Varied immune responses of HBV-specific B cells in patients undergoing pegylated interferon-alpha treatment for chronic hepatitis B.

BACKGROUND & AIMS: The changes of HBV-specific B-cells in chronic hepatitis B (CHB) patients underwent pegylated interferon-alfa (PEG-IFNα) treatment and achieved functional cure remain unclear. We aimed to evaluate the alterations in HBV-specific B-cells during treatment and therefore explored the mechanism of functional recovery of HBsAg-specific B-cells. METHODS: We included 39 nucleos(t)ide analogues-treated CHB patients who received sequential combination therapy with PEG-IFNα and 8 treatment-naive CHB patients. HBV-specific B-cells were characterized ex vivo using fluorescent labeled HBsAg and HBcAg. The frequency, phenotype, and subsets of HBV-specific B-cells and follicular helper T cells (Tfh-cells) were detected using flow cytometry. The functionality of HBV-specific B-cells was quantified through ELISpot assays. RESULTS: During treatment, the fraction of activated memory B-cells (MBCs) among HBsAg-specific B-cells and the expression of IgG, CXCR3, and CD38 increased. Antibody-secretion capacity of HBsAg-specific B-cell was restored after treatment only in patients with a functional cure and it showed a positive correlation with serum hepatitis B surface antibody levels. The phenotype and function of HBsAg-specific B-cells differed between patients with and without functional cure. Patients with functional cure exhibited IgG+ classical MBCs and plasmablasts in HBsAg-specific B-cells. HBcAg-specific B-cells displayed both attenuated antibody secretion with reduced IgG expression and an IgM+ atypical type of MBCs after treatment, irrespective of with and without functional cure. The number of CD40L+ Tfh-cells increased after PEG-IFNα treatment and positively correlated with HBsAg-specific B-cell activation. CONCLUSIONS: After PEG-IFNα treatment, HBsAg- and HBcAg-specific B-cells exhibit various changes in antibody secretion. Their functional differences are reflected in the alterations in phenotypes and subtypes. The presence of CD40L+ Tfh-cells is associated with the active recovery of HBsAg-specific B-cells. IMPACT AND IMPLICATIONS: HBV-related complications and hepatocellular carcinoma remain the leading causes of mortality from chronic liver disease worldwide, and a cure is rarely achieved with antiviral therapies. Elucidating the immunological mechanisms underlying the functional cure of CHB patients offers a promising therapeutic strategy for viral clearance, such as therapeutic vaccine. We analyzed the alterations in HBV-specific B-cells in patients treated with PEG-IFNα and identified novel pathways for immunotherapeutic boosting of B cell immunity.

Hysteretic and asynchronous regime shifts of bacterial and micro-eukaryotic communities driven by nutrient loading.

Nutrient pollution is pervasive in many urban rivers, while restoration measures that reduce nutrient loading but fail to improve biological communities often lack effectiveness due to the indispensable role of biota, especially multi-taxa, in enhancing ecosystem stability and function. The investigation of the response patterns of multi-taxa to the nutrient loading in urban rivers is important for the recovery of biota structure and thus ecosystem function. However, little is known about the response patterns of multi-taxa and their impact on ecosystem structure and function in urban rivers. Here, the study, from the perspective of alternative stable states theory, showed the hysteretic response of both bacterial and micro-eukaryotic communities to nutrient loading based on the field investigation and environmental DNA metabarcoding. Bistability was shown to exist in both bacterial and micro-eukaryotic communities, demonstrating that the response of microbiota to nutrient loading was a regime shifts with hysteresis. Potential analysis then indicated that the increased nutrient loading drove regime shifts in the bacterial community and the micro-eukaryotic community towards a state dominated by anaerobic bacteria and benthic Bacillariophyta, respectively. High nutrient loading was found to reduce the relative abundance of metazoan, but increase that of eukaryotic algae, which made the trophic pyramid top-lighter and bottom-heavier, probably exacerbating the degradation of ecosystem function. It should be noted that, in response to the reduced nutrient loading, the recovery threshold of micro-eukaryotic communities (nutrient loading = ∼0.5) was lower than that of bacterial communities (nutrient loading = ∼1.2), demonstrating longer hysteresis of micro-eukaryotic communities. In addition, the markedly positive correlation between the status of microbial communities and N-related enzyme activities suggested the recovery of microbial communities probably will benefit the improvement of N-cycling functionality. The obtained results provide a deep insight into the collapse and recovery trajectories of multi-trophic microbiota to the nutrient loading gradient and their impact on the N transformation potential, therefore benefiting the restoration and management of urban rivers.

The anti-inflammatory effects of itaconate and its derivatives in neurological disorders.

Almost 16 % of the global population is affected by neurological disorders, including neurodegenerative and cerebral neuroimmune diseases, triggered by acute or chronic inflammation. Neuroinflammation is recognized as a common pathogenic mechanism in a wide array of neurological conditions including Alzheimer's disease, Parkinson's disease, postoperative cognitive dysfunction, stroke, traumatic brain injury, and multiple sclerosis. Inflammatory process in the central nervous system (CNS) can lead to neuronal damage and neuronal apoptosis, consequently exacerbating these diseases. Itaconate, an immunomodulatory metabolite from the tricarboxylic acid cycle, suppresses neuroinflammation and modulates the CNS immune response. Emerging human studies suggest that itaconate levels in plasma and cerebrospinal fluid may serve as biomarkers associated with inflammatory responses in neurological disorders. Preclinical studies have shown that itaconate and its highly cell-permeable derivatives are promising candidates for preventing and treating neuroinflammation-related neurological disorders. The underlying mechanism may involve the regulation of immune cells in the CNS and neuroinflammation-related signaling pathways and molecules including Nrf2/KEAP1 signaling pathway, reactive oxygen species, and NLRP3 inflammasome. Here, we introduce the metabolism and function of itaconate and the synthesis and development of its derivatives. We summarize the potential impact and therapeutic potential of itaconate and its derivatives on brain immune cells and the associated signaling pathways and molecules, based on preclinical evidence via various neurological disorder models. We also discuss the challenges and potential solutions for clinical translation to promote further research on itaconate and its derivatives for neuroinflammation-related neurological disorders.

Comparison of Mitral Valve Repair Versus Percutaneous Mitral Balloon Commissurotomy for Patients With Rheumatic Heart Disease: A Single-Centre Study.

BACKGROUND: Percutaneous mitral balloon commissurotomy (PMBC) is the standard treatment option for patients with rheumatic mitral stenosis (MS), according to current guidelines. This study aimed to compare the outcomes of rheumatic mitral valve repair (rMVR) and PMBC in this patient population. METHODS: Baseline, clinical, and follow-up data from 703 patients with rheumatic heart disease who underwent PMBC or rMVR at the current centre were collected and analysed. A 1:1 propensity score (PS) matching method was used to balance the differences in baseline characteristics between the two groups. The primary outcome was mitral valve reoperation, and the secondary outcome was all-cause mortality. RESULTS: Propensity score matching generated 101 patient pairs for comparison. In the matched population, there were no significant differences in the early clinical outcomes between the groups. The median follow-up time was 40.9 months. Overall, patients in the rMVR group had a statistically significantly lower risk of mitral valve reoperation than those in the PMBC group (HR 0.186; 95% CI 0.041-0.835; p=0.028). Regarding all-cause mortality, no statistically significant differences were observed between the rMVR and PMBC groups (HR 4.065; 95% CI 0.454-36.374; p=0.210). CONCLUSIONS: Compared with PMBC, rMVR has more advantages for the correction of valve lesions; therefore, it may offer a better prognosis than PMBC in select patients with rheumatic MS. However, this finding needs to be verified in future studies with larger sample sizes and longer follow-up periods.

Self-Assembled Tetranuclear Square Complex of Chromium(III) Bridged by Radical Pyrazine: A Molecular Model for Metal-Organic Magnets.

The attractive electronic properties of metal-pyrazine materials─electrical conductivity, magnetic order, and strong magnetic coupling─can be tuned in a wide range depending on the metal employed, as well as its ligand-imposed redox environment. Using solvent-directed synthesis to control the dimensionality of such systems, a discrete tetranuclear chromium(III) complex, exhibiting a rare example of bridging radical pyrazine, has been prepared from chromium(II) triflate and neutral pyrazine. The strong antiferromagnetic interaction between CrIII (S = 3/2) and radical pyrazine (S = 1/2) spins, theoretically estimated at about -932 K, leads to a thermally isolated ST = 4 ground state, which remains the only populated state observable even at room temperature.

Carbon-fixing bacteria in diverse groundwaters of karst area: Distribution patterns, ecological interactions, and driving factors.

The biological carbon pump in karst areas is of great significance for maintaining the effectiveness of karst carbon sinks. However, the spatial distribution and carbon-fixing potential of microorganisms in different aquifers within karst areas remain poorly understood. In this study, the distribution patterns, ecological roles, and environmental drivers of microbiota associated with CO2 fixation were investigated in karst groundwater (KW), porous groundwater (PW), fractured groundwater (FW), and surface water (SW) within a typical karst watershed, located in Guilin, southwest China. KW, PW, and FW displayed the similar community structure and indicative carbon-fixing bacteria composition, which were dominated by chemoautotrophic bacteria compared to SW. Higher abundances of indicative carbon-fixing bacteria and carbon-fixing genes, as well as richer proportions of microbial-derived DOC, indicated the more significant microbial carbon-fixing potential in KW and PW. At the profile of KW, a carbon-fixing hotspot was discovered at the depths of 0-50 m. Correlation analysis between carbon-fixing bacteria and DOC revealed that the chemoautotrophic process driven by nitrogen and sulfur oxidation predominated the microbial carbon fixation in groundwater. Co-occurrence network analysis demonstrated that carbon-fixing bacteria exhibited cooperation with other bacterial taxa in KW, while competition was the dominant interaction in PW. Moreover, carbon-fixing bacteria was found to lead bacterial assembly more deterministic in KW. The analysis of environmental factors and microbial diversity illustrated that inorganic carbon and redox state drove community variations across groundwaters. Structural equation model (SEM) further confirmed that ORP was the primary factor influencing the carbon fixation potential. This study provides a new insight into biological carbon fixation in karst aquatic systems, which holds significance in the accurate assessment of karst carbon sinks.

Deep-learning enabled smart insole system aiming for multifunctional foot-healthcare applications.

Real-time foot pressure monitoring using wearable smart systems, with comprehensive foot health monitoring and analysis, can enhance quality of life and prevent foot-related diseases. However, traditional smart insole solutions that rely on basic data analysis methods of manual feature extraction are limited to real-time plantar pressure mapping and gait analysis, failing to meet the diverse needs of users for comprehensive foot healthcare. To address this, we propose a deep learning-enabled smart insole system comprising a plantar pressure sensing insole, portable circuit board, deep learning and data analysis blocks, and software interface. The capacitive sensing insole can map both static and dynamic plantar pressure with a wide range over 500 kPa and excellent sensitivity. Statistical tools are used to analyze long-term foot pressure usage data, providing indicators for early prevention of foot diseases and key data labels for deep learning algorithms to uncover insights into the relationship between plantar pressure patterns and foot issues. Additionally, a segmentation method assisted deep learning model is implemented for exercise-fatigue recognition as a proof of concept, achieving a high classification accuracy of 95%. The system also demonstrates various foot healthcare applications, including daily activity statistics, exercise injury avoidance, and diabetic foot ulcer prevention.

Comparison of Different Ultrasonic Screening Methods and Analysis of High Risk Factors for Fetal Cardiac Malformation in Second Trimester of Pregnancy.

Current study aims to compare the application of two-dimensional (2D) color doppler ultrasound (CDU) and four-dimensional (4D) ultrasound spatiotemporal image correlation (STIC) in fetal congenital heart disease in the second trimester of pregnancy and to analyze the high risk factors of the disease. From August 2019 to July 2021, 135 second-trimester patients with highly suspected congenital heart malformations were selected who underwent prenatal screening at South Taihu Hospital Affiliated to Huzhou University. 2D-CDU, 4D STIC, and postnatal examination were completed in all patients. 2D-CDU, 4D STIC and 2D-CDU combined with 4D STIC were used to detect fetal cardiac malformations and classify cardiac malformations. The sensitivity, specificity, positive predictive value, negative predictive value and coincidence rate of 2D-CDU, 4D STIC and 2D-CDU combined with 4D STIC were compared. The results of 2D-CDU, 4D STIC and 2D-CDU combined with 4D STIC screening were analyzed for consistency using the results of postpartum diagnosis as the gold standard. Moreover, effects of maternal gestational factors on fetal cardiac malformations by univariate and multivariate analysis. 2D-CDU combined with 4D STIC showed significantly higher section display number than 2D-CDU or 4D STIC in the view of ductal arch, aortic arch, and aortic short-axis. A total of 45 cases of fetal congenital heart malformation were detected in 135 patients in the second trimester, 40, 38 or 42 cases were detected by 2D-CDU, 4D STIC or 2D-CDU combined with 4D STIC, respectively. The sensitivity, specificity, positive predictive value, negative predictive value and coincidence rate of 2D-CDU combined with 4D ultrasound in congenital heart malformation screening were higher than those of 2D-CDU or 4D STIC. Kappa agreement analysis showed that the diagnostic results of 4D STIC and 2D-CDU combined with 4D ultrasound in fetuses with suspected congenital heart malformation were in excellent agreement (κ > 0.75), while 2D-CDU was in good agreement with postpartum diagnosis (κ < 0.75). Univariate and multivariate regression analysis revealed that maternal age ≥ 35, drinking during pregnancy, and history of adverse pregnancy and childbirth were all independent risk factors for fetal cardiac malformations, while folic acid supplementation was an independent protective factor for fetal cardiac malformations. 2D-CDU combined with 4D echocardiography may be superior to single 2D-CDU or 4D STIC in the screening of fetal congenital heart malformation in the second trimester. In order to reduce the incidence of fetal heart anomalies, we should strengthen the screening of pregnancy anomalies in high-risk pregnant women and control the risk factors.

Phage defence system CBASS is regulated by a prokaryotic E2 enzyme that imitates the ubiquitin pathway.

The cyclic-oligonucleotide-based anti-phage signalling system (CBASS) is a type of innate prokaryotic immune system. Composed of a cyclic GMP-AMP synthase (cGAS) and CBASS-associated proteins, CBASS uses cyclic oligonucleotides to activate antiviral immunity. One major class of CBASS contains a homologue of eukaryotic ubiquitin-conjugating enzymes, which is either an E1-E2 fusion or a single E2. However, the functions of single E2s in CBASS remain elusive. Here, using biochemical, genetic, cryo-electron microscopy and mass spectrometry investigations, we discover that the E2 enzyme from Serratia marcescens regulates cGAS by imitating the ubiquitination cascade. This includes the processing of the cGAS C terminus, conjugation of cGAS to a cysteine residue, ligation of cGAS to a lysine residue, cleavage of the isopeptide bond and poly-cGASylation. The poly-cGASylation activates cGAS to produce cGAMP, which acts as an antiviral signal and leads to cell death. Thus, our findings reveal a unique regulatory role of E2 in CBASS.

Comparison of indocyanine green and blue-stained glue for preoperative localization for pulmonary nodules.

Background: In patients with pulmonary nodules undergoing computed tomography (CT)-guided localization procedures, a range of liquid-based materials have been employed to date in an effort to guide video-assisted thoracoscopic surgery (VATS) procedures to resect target nodules. However, the relative performance of these different liquid-based localization strategies has yet to be systematically evaluated. Accordingly, this study was developed with the aim of examining the relative safety and efficacy of CT-guided indocyanine green (IG) and blue-stained glue (BSG) PN localization. Methods: Consecutive patients with PNs undergoing CT-guided localization prior to VATS from November 2021 - April 2022 were enrolled in this study. Safety and efficacy outcomes were compared between patients in which different localization materials were used. Results: In total, localization procedures were performed with IG for 121 patients (140 PNs), while BSG was used for localization procedures for 113 patients (153 PNs). Both of these materials achieved 100% technical success rates for localization, with no significant differences between groups with respect to the duration of localization (P = 0.074) or visual analog scale scores (P = 0.787). Pneumothorax affected 8 (6.6%) and 8 (7.1%) patients in the respective IG and BSG groups (P = 0.887), while 12 (9.9%) and 10 (8.8%) patients of these patients experienced pulmonary hemorrhage. IG was less expensive than BSG ($17.2 vs. $165). VATS sublobar resection procedure technical success rates were also 100% in both groups, with no instances of conversion to thoracotomy. Conclusions: IG and BSG both offer similarly high levels of clinical safety and efficacy when applied for preoperative CT-guided PN localization, with IG being less expensive than BSG.

Regulating Protein-RNA Interactions: Advances in Targeting the LIN28/Let-7 Pathway.

Originally discovered in C. elegans, LIN28 is an evolutionarily conserved zinc finger RNA-binding protein (RBP) that post-transcriptionally regulates genes involved in developmental timing, stem cell programming, and oncogenesis. LIN28 acts via two distinct mechanisms. It blocks the biogenesis of the lethal-7 (let-7) microRNA (miRNA) family, and also directly binds messenger RNA (mRNA) targets, such as IGF-2 mRNA, and alters downstream splicing and translation events. This review focuses on the molecular mechanism of LIN28 repression of let-7 and current strategies to overcome this blockade for the purpose of cancer therapy. We highlight the value of the LIN28/let-7 pathway as a drug target, as multiple oncogenic proteins that the pathway regulates are considered undruggable due to their inaccessible cellular location and lack of cavities for small molecule binding.

FL% is associated with the severity of acute DeBakey type I aortic dissection in patients undergoing frozen elephant trunk and total arch replacement.

Objectives: The diameter, area, and volume of the true lumen and false lumen (FL) have been measured in previous studies to evaluate the extent of DeBakey type I aortic dissection. However, these indicators have limitations because of the irregular shapes of the true and false lumens and the constant oscillation of intimal flap during systole and diastole. The ratio of arch lengths seems to be a more reliable indicator. FL% was defined as the ratio of the arch length of FL to the circumference of the aorta at the different levels of the aorta. The purpose of this article was to investigate whether FL% is a predictor of the severity of acute DeBakey type I aortic dissection in patients undergoing frozen elephant trunk (FET) and total arch replacement. Methods: In this retrospective observational study, we analyzed a total of 344 patients with acute DeBakey type I aortic dissection that underwent FET and total arch replacement at our center from October 2015 to October 2019. The patients were divided into two groups by cluster analysis according to the perioperative course. Binary logistic regression analyses were performed to determine whether FL% could predict the severity of acute DeBakey type I aortic dissection. The area under the receiver operating characteristic curve (AUROC) was used to assess the power of the multivariate logistic regression model for the severity of acute DeBakey type I aortic dissection. Results: The patients in the ultra-high-risk group (109 patients) had significantly more severe clinical comorbidities and complications than the patients in the high-risk group (235 patients). The ascending aortic FL% [odds ratio (OR), 11.929 (95% CI: 1.421-100.11); P = 0.022], location of initial tear [OR, 0.68 (95% CI: 0.47-0.98); P = 0.041], the degree of left iliac artery involvement [OR, 1.95 (95% CI: 1.15-3.30); P = 0.013], and the degree of right coronary artery involvement [OR, 1.46 (95% CI: 1.01-2.12); P = 0.045] on preoperative computed tomography angiography were associated with the severity of acute DeBakey type I aortic dissection. The AUROC value of this multivariate logistic regression analysis was 0.940 (95% CI: 0.914-0.967; P < 0.001). The AUROC value of ascending aortic FL% was 0.841 (95% CI: 0.798-0.884; P < 0.001) for the severity of acute DeBakey type I aortic dissection in patients undergoing FET and total arch replacement. Conclusions: Ascending aortic FL% was validated as an essential radiologic index for assessing the severity of acute DeBakey type I aortic dissection in patients undergoing FET and total arch replacement. Higher values of ascending aortic FL% were more severe.

Prediction of microbial activity and abundance using interpretable machine learning models in the hyporheic zone of effluent-dominated receiving rivers.

Serving as a vital linkage between surface water and groundwater, the hyporheic zone (HZ) plays a fundamental role in improving water quality and maintaining ecological security. In arid or semi-arid areas, effluent discharge from wastewater treatment facilities could occupy a predominant proportion of the total base flow of receiving rivers. Nonetheless the relationship between microbial activity, abundance and environmental factors in the HZ of effluent-receiving rivers appear to be rarely addressed. In this study, a spatiotemporal field study was performed in two representative effluent-dominated receiving rivers in Xi'an, China. Land use data, physical and chemical water quality parameters of surface and subsurface water were used as predictive variables, while the microbial respiratory electron transport system activity (ETSA), the Chao1 and Shannon index of total microbial community, as well as the Chao1 and Shannon index of denitrifying bacteria community were used as response variables, while ETSA was used as response variables indicating ecological processes and Shannon and Chao1 were utilized as parameters indicating microbial diversity. Two machine learning models were utilized to provide evidence-based information on how environmental factors interact and drive microbial activity and abundance in the HZ at variable depths. The models with Chao1 and Shannon as response variables exhibited excellent predictive performances (R2: 0.754-0.81 and 0.783-0.839). Dissolved organic nitrogen (DON) was the most important factor affecting the microbial functions, and an obvious threshold value of ∼2 mg/L was observed. Credible predictions of models with Chao1 and Shannon index of denitrifying bacteria community as response variables were detected (R2: 0.484-0.624 and 0.567-0.638), with soluble reactive phosphorus (SRP) being the key influencing factor. Fe (Ⅱ) was favorable in predicting denitrifying bacteria community. The ESTA model highlighted the importance of total nitrogen in the ecological health monitoring in HZ. These findings provide novel insights in predicting microbial activity and abundance in highly-impacted areas such as the HZ of effluent-dominated receiving rivers.

Stress analysis of a large diameter aspheric plastic lens in the variable temperature assisted injection molding process.

The technology known as precision injection molding (PIM) has shown great promise in the large-scale manufacturing of optical plastic lenses. The primary challenge with the PIM process is accurately predicting and reducing residual stress in optical plastic lenses. In this work, the finite element method (FEM) was used to analyze the residual stress distribution in plastic lenses. A three-dimensional model was created using COMSOL software to investigate how residual stress and temperature varied in optical plastic lenses during the packing and cooling stages. Based on the results, variable temperature assisted injection molding experiments were conducted. The results show that the average residual stress in the optical plastic lenses has decreased by 56%, while the minimum and maximum residual stress levels have decreased by 60% and 61%, respectively. Since this method does not require the extra heat treatment of the optical lenses, it offers considerable cost and efficiency benefits.

Bolus administration of remimazolam was superior to midazolam for deep sedation in elderly patients undergoing diagnostic bronchoscopy: A randomized, double-blind, controlled trial.

BACKGROUND: To date, there is no standardized practice for the use of pharmacological sedatives during flexible bronchoscopy, particularly for elderly patients. This exploratory study aimed to assess the efficacy and safety of remimazolam at a single induced dose for deep sedation in elderly patients undergoing diagnostic flexible bronchoscopy (DFB), and compare with midazolam, a commonly used sedative. METHODS: A total of 100 elderly patients (age range 65-80 yr; American Society of Anesthesiologists Physical Status I-III) undergoing DFB were randomly allocated into 2 groups according to the sedatives used for induction: the remimazolam group and the midazolam group. Sedation induction was initiated by an intravenous bolus of remimazolam (0.135 mg/kg) or midazolam (0.045 mg/kg), respectively, both groups were combined with a high-dose of alfentanil (18 µg/kg), and supplemented with high-flow nasal cannula (HFNC) oxygen supply at a flow rate of 45 L/min. If the target depth of sedation was not achieved, propofol would be titrated as a rescue. The primary outcome was the success rate of sedation at a single induced dose to achieve target depth (Ramsay sedation score [RSS] = 4) during induction, intraoperative changes in vital signs, postoperative follow-up situation and incidence of post-bronchoscopy adverse events were evaluated as secondary outcomes. RESULTS: The success rate of sedation in the remimazolam group was significantly higher than that in the midazolam group (65.2% vs 39.6%, P = .013), while the incidence of extra sleep within 6 hours after procedure was lower in the remimazolam group as compared to the midazolam group (10.9% vs 31.3%, P = .016). No statistically significant differences were observed between the 2 groups regarding hemodynamic fluctuations, incidence of hypoxemia, and cough response during the procedure, as well as postoperative recall, willingness to undergo reexamination, and other post-bronchoscopy adverse events. CONCLUSIONS: Bolus administration of remimazolam offers advantages over midazolam for deep sedation in elderly patients undergoing DFB, in terms of a higher success rate of sedation and a lower incidence of extra sleep within 6 hours after procedure, though the safety profiles of both groups were favorable.

Structures and activation mechanism of the Gabija anti-phage system.

Prokaryotes have evolved intricate innate immune systems against phage infection1-7. Gabija is a highly widespread prokaryotic defence system that consists of two components, GajA and GajB8. GajA functions as a DNA endonuclease that is inactive in the presence of ATP9. Here, to explore how the Gabija system is activated for anti-phage defence, we report its cryo-electron microscopy structures in five states, including apo GajA, GajA in complex with DNA, GajA bound by ATP, apo GajA-GajB, and GajA-GajB in complex with ATP and Mg2+. GajA is a rhombus-shaped tetramer with its ATPase domain clustered at the centre and the topoisomerase-primase (Toprim) domain located peripherally. ATP binding at the ATPase domain stabilizes the insertion region within the ATPase domain, keeping the Toprim domain in a closed state. Upon ATP depletion by phages, the Toprim domain opens to bind and cleave the DNA substrate. GajB, which docks on GajA, is activated by the cleaved DNA, ultimately leading to prokaryotic cell death. Our study presents a mechanistic landscape of Gabija activation.

Design, synthesis and bioactivity of a new class of antifungal amino acid-directed phthalide compounds.

BACKGROUND: Peanut southern blight disease, caused by Sclerotium rolfsii, is a destructive soil-borne fungal disease. The current control measures, which mainly employ succinate dehydrogenase inhibitors, are prone to resistance and toxicity to non-target organisms. As a result, it is necessary to explore the potential of eco-friendly fungicides for this disease. RESULTS: Fourteen novel phthalide compounds incorporating amino acid moieties were designed and synthesized. The in vitro activity of analog A1 [half maximal effective concentration (EC50) = 332.21 mg L-1] was slightly lower than that of polyoxin (EC50 = 284.32 mg L-1). It was observed that on the seventh day, the curative activity of A1 at a concentration of 600.00 mg L-1 was 57.75%, while the curative activity of polyoxin at a concentration of 300.00 mg L-1 was 42.55%. These results suggested that our compound exhibited in vivo activity. Peanut plants treated with A1 showed significant agronomic improvements compared to the untreated control. Several compounds in this series exhibited superior root absorption and conduction in comparison to the endothermic fungicide thifluzamide. The growth promotion and absorption-conduction experiments demonstrated the reason for the superior in vivo activity of the target compound. Cytotoxic assays have demonstrated that this series of targeted compounds exhibit low toxicity levels toward human lo2 liver cells. CONCLUSION: Our results provide a new strategy for the design and synthesis of novel green compounds. Furthermore, the target compound A1 can serve as a lead for further development of green fungicides. © 2024 Society of Chemical Industry.

Integrative omics analysis elucidates the genetic basis underlying seed weight and oil content in soybean.

Synergistic optimization of key agronomic traits by traditional breeding has dramatically enhanced crop productivity in the past decades. However, the genetic basis underlying coordinated regulation of yield- and quality-related traits remains poorly understood. Here, we dissected the genetic architectures of seed weight and oil content by combining genome-wide association studies (GWAS) and transcriptome-wide association studies (TWAS) using 421 soybean (Glycine max) accessions. We identified 26 and 33 genetic loci significantly associated with seed weight and oil content by GWAS, respectively, and detected 5,276 expression quantitative trait loci (eQTLs) regulating expression of 3,347 genes based on population transcriptomes. Interestingly, a gene module (IC79), regulated by two eQTL hotspots, exhibited significant correlation with both seed weigh and oil content. Twenty-two candidate causal genes for seed traits were further prioritized by TWAS, including Regulator of Weight and Oil of Seed 1 (GmRWOS1), which encodes a sodium pump protein. GmRWOS1 was verified to pleiotropically regulate seed weight and oil content by gene knockout and overexpression. Notably, allelic variations of GmRWOS1 were strongly selected during domestication of soybean. This study uncovers the genetic basis and network underlying regulation of seed weight and oil content in soybean and provides a valuable resource for improving soybean yield and quality by molecular breeding.

Presurgical computed tomography-guided localization of lung ground glass nodules: comparing hook-wire and indocyanine green.

BACKGROUND: Presurgical computed tomography (CT)-guided localization is frequently employed to reduce the thoracotomy conversion rate, while increasing the rate of successful sublobar resection of ground glass nodules (GGNs) via video-assisted thoracoscopic surgery (VATS). In this study, we compared the clinical efficacies of presurgical CT-guided hook-wire and indocyanine green (IG)-based localization of GGNs. METHODS: Between January 2018 and December 2021, we recruited 86 patients who underwent CT-guided hook-wire or IG-based GGN localization before VATS resection in our hospital, and compared the clinical efficiency and safety of both techniques. RESULTS: A total of 38 patients with 39 GGNs were included in the hook-wire group, whereas 48 patients with 50 GGNs were included in the IG group. There were no significant disparities in the baseline data between the two groups of patients. According to our investigation, the technical success rates of CT-based hook-wire- and IG-based localization procedures were 97.4% and 100%, respectively (P = 1.000). Moreover, the significantly longer localization duration (15.3 ± 6.3 min vs. 11.2 ± 5.3 min, P = 0.002) and higher visual analog scale (4.5 ± 0.6 vs. 3.0 ± 0.5, P = 0.001) were observed in the hook-wire patients, than in the IG patients. Occurrence of pneumothorax was significantly higher in hook-wire patients (27.3% vs. 6.3%, P = 0.048). Lung hemorrhage seemed higher in hook-wire patients (28.9% vs. 12.5%, P = 0.057) but did not reach statistical significance. Lastly, the technical success rates of VATS sublobar resection were 97.4% and 100% in hook-wire and IG patients, respectively (P = 1.000). CONCLUSIONS: Both hook-wire- and IG-based localization methods can effectively identified GGNs before VATS resection. Furthermore, IG-based localization resulted in fewer complications, lower pain scores, and a shorter duration of localization.

How redox gradient potentially influences nitrate reduction coupled with sulfur cycling: A new insight into nitrogen cycling in the hyporheic zone of effluent-dominated rivers.

The coupled N and S cycling in variable redox gradients in the hyporheic zone (HZ) of the rivers receiving effluents from wastewater treatment plants is unclear. Using two representative effluent-dominated rivers as model systems, a metagenome approach was employed to explore the spatiotemporal redox zonation of the HZ and the N/S cycling processes within the system. The results manifested that nitrate reduction represented the fundamental nitrogen pathway in the HZ. Interestingly, DNRA coupled with sulfur reduction, and denitrification coupled with sulfur oxidation were respectively abundant in the oxic and anoxic zone. Lower nitrate concentration (0-2.72 mg-N/L) and more abundant genes involved in denitrification (napB, NarGHI) and sulfur oxidation (sseA, glpE) were detected in the anoxic zone. Contrarily, the nitrate concentration (0.07-4.87 mg-N/L) and the abundance of genes involved in sulfur reduction (ttrB, sudA) and DNRA (nirBD) were observed more abundant in the oxic zone. Therefore, the results verified the oxygen-limited condition did not suppress but rather facilitated the denitrification process in the presence of active S cycling. The high relative abundances of nosZ gene encoding sequence (3-5 % relative to all nitrogen-cycling processes) in both the effluent-discharging area and downstream area highly confirmed that HZ was capable of alleviating the N2O emission in the region. The functional keystone taxa were revealed through co-occurrence network analysis. The structural equation model shows that the genes of N/S cycling were positively impacted by functional keystone taxa, especially the N cycling genes. Functional keystone taxa were proven driven by the redox gradient, demonstrating their positive roles in mediating N/S cycling processes. The promoting effect on nitrate reduction coupled with sulfur cycling was clarified when redox conditions oscillated, providing a new perspective on mitigating nitrogen pollution and greenhouse gas emissions in effluent-receiving rivers.