Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer.

Broad-spectrum RAS inhibition has the potential to benefit roughly a quarter of human patients with cancer whose tumours are driven by RAS mutations1,2. RMC-7977 is a highly selective inhibitor of the active GTP-bound forms of KRAS, HRAS and NRAS, with affinity for both mutant and wild-type variants3. More than 90% of cases of human pancreatic ductal adenocarcinoma (PDAC) are driven by activating mutations in KRAS4. Here we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models. We observed broad and pronounced anti-tumour activity across models following direct RAS inhibition at exposures that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumour versus normal tissues. Treated tumours exhibited waves of apoptosis along with sustained proliferative arrest, whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. In the autochthonous KPC mouse model, RMC-7977 treatment resulted in a profound extension of survival followed by on-treatment relapse. Analysis of relapsed tumours identified Myc copy number gain as a prevalent candidate resistance mechanism, which could be overcome by combinatorial TEAD inhibition in vitro. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS-GTP inhibition in the setting of PDAC and identify a promising candidate combination therapeutic regimen to overcome monotherapy resistance.

Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy.

RAS oncogenes (collectively NRAS, HRAS and especially KRAS) are among the most frequently mutated genes in cancer, with common driver mutations occurring at codons 12, 13 and 611. Small molecule inhibitors of the KRAS(G12C) oncoprotein have demonstrated clinical efficacy in patients with multiple cancer types and have led to regulatory approvals for the treatment of non-small cell lung cancer2,3. Nevertheless, KRASG12C mutations account for only around 15% of KRAS-mutated cancers4,5, and there are no approved KRAS inhibitors for the majority of patients with tumours containing other common KRAS mutations. Here we describe RMC-7977, a reversible, tri-complex RAS inhibitor with broad-spectrum activity for the active state of both mutant and wild-type KRAS, NRAS and HRAS variants (a RAS(ON) multi-selective inhibitor). Preclinically, RMC-7977 demonstrated potent activity against RAS-addicted tumours carrying various RAS genotypes, particularly against cancer models with KRAS codon 12 mutations (KRASG12X). Treatment with RMC-7977 led to tumour regression and was well tolerated in diverse RAS-addicted preclinical cancer models. Additionally, RMC-7977 inhibited the growth of KRASG12C cancer models that are resistant to KRAS(G12C) inhibitors owing to restoration of RAS pathway signalling. Thus, RAS(ON) multi-selective inhibitors can target multiple oncogenic and wild-type RAS isoforms and have the potential to treat a wide range of RAS-addicted cancers with high unmet clinical need. A related RAS(ON) multi-selective inhibitor, RMC-6236, is currently under clinical evaluation in patients with KRAS-mutant solid tumours (ClinicalTrials.gov identifier: NCT05379985).

Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers.

RAS-driven cancers comprise up to 30% of human cancers. RMC-6236 is a RAS(ON) multi-selective noncovalent inhibitor of the active, GTP-bound state of both mutant and wild-type variants of canonical RAS isoforms with broad therapeutic potential for the aforementioned unmet medical need. RMC-6236 exhibited potent anticancer activity across RAS-addicted cell lines, particularly those harboring mutations at codon 12 of KRAS. Notably, oral administration of RMC-6236 was tolerated in vivo and drove profound tumor regressions across multiple tumor types in a mouse clinical trial with KRASG12X xenograft models. Translational PK/efficacy and PK/PD modeling predicted that daily doses of 100 mg and 300 mg would achieve tumor control and objective responses, respectively, in patients with RAS-driven tumors. Consistent with this, we describe here objective responses in two patients (at 300 mg daily) with advanced KRASG12X lung and pancreatic adenocarcinoma, respectively, demonstrating the initial activity of RMC-6236 in an ongoing phase I/Ib clinical trial (NCT05379985). SIGNIFICANCE: The discovery of RMC-6236 enables the first-ever therapeutic evaluation of targeted and concurrent inhibition of canonical mutant and wild-type RAS-GTP in RAS-driven cancers. We demonstrate that broad-spectrum RAS-GTP inhibition is tolerable at exposures that induce profound tumor regressions in preclinical models of, and in patients with, such tumors.

Transcriptomic and Physiological Analysis of the Effects of Exogenous Phloretin and Pterostilbene on Resistance Responses of Stylosanthes against Anthracnose.

Anthracnose caused by Colletotrichum gloeosporioides is a destructive disease of Stylosanthes (stylo). Combination treatment of phloretin and pterostilbene (PP) has been previously shown to effectively inhibit the conidial germination and mycelial growth of C. gloeosporioides in vitro. In this study, the effects of PP treatment on the growth of C. gloeosporioides in vivo and the biocontrol mechanisms were investigated. We found that exogenous PP treatment could limit the growth of C. gloeosporioides and alleviate the damage of anthracnose in stylo. Comparative transcriptome analysis revealed that 565 genes were up-regulated and 239 genes were down-regulated upon PP treatment during the infection by C. gloeosporioides. The differentially expressed genes were mainly related to oxidative stress and chloroplast organization. Further physiological analysis revealed that application of PP after C. gloeosporioides inoculation significantly reduced the accumulation of O2•- level and increased the accumulation of antioxidants (glutathione, ascorbic acid and flavonoids) as well as the enzyme activity of total antioxidant capacity, superoxide dismutase, catalase, glutathione reductase, peroxidase and ascorbate peroxidase. PP also reduced the decline of chlorophyll a + b and increased the content of carotenoid in response to C. gloeosporioides infection. These results suggest that PP treatment alleviates anthracnose by improving antioxidant capacity and reducing the damage of chloroplasts, providing insights into the biocontrol mechanisms of PP on the stylo against anthracnose.

High-Level Biosynthesis of Chlorogenic Acid from Mixed Carbon Sources of Xylose and Glucose through a Rationally Refactored Pathway Network.

Chlorogenic acid (CGA) has incredible potential for various pharmaceutical, nutraceutical, and agricultural applications. However, the traditional extraction approach from plants is time-consuming, further limiting its production. Herein, we design and construct the de novo biosynthesis pathway of CGA using modular coculture engineering in Escherichia coli, which is composed of MG09 and BD07 strains. To accomplish this, the phenylalanine-deficient MG09 strain was engineered to utilize xylose preferentially and to overproduce precursor caffeic acid, while the tyrosine-deficient BD07 strain was constructed to consume glucose exclusively to enhance another precursor quinic acid availability for the biosynthesis of CGA. Further pathway modularization and balancing in the context of syntrophic cocultures resulted in additional production improvement. The coculture strategy avoids metabolic flux competition in the biosynthesis of two CGA precursors, caffeic acid and quinic acid, and allows for production improvement by balancing module proportions. Finally, the optimized coculture based on the aforementioned efforts produced 131.31 ± 7.89 mg/L CGA. Overall, the modular coculture engineering strategy in this study provides a reference for constructing microbial cell factories that can efficiently biomanufacture complex natural products.

Uropathogenic Escherichia coli subverts host autophagic defenses by stalling pre-autophagosomal structures to escape lysosome exocytosis.

Urinary tract infections are primarily caused by uropathogenic Escherichia coli (UPEC). UPEC infects bladder epithelial cells (BECs) via fusiform vesicles and escapes into the cytosol by disrupting fusiform vesicle membrane using outer membrane phospholipase PldA, and establishes biofilm-like intracellular bacterial communities (IBCs) for protection from host immune clearance. Cytosolic UPEC is captured by autophagy to form autophagosomes, then transport to lysosomes, triggering the spontaneous exocytosis of lysosomes. The mechanism by which UPEC evades autophagy to recognize and form IBCs remains unclear. Here, we demonstrate that by inhibiting autophagic flux, UPEC PldA reduces the lysosome exocytosis of BECs. By reducing intracellular PI3P levels, UPEC PldA increases the accumulation of NDP52 granules and decreases the targeting of NDP52 to autophagy, hence stalling pre-autophagosome structures. Thus, our results uncover a critical role for PldA to inhibit autophagic flux, favoring UPEC escapes from lysosome exocytosis, thereby contributing to acute UTI.

Individualized PEEP guided by EIT in patients undergoing general anesthesia: A systematic review and meta-analysis.

BACKGROUND: The determination of optimal positive end-expiratory pressure (PEEP) values in patients undergoing general anesthesia remains controversial. Electrical impedance tomography (EIT) directed individualized PEEP has emerged as a novel approach to PEEP setting and has garnered increasing attention. This meta-analysis aims to systematically assess the effect of EIT-guided PEEP setting compared to traditional fixed PEEP values or other PEEP titration strategies in patients undergoing general anesthesia. METHODS: A comprehensive search of electronic databases, including PubMed, Web of Science, EMBASE, and the Cochrane Library, was conducted from inception to January 2023, with no language restrictions. The search terms used were "EIT"and "PEEP" with their corresponding free words. Two researchers independently conducted literature screening, data extraction, and quality evaluation. The primary outcomes of interest were oxygenation index (OI), lung compliance, and number of postoperative pulmonary complications (PPCs). The secondary outcomes included mean arterial blood pressure (MAP) and number of vasoactive drug injections. RevMan 5.3 software was used to analyze the data and draw the forest plot, and Stata 14.2 software was used to conduct sensitivity analysis to assess the stability of the results. RESULTS: 5 studies involving 272 participants were included in this meta-analysis. Our findings suggest that EIT-guided individualized PEEP setting is superior to traditional fixed PEEP values and other individualized PEEP titration methods in terms of intraoperative OI(OR = 95.73, 95%CI: (49.10, 142.37); P < 0.0001) and lung compliance(OR = 7.69, 95%CI: (5.55, 9.83); P < 0.00001), without affecting intraoperative hemodynamic parameters such as MAP(OR = 2.07, 95%CI: (-1.00, 5.13); P = 0.19) and the number of intravenous vasoactive drugs(OR = 1.22, 95%CI: (0.68, 2.21); P = 0.51) or increasing the incidence of postoperative PPCs(OR = 0.87, 95%CI: (0.41, 1.82); P = 0.71). CONCLUSIONS: Our meta-analysis suggests potential benefits of EIT-guided individualized PEEP setting in improving intraoperative oxygenation and lung compliance in patients undergoing general anesthesia. However, further research is needed to establish conclusive evidence, and caution should be exercised in interpreting these findings as the current literature remains inconclusive regarding the impact on intraoperative hemodynamics and postoperative complications.

Tumor-selective effects of active RAS inhibition in pancreatic ductal adenocarcinoma.

Broad-spectrum RAS inhibition holds the potential to benefit roughly a quarter of human cancer patients whose tumors are driven by RAS mutations. However, the impact of inhibiting RAS functions in normal tissues is not known. RMC-7977 is a highly selective inhibitor of the active (GTP-bound) forms of KRAS, HRAS, and NRAS, with affinity for both mutant and wild type (WT) variants. As >90% of human pancreatic ductal adenocarcinoma (PDAC) cases are driven by activating mutations in KRAS, we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models, including human and murine cell lines, human patient-derived organoids, human PDAC explants, subcutaneous and orthotopic cell-line or patient derived xenografts, syngeneic allografts, and genetically engineered mouse models. We observed broad and pronounced anti-tumor activity across these models following direct RAS inhibition at doses and concentrations that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumor versus normal tissues. Treated tumors exhibited waves of apoptosis along with sustained proliferative arrest whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS inhibition in the setting of PDAC.

Abdominal obesity and digestive system cancer: a systematic review and meta-analysis of prospective studies.

BACKGROUND: The diagnostic criteria for abdominal obesity are usually waist circumference or waist-to-hip ratio. The magnitude of the risks for cancers of the digestive system and abdominal obesity is unknown. To assess whether abdominal obesity increases the risk of digestive cancer, we conducted a systematic review and meta-analysis of prospective cohort studies in a database. METHODS: PubMed, Embase, and Web of Science databases were searched from their inception to December 2022. The 9-star Newcastle Ottawa Scale was used to assess  study quality. Pooled relative risks and 95% confidence intervals were calculated using fixed or random effect models respectively. The stability of the results was explored by one-by-one exclusion. Subgroup analysis was conducted to explore sources of heterogeneity. Publication bias was evaluated by Begg's and Egger's tests. RESULTS: A total of 43 cohort studies were included. There were 42 and 31 studies in the meta-analysis of waist circumference and waist-to-hip ratio on digestive system cancer, respectively. The results of the meta-analysis revealed that the greater waist circumference and waist-to-hip ratio were correlated with increased incidence of digestive system cancers: waist circumference: RR 1.48, 95% CI 1.38-1.59, p < 0.001; waist-to-hip ratio: RR 1.33, 95% CI 1.28-1.38, p = 0.001. Subgroup analysis by cancer type showed that higher WC and WHR would increase the prevalence of LC, PC, GC, EC, and CRC. The sensitivity analysis was conducted by a one-by-one elimination method, and the results of the meta-analysis remained stable. It is proved that the results were robust by the trim-and-fill method. CONCLUSIONS: There was evidence to suggest that abdominal obesity increased the incidence of digestive cancer, it is necessary to take appropriate measures to reduce abdominal obesity. Waist circumference and waist-to-hip ratio may be better predictors of digestive system cancers. However, the association between waist circumference and digestive system cancer was greater, so more attention should be paid to measuring abdominal obesity with waist circumference.

Enterohaemorrhagic E. coli utilizes host- and microbiota-derived L-malate as a signaling molecule for intestinal colonization.

The mammalian gastrointestinal tract is a complex environment that hosts a diverse microbial community. To establish infection, bacterial pathogens must be able to compete with the indigenous microbiota for nutrients, as well as sense the host environment and modulate the expression of genes essential for colonization and virulence. Here, we found that enterohemorrhagic Escherichia coli (EHEC) O157:H7 imports host- and microbiota-derived L-malate using the DcuABC transporters and converts these substrates into fumarate to fuel anaerobic fumarate respiration during infection, thereby promoting its colonization of the host intestine. Moreover, L-malate is important not only for nutrient metabolism but also as a signaling molecule that activates virulence gene expression in EHEC O157:H7. The complete virulence-regulating pathway was elucidated; the DcuS/DcuR two-component system senses high L-malate levels and transduces the signal to the master virulence regulator Ler, which in turn activates locus of enterocyte effacement (LEE) genes to promote EHEC O157:H7 adherence to epithelial cells of the large intestine. Disruption of this virulence-regulating pathway by deleting either dcuS or dcuR significantly reduced colonization by EHEC O157:H7 in the infant rabbit intestinal tract; therefore, targeting these genes and altering physiological aspects of the intestinal environment may offer alternatives for EHEC infection treatment.

Lactate promotes Salmonella intracellular replication and systemic infection via driving macrophage M2 polarization.

IMPORTANCE: The important enteropathogen Salmonella can cause lethal systemic infection via survival and replication in host macrophages. Lactate represents an abundant intracellular metabolite during bacterial infection, which can also induce macrophage M2 polarization. In this study, we found that macrophage-derived lactate promotes the intracellular replication and systemic infection of Salmonella. During Salmonella infection, lactate via the Salmonella type III secretion system effector SteE promotes macrophage M2 polarization, and the induction of macrophage M2 polarization by lactate is responsible for lactate-mediated Salmonella growth promotion. This study highlights the complex interactions between Salmonella and macrophages and provides an additional perspective on host-pathogen crosstalk at the metabolic interface.

Changes in the structural and physicochemical characteristics of sonicated potato flour.

Ultrasound has been widely used for physical modifications of starch because of its effectiveness and environment friendliness; however, only a few reports have focused on the effect of varying ultrasonic treatments on the physicochemical properties of potato flour. In the present study, ultrasound at varying power levels (200, 300, 400, 500, and 600 W) and time intervals (20, 40, 60, 80, and 100 min) were used to obtain sonicated flour. Sonicated potato flour exhibited a significant (P < 0.05) decrease in blue value and oil holding capacity but an increase in swelling power, water solubility, syneresis rate, and transparency. Moreover, ultrasound decreased the RDS content while increasing RS and SDS contents. Thermal properties demonstrated significant (P < 0.05) increases in T0 (64.39℃-83.52℃) and TC (144.29℃-146.87℃) but a decrease in ΔH of the sonicated flour. SEM revealed wrinkles, less debris, and larger particle size at the surface of the sonicated flour. FTIR profiles of all samples exhibited similar characteristics peaks, but the sonicated flour had a higher R1047/1022 value. Additionally, ultrasound did not affect crystalline patterns, but it increased the crystallinity of the sonicated flour. Our study contributes to the understanding of physicochemical property changes of sonicated potato flour, which could have industrial applications.

The therapeutic effect of glycyrrhizic acid compound ointment on imiquimod-induced psoriasis-like disease in mice.

Glycyrrhetinic acid, a drug with anti-inflammatory effects, enhanced the activity of antipsoriatic efficacy. In this research, an ointment with glycyrrhetinic acid was prepaired as the major component and several other herbal monomers (astilbin, osthole, and momordin Ic) have antipsoriatic activity as minor components. Then an Imiquimod-induced psoriasis-like mouse model was established and the damaged skin condition of the administered group, the changes in the spleen index and the secretion of inflammatory factors in mouse skin were observed. Calcipotriol ointment was used as a positive control to compare the efficacy. Glycyrrhizic acid compound ointment significantly improved imiquimod-induced psoriasis in mice and reduced the secretion of TNF-α, IL-12, IL-17, and IL-23 in mouse skin, and showed a stronger therapeutic effect than calcipotriol ointment. Calcipotriol ointment did not significantly alleviate imiquimod-induced splenomegaly and did not significantly reduce the expression of IL-17 and IL-23 in mouse skin. Glycyrrhetinic acid compound ointment was more effective than calcipotriol and was dose-dependent in the treatment of imiquimod-induced psoriatic dermatitis in mice. Meanwhile,calcipotriol was not suitable for the treatment of Imiquimod -induced psoriasis-like mice.

Facile production of cellulose nanofibers from raw elephant grass by an aluminum chloride-enhanced acidic deep eutectic solvent.

To develop a greener and more efficient method for producing cellulose nanofibers (CNFs) from raw plants, an AlCl3-enhanced ternary deep eutectic solvent, DES2 (consisting of choline chloride, citric acid, and AlCl3·6H2O in a molar ratio of 1:0.4:0.08), was synthesized. Raw elephant grass (EG) was pretreated with DES2, followed by sodium chlorite (NaClO2) bleaching and ultrasonic disruption to extract high-performance CNFs. The DES2 and NaClO2 treatments effectively removed hemicellulose and lignin, achieving removal rates of 99.23 % and 99.62 %, respectively, while maintaining a cellulose content of 78.3 %. DES2 demonstrated easy recyclability and maintained excellent biomass pretreatment performance even after multiple cycles. Following a brief 30-min intermittent ultrasound treatment, the resulting CNFs demonstrated superior crystallinity, increased carboxyl content, and a narrower width distribution compared to CNFs obtained from AlCl3-free DES1. Optimized conditions at 110 °C yielded CNFs with 85.3 % crystallinity, 0.64 mmol/g carboxyl content, 5.15 nm width distribution, and excellent dispersion in water for at least six months. Additionally, CNFs enhanced the tensile strength of chia seed mucilage (CM) composite films, showing a significant improvement to 26.6 MPa, representing a 231.3 % increase over the control film. This study offers a promising approach for efficiently producing CNFs from raw plants.

PEEP titration by EIT strategies for patients with ARDS: A systematic review and meta-analysis / Evaluación sistemática y metaanálisis de la estrategia eit para la titulación Peep en pacientes con sdra

Objective To determine which method of Positive End-expiratory Pressure (PEEP) titration is more useful, and to establish an evidence base for the clinical impact of Electrical Impedance Tomography (EIT) based individual PEEP setting which appears to be a promising method to optimize PEEP in Acute Respiratory Distress Syndrome (ARDS) patients. Design A systematic review and meta-analysis. Setting 4 databases (PUBMED, EMBASE, Web Of Science, and the Cochrane Library) from 1980 to December 2020 were performed. Participants Randomized clinical trials patients with ARDS. Main variables PaO2/FiO2-ratio and respiratory system compliance. Intervension The quality of the studies was assessed with the Cochrane risk and bias tool. Results 8 trials, including a total of 222 participants, were eligible for analysis. Meta-analysis demonstrates a significantly EIT-based individual PEEP setting for patients receiving higher PaO2/FiO2 ratio as compared to other PEEP titration strategies [5 trials, 202 patients, SMD 0.636, (95% CI 0.364−0.908)]. EIT-drived PEEP titration strategy did not significantly increase respiratory system compliance when compared to other peep titration strategies, [7 trials, 202 patients, SMD −0.085, (95% CI −0.342 to 0.172)]. Conclusions The benefits of PEEP titration with EIT on clinical outcomes of ARDS in placebo-controlled trials probably result from the visible regional ventilation of EIT. These findings offer clinicians and stakeholders a comprehensive assessment and high-quality evidence for the safety and efficacy of the EIT-based individual PEEP setting as a superior option for patients who undergo ARDS (AU)

Objetivo Para determinar qué método de valoración de la presión espirfinal positiva (PEEP) es más útil, y para establecer una base de evidencia para el impacto clínico de la tomode impedeléctrica (EIT) basada en el ajuste individual de PEEP que parece ser un método prometedor para optimizar la PEEP en pacientes con síndrome de dificultad respiraguda (ARDS). Diseño Una revisión sistemática y metanálisis. Ámbito Se realizaron 4 bases de datos (PUBMED, EMBASE, Web Of Science y Cochrane Library) de 1980 a diciembre de 2020. Participantes Ensayos clínicos aleatorizados de pacientes con SDRA. Variables principals PaO2/FiO2 ratio y compatibilidad respiratoria. Intervención La calidad de los estudios se evaluó con la Cochrane risk and bias tool. Resultados Ocho ensayos, incluyendo un total de 222 participantes, fueron elegibles para el análisis. El análisis de ≥ eta demuestra una configuración individual significativamente basada en MEITPpara pacientes que reciben una mayor proporción EE2/P PiO2en comparación con otras estrategias de titulación FOPEEP SMD CI. La estrategia de titulación de PEEP derivada del tie no aumentó significativamente el cumplimiento del sistema respiren comparación con otras estrategias de titulación de PEEP, [7 ensayos, 202 pacientes, DME -0,085, (IC del 95%: −0,342−0,172)]. Conclusiones Los beneficios de la valoración de la PEEP con EIT en los resultados clínicos de SDRA en ensayos controlados con placebo probablemente sean el resultado de la ventilación regional visible del EIT. Estos hallazgos ofrecen a los médicos y a las partes interesadas una evaluación integral y evidencia de alta calidad para la seguridad y eficacia de la configuración individual de PEEP basada en EIT como una opción superior para los pacientes que se someten a SDRA (AU)

Nitric oxide is a host cue for Salmonella Typhimurium systemic infection in mice.

Nitric oxide (NO) is produced as an innate immune response against microbial infections. Salmonella Typhimurium (S. Typhimurium), the major causative pathogen of human gastroenteritis, induces more severe systemic disease in mice. However, host factors contributing to the difference in species-related virulence are unknown. Here, we report that host NO production promotes S. Typhimurium replication in mouse macrophages at the early infection stage by activating Salmonella pathogenicity island-2 (SPI-2). The NO signaling-induced SPI-2 activation is mediated by Fnr and PhoP/Q two-component system. NO significantly induced fnr transcription, while Fnr directly activated phoP/Q transcription. Mouse infection assays revealed a NO-dependent increase in bacterial burden in systemic organs during the initial days of infection, indicating an early contribution of host NO to virulence. This study reveals a host signaling-mediated virulence activation pathway in S. Typhimurium that contributes significantly to its systemic infection in mice, providing further insights into Salmonella pathogenesis and host-pathogen interaction.

Multi-omics-based identification of purple acid phosphatases and metabolites involved in phosphorus recycling in stylo root exudates.

Stylo (Stylosanthes guianensis) is a tropical forage and cover crop that possesses low phosphate (Pi) tolerance traits. However, the mechanisms underlying its tolerance to low-Pi stress, particularly the role of root exudates, remain unclear. This study employed an integrated approach using physiological, biochemical, multi-omics, and gene function analyses to investigate the role of stylo root exudates in response to low-Pi stress. Widely targeted metabolomic analysis revealed that eight organic acids and one amino acid (L-cysteine) were significantly increased in the root exudates of Pi-deficient seedlings, among which tartaric acid and L-cysteine had strong abilities to dissolve insoluble-P. Furthermore, flavonoid-targeted metabolomic analysis identified 18 flavonoids that were significantly increased in root exudates under low-Pi conditions, mainly belonging to the isoflavonoid and flavanone subclasses. Additionally, transcriptomic analysis revealed that 15 genes encoding purple acid phosphatases (PAPs) had upregulated expression in roots under low-Pi conditions. Among them, SgPAP10 was characterized as a root-secreted phosphatase, and overexpression of SgPAP10 enhanced organic-P utilization by transgenic Arabidopsis. Overall, these findings provide detailed information regarding the importance of stylo root exudates in adaptation to low-Pi stress, highlighting the plant's ability to release Pi from organic-P and insoluble-P sources through root-secreted organic acids, amino acids, flavonoids, and PAPs.

The LysR-Type Transcription Regulator YhjC Promotes the Systemic Infection of Salmonella Typhimurium in Mice.

Salmonella Typhimurium is a Gram-negative intestinal pathogen that can infect humans and a variety of animals, causing gastroenteritis or serious systemic infection. Replication within host macrophages is essential for S. Typhimurium to cause systemic infection. By analyzing transcriptome data, the expression of yhjC gene, which encodes a putative regulator in S. Typhimurium, was found to be significantly up-regulated after the internalization of Salmonella by macrophages. Whether yhjC gene is involved in S. Typhimurium systemic infection and the related mechanisms were investigated in this study. The deletion of yhjC reduced the replication ability of S. Typhimurium in macrophages and decreased the colonization of S. Typhimurium in mouse systemic organs (liver and spleen), while increasing the survival rate of the infected mice, suggesting that YhjC protein promotes systemic infection by S. Typhimurium. Furthermore, by using transcriptome sequencing and RT-qPCR assay, the transcription of several virulence genes, including spvD, iroCDE and zraP, was found to be down-regulated after the deletion of yhjC. Electrophoretic mobility shift assay showed that YhjC protein can directly bind to the promoter region of spvD and zraP to promote their transcription. These findings suggest that YhjC contributes to the systemic virulence of S. Typhimurium via the regulation of multiple virulence genes and YhjC could represent a promising target to control S. Typhimurium infection.

PEEP titration by EIT strategies for patients with ARDS: A systematic review and meta-analysis.

OBJECTIVE: To determine which method of Positive End-expiratory Pressure (PEEP) titration is more useful, and to establish an evidence base for the clinical impact of Electrical Impedance Tomography (EIT) based individual PEEP setting which appears to be a promising method to optimize PEEP in Acute Respiratory Distress Syndrome (ARDS) patients. DESIGN: A systematic review and meta-analysis. SETTING: 4 databases (PUBMED, EMBASE, Web Of Science, and the Cochrane Library) from 1980 to December 2020 were performed. PARTICIPANTS: Randomized clinical trials patients with ARDS. MAIN VARIABLES: PaO2/FiO2-ratio and respiratory system compliance. INTERVENSION: The quality of the studies was assessed with the Cochrane risk and bias tool. RESULTS: 8 trials, including a total of 222 participants, were eligible for analysis. Meta-analysis demonstrates a significantly EIT-based individual PEEP setting for patients receiving higher PaO2/FiO2 ratio as compared to other PEEP titration strategies [5 trials, 202 patients, SMD 0.636, (95% CI 0.364-0.908)]. EIT-drived PEEP titration strategy did not significantly increase respiratory system compliance when compared to other peep titration strategies, [7 trials, 202 patients, SMD -0.085, (95% CI -0.342 to 0.172)]. CONCLUSIONS: The benefits of PEEP titration with EIT on clinical outcomes of ARDS in placebo-controlled trials probably result from the visible regional ventilation of EIT. These findings offer clinicians and stakeholders a comprehensive assessment and high-quality evidence for the safety and efficacy of the EIT-based individual PEEP setting as a superior option for patients who undergo ARDS.

A noncoding single-nucleotide polymorphism at 8q24 drives IDH1-mutant glioma formation.

Establishing causal links between inherited polymorphisms and cancer risk is challenging. Here, we focus on the single-nucleotide polymorphism rs55705857, which confers a sixfold greater risk of isocitrate dehydrogenase (IDH)-mutant low-grade glioma (LGG). We reveal that rs55705857 itself is the causal variant and is associated with molecular pathways that drive LGG. Mechanistically, we show that rs55705857 resides within a brain-specific enhancer, where the risk allele disrupts OCT2/4 binding, allowing increased interaction with the Myc promoter and increased Myc expression. Mutating the orthologous mouse rs55705857 locus accelerated tumor development in an Idh1R132H-driven LGG mouse model from 472 to 172 days and increased penetrance from 30% to 75%. Our work reveals mechanisms of the heritable predisposition to lethal glioma in ~40% of LGG patients.