobin resistance need to be taken into consideration to manage taro leaf blight in southeastern of China.

Transcriptome Analysis Reveals Antioxidant Defense Mechanisms in the Silkworm Bombyx mori after Exposure to Lead.

Lead (Pb) is a major source of heavy metal contamination, and poses a threat to biodiversity and human health. Elevated levels of Pb can hinder insect growth and development, leading to apoptosis via mechanisms like oxidative damage. The midgut of silkworms is the main organ exposed to heavy metals. As an economically important lepidopteran model insect in China, heavy metal-induced stress on silkworms causes considerable losses in sericulture, thereby causing substantial economic damage. This study aimed to investigate Pb-induced detoxification-related genes in the midgut of silkworms using high-throughput sequencing methods to achieve a deeper comprehension of the genes' reactions to lead exposure. This study identified 11,567 unigenes and 14,978 transcripts. A total of 1265 differentially expressed genes (DEGs) were screened, comprising 907 upregulated and 358 downregulated genes. Subsequently, Gene Ontology (GO) classification analysis revealed that the 1265 DEGs were distributed across biological processes, cellular components, and molecular functions. This suggests that the silkworm midgut may affect various organelle functions and biological processes, providing crucial clues for further exploration of DEG function. Additionally, the expression levels of 12 selected detoxification-related DEGs were validated using qRT-PCR, which confirmed the reliability of the RNA-seq results. This study not only provides new insights into the detoxification defense mechanisms of silkworms after Pb exposure, but also establishes a valuable foundation for further investigation into the molecular detoxification mechanisms in silkworms.

GITR exacerbates lysophosphatidylcholine-induced macrophage pyroptosis in sepsis via posttranslational regulation of NLRP3.

The NLRP3 inflammasome functions as an inflammatory driver, but its relationship with lipid metabolic changes in early sepsis remains unclear. Here, we found that GITR expression in monocytes/macrophages was induced by lysophosphatidylcholine (LPC) and was positively correlated with the severity of sepsis. GITR is a costimulatory molecule that is mainly expressed on T cells, but its function in macrophages is largely unknown. Our in vitro data showed that GITR enhanced LPC uptake by macrophages and specifically enhanced NLRP3 inflammasome-mediated macrophage pyroptosis. Furthermore, in vivo studies using either cecal ligation and puncture (CLP) or LPS-induced sepsis models demonstrated that LPC exacerbated sepsis severity/lethality, while conditional knockout of GITR in myeloid cells or NLRP3/caspase-1/IL-1ß deficiency attenuated sepsis severity/lethality. Mechanistically, GITR specifically enhanced inflammasome activation by regulating the posttranslational modification (PTM) of NLRP3. GITR competes with NLRP3 for binding to the E3 ligase MARCH7 and recruits MARCH7 to induce deacetylase SIRT2 degradation, leading to decreasing ubiquitination but increasing acetylation of NLRP3. Overall, these findings revealed a novel role of macrophage-derived GITR in regulating the PTM of NLRP3 and systemic inflammatory injury, suggesting that GITR may be a potential therapeutic target for sepsis and other inflammatory diseases. GITR exacerbates LPC-induced macrophage pyroptosis in sepsis via posttranslational regulation of NLRP3. According to the model, LPC levels increase during the early stage of sepsis, inducing GITR expression on macrophages. GITR not only competes with NLRP3 for binding to the E3 ligase MARCH7 but also recruits MARCH7 to induce the degradation of the deacetylase SIRT2, leading to decreasing ubiquitination but increasing acetylation of NLRP3 and therefore exacerbating LPC-induced NLRP3 inflammasome activation, macrophage pyroptosis and systemic inflammatory injury.

Therapeutic mechanism of Cornus Officinalis Fruit Coreon on ALI by AKT/Nrf2 pathway and gut microbiota.

BACKGROUND: Acute liver injury (ALI) often precipitates severe liver function impairment and is associated with high mortality rates. Traditional Chinese Medicine (TCM) has demonstrated efficacy in mitigating hepatic damage by exhibiting anti-inflammatory effects, enhancing antioxidant activity, and modulating gut microbiota (GM). Numerous studies have identified similar or identical bioactive compounds within the Cornus Officinalis Fruit Coreon(COFO) and its flesh. Notably, Cornus Officinalis has been shown to possess potent hepatoprotective properties. However, studies on the pharmacological effects and mechanism of action of COFO for hepatoprotection have received little attention. PURPOSE: To elucidate the mechanisms underlying the COFO effect in ALI by integrating GM gene sequencing, quantifying Short-Chain Fatty Acids (SCFAs), and examining relevant signaling pathways. MATERIALS AND METHODS: A rat model for carbon tetrachloride (CCl4)-induced ALI was established, and the best liver protective components of COFO were selected by pathological observation and biochemical determination. The therapeutic efficacy of COFO in mitigating liver injury was elucidated through an integrated approach that included network pharmacology, biochemical indexes, 16S rDNA sequencing analyses, short-chain fatty acids, Western blotting analysis of protein levels, and immunohistochemical evaluations. RESULTS: Pharmacological evaluation established that the n-butanol fraction (CNBP) provided optimal hepatoprotective effects. Firstly, the chemical constituents of CNBP were characterized, and its principal anti-ALI targets, such as ALI, AKT1, TNF, and IL-6, were identified through network pharmacology analysis. Secondly, experimental validation revealed that CNBP may enhance the genetic diversity of the GM, augmenting the diversity of the microbial community, increasing the levels of three SCFAs, and activating key proteins in the AKT/Nrf2 signaling pathway (AKT1, TNF-α, IL-6, NF-κB p65, Nrf2, and HO-1). Consequently, CNBP exhibited hepatoprotective effects, with antioxidative and anti-inflammatory properties. CONCLUSION: CNBP may mitigate GM-induced disturbances, augment the levels of three SCFAs, activate the AKT/Nrf2 signaling pathway, and exhibit antioxidant and anti-inflammatory effects, thereby conferring hepatoprotective benefits.

Sensitivity analysis and point mutations in BcSDHB confer cyclobutrifluram resistance in Botrytis cinerea from China.

Botrytis cinerea is one of the most destructive pathogens worldwide. It can damage over 200 crops, resulting in significant yield and quality losses. Cyclobutrifluram, a new generation of succinate dehydrogenase inhibitors, exhibits excellent inhibitory activity against B. cinerea. However, the baseline sensitivity and resistance of B. cinerea to cyclobutrifluram remains poorly understood. This study was designed to monitor the sensitivity frequency distribution, assess the resistance risk, and clarify the resistance mechanism of B. cinerea to cyclobutrifluram. The baseline sensitivity of B. cinerea isolates to cyclobutrifluram was 0.89 µg/mL. Cyclobutrifluram-resistant B. cinerea populations are present in the field. Six resistant B. cinerea isolates investigated in this study possessed enhanced compound fitness index compared to the sensitive isolates according to mycelial growth, mycelial dry weight, conidiation, conidial germination rate, and pathogenicity. Cyclobutrifluram exhibited no cross-resistance with tebuconazole, fludioxonil, cyprodinil, or iprodione. Sequence alignment revealed that BcSDHB from cyclobutrifluram-resistant B. cinerea isolates had three single substitutions (P225F, N230I, or H272R). Molecular docking verified that these mutations in BcSDHB conferred cyclobutrifluram resistance in B. cinerea. In conclusion, the resistance risk of B. cinerea to cyclobutrifluram is high, and the point mutations in BcSDHB (P225F, N230I, or H272R) confer cyclobutrifluram resistance in B. cinerea. This study provided important insights into cyclobutrifluram resistance in B. cinerea and offered valuable information for monitoring and managing cyclobutrifluram resistance in the future.

The application value of cerebrospinal fluid immunoglobulin in tuberculous meningitis.

This article aims to study the value of cerebrospinal fluid (CSF) immunoglobulin in differential diagnosis, prediction, and prognosis of tuberculous meningitis (TBM). The clinical data of 65 patients with TBM in our hospital were collected, and 65 patients with cryptococcal meningitis (CM) were enrolled in 1:1 matching. Relevant data were collected for comparison. CSFs IgG [331.51 (164.85, 645.00) vs 129.00 (55.05, 251.00) ng/mL], IgM [22.38 (8.52, 40.18) vs 6.08 (2.19, 23.30) ng/mL], and IgA [64.11 (21.44, 115.48) vs 16.55 (4.76, 30.36) ng/mL] in the TBM group were higher than those in the CM group (P < 0.001). In the TBM group, after 24 weeks of treatment, the CSFs IgG, IgM, and IgA were significantly decreased, and the difference was statistically significant (P < 0.05). The predictive results of CSF immunoglobulin for TBM showed that IgG, IgM, and IgA all had some predictive value for TBM, and the combined predictive value of the three was the highest, with an area under the curve of 0.831 (95% CI: 0.774-0.881). Logistic regression analysis of CSF immunoglobulins and TBM prognosis showed that IgG [odds ratio (OR) = 4.796, 95% confidence interval (CI): 2.575-8.864], IgM (OR = 3.456, 95% CI: 2.757-5.754), and IgA (OR = 4.371, 95% CI: 2.731-5.856) were TBM risk factors for poor prognosis in patients. The levels of IgG, IgM, and IgA in CSF were positively correlated with the severity of cranial magnetic resonance imaging (MRI) in TBM patients (R2 = 0.542, F = 65.392, P < 0.05). CSFs IgG, IgM, and IgA can be used as a routine monitoring index for TBM patients, which has a certain reference value in differential diagnosis and efficacy evaluation. IMPORTANCE: In clinical practice, physicians can determine the physical conditions of patients based on the levels of cerebrospinal fluids (CSFs) IgG, IgM, and IgA. Higher levels of CSFs IgG, IgM, and IgA suggest more possibility of tuberculous meningitis and worse prognosis and magnetic resonance imaging manifestations.

PsAF5 functions as an essential adapter for PsPHB2-mediated mitophagy under ROS stress in Phytophthora sojae.

Host-derived reactive oxygen species (ROS) are an important defense means to protect against pathogens. Although mitochondria are the main intracellular targets of ROS, how pathogens regulate mitochondrial physiology in response to oxidative stress remains elusive. Prohibitin 2 (PHB2) is an inner mitochondrial membrane (IMM) protein, recognized as a mitophagy receptor in animals and fungi. Here, we find that an ANK and FYVE domain-containing protein PsAF5, is an adapter of PsPHB2, interacting with PsATG8 under ROS stress. Unlike animal PHB2 that can recruit ATG8 directly to mitochondria, PsPHB2 in Phytophthora sojae cannot recruit PsATG8 to stressed mitochondria without PsAF5. PsAF5 deletion impairs mitophagy under ROS stress and increases the pathogen's sensitivity to H2O2, resulting in the attenuation of P. sojae virulence. This discovery of a PsPHB2-PsATG8 adapter (PsAF5) in plant-pathogenic oomycetes reveals that mitophagy induction by IMM proteins is conserved in eukaryotes, but with differences in the details of ATG8 recruitment.

Prediction of risk factors for linezolid-induced thrombocytopenia based on neural network model.

Background: Based on real-world medical data, the artificial neural network model was used to predict the risk factors of linezolid-induced thrombocytopenia to provide a reference for better clinical use of this drug and achieve the timely prevention of adverse reactions. Methods: The artificial neural network algorithm was used to construct the prediction model of the risk factors of linezolid-induced thrombocytopenia and further evaluate the effectiveness of the artificial neural network model compared with the traditional Logistic regression model. Results: A total of 1,837 patients receiving linezolid treatment in a hospital in Xi 'an, Shaanxi Province from 1 January 2011 to 1 January 2021 were recruited. According to the exclusion criteria, 1,273 cases that did not meet the requirements of the study were excluded. A total of 564 valid cases were included in the study, with 89 (15.78%) having thrombocytopenia. The prediction accuracy of the artificial neural network model was 96.32%, and the AUROC was 0.944, which was significantly higher than that of the Logistic regression model, which was 86.14%, and the AUROC was 0.796. In the artificial neural network model, urea, platelet baseline value and serum albumin were among the top three important risk factors. Conclusion: The predictive performance of the artificial neural network model is better than that of the traditional Logistic regression model, and it can well predict the risk factors of linezolid-induced thrombocytopenia.

Physiological and Biochemical Analysis Revealing the Key Factors Influencing 2-Phenylethanol and Benzyl Alcohol Production in Crabapple Flowers.

Floral scent (FS) plays a crucial role in the ecological functions and industrial applications of plants. However, the physiological and metabolic mechanisms underlying FS formation remain inadequately explored. Our investigation focused on elucidating the differential formation mechanisms of 2-phenylethanol (2-PE) and benzyl alcohol (BA) by examining seven related enzyme concentrations and the content of soluble sugar, soluble proteins, carbon (C) and nitrogen (N), as well as the C/N ratio. The findings revealed that the peak content of 2-PE in M. 'Praire Rose' and BA in M. 'Lollipop' occurred during the end flowering stage (S4) and flowering stage (S3) periods, respectively. The enzyme concentration change trends of phenylpyruvate decarboxylase (PDL), phenylacetaldehyde reductase (PAR), soluble protein, C, N, and C/N ratio changes during the S3-S4 period in M. 'Praire Rose' and M. 'Lollipop' were entirely opposite. Correlation and PCA analysis demonstrated that the content of CYP79D73 (a P450) and N, and the C/N ratio were key factors in 2-PE production in M. 'Praire Rose'. The production of BA in M. 'Lollipop' was more influenced by the content of phenylacetaldehyde synthase (PAAS), CYP79D73, and soluble sugar. As CYP79D73 exits oppositely in correlation to 2-PE (M. 'Praire Rose') and BA (M. 'Lollipop'), it is hypothesized that CYP79D73 was postulated as the primary factor contributing to the observed differences of 2-PE (M. 'Praire Rose') and BA (M. 'Lollipop') formation. These results carry significant implications for crabapple aromatic flower breeding and the essential oil industry etc.

Engineering a Programmed Death-Ligand 1-Targeting Monobody Via Directed Evolution for SynNotch-Gated Cell Therapy.

Programmed death-ligand 1 (PD-L1) is a promising target for cancer immunotherapy due to its ability to inhibit T cell activation; however, its expression on various noncancer cells may cause on-target off-tumor toxicity when designing PD-L1-targeting Chimeric Antigen Receptor (CAR) T cell therapies. Combining rational design and directed evolution of the human fibronectin-derived monobody scaffold, "PDbody" was engineered to bind to PD-L1 with a preference for a slightly lower pH, which is typical in the tumor microenvironment. PDbody was further utilized as a CAR to target the PD-L1-expressing triple negative MDA-MB-231 breast cancer cell line. To mitigate on-target off-tumor toxicity associated with targeting PD-L1, a Cluster of Differentiation 19 (CD19)-recognizing SynNotch IF THEN gate was integrated into the system. This CD19-SynNotch PDbody-CAR system was then expressed in primary human T cells to target CD19-expressing MDA-MB-231 cancer cells. These CD19-SynNotch PDbody-CAR T cells demonstrated both specificity and efficacy in vitro, accurately eradicating cancer targets in cytotoxicity assays. Moreover, in an in vivo bilateral murine tumor model, they exhibited the capability to effectively restrain tumor growth. Overall, CD19-SynNotch PDbody-CAR T cells represent a distinct development over previously published designs due to their increased efficacy, proliferative capability, and mitigation of off-tumor toxicity for solid tumor treatment.

N6-methyladenosine facilitates mitochondrial fusion of colorectal cancer cells via induction of GSH synthesis and stabilization of OPA1 mRNA.

Mitochondria undergo fission and fusion that are critical for cell survival and cancer development, while the regulatory factors for mitochondrial dynamics remain elusive. Herein we found that RNA m6A accelerated mitochondria fusion of colorectal cancer (CRC) cells. Metabolomics analysis and function studies indicated that m6A triggered the generation of glutathione (GSH) via the upregulation of RRM2B-a p53-inducible ribonucleotide reductase subunit with anti-reactive oxygen species potential. This in turn resulted in the mitochondria fusion of CRC cells. Mechanistically, m6A methylation of A1240 at 3'UTR of RRM2B increased its mRNA stability via binding with IGF2BP2. Similarly, m6A methylation of A2212 at the coding sequence (CDS) of OPA1-an essential GTPase protein for mitochondrial inner membrane fusion-also increased mRNA stability and triggered mitochondria fusion. Targeting m6A through the methyltransferase inhibitor STM2457 or the dm6ACRISPR system significantly suppressed mitochondria fusion. In vivo and clinical data confirmed the positive roles of the m6A/mitochondrial dynamics in tumor growth and CRC progression. Collectively, m6A promoted mitochondria fusion via induction of GSH synthesis and OPA1 expression, which facilitated cancer cell growth and CRC development.