An additional proofreader contributes to DNA replication fidelity in mycobacteria.

The removal of mis-incorporated nucleotides by proofreading activity ensures DNA replication fidelity. Whereas the ε-exonuclease DnaQ is a well-established proofreader in the model organism Escherichia coli, it has been shown that proofreading in a majority of bacteria relies on the polymerase and histidinol phosphatase (PHP) domain of replicative polymerase, despite the presence of a DnaQ homolog that is structurally and functionally distinct from E. coli DnaQ. However, the biological functions of this type of noncanonical DnaQ remain unclear. Here, we provide independent evidence that noncanonical DnaQ functions as an additional proofreader for mycobacteria. Using the mutation accumulation assay in combination with whole-genome sequencing, we showed that depletion of DnaQ in Mycolicibacterium smegmatis leads to an increased mutation rate, resulting in AT-biased mutagenesis and increased insertions/deletions in the homopolymer tract. Our results showed that mycobacterial DnaQ binds to the ß clamp and functions synergistically with the PHP domain proofreader to correct replication errors. Furthermore, the loss of dnaQ results in replication fork dysfunction, leading to attenuated growth and increased mutagenesis on subinhibitory fluoroquinolones potentially due to increased vulnerability to fork collapse. By analyzing the sequence polymorphism of dnaQ in clinical isolates of Mycobacterium tuberculosis (Mtb), we demonstrated that a naturally evolved DnaQ variant prevalent in Mtb lineage 4.3 may enable hypermutability and is associated with drug resistance. These results establish a coproofreading model and suggest a division of labor between DnaQ and PHP domain proofreader. This study also provides real-world evidence that a mutator-driven evolutionary pathway may exist during the adaptation of Mtb.

Rapid and Repeated Climate Adaptation Involving Chromosome Inversions following Invasion of an Insect.

Following invasion, insects can become adapted to conditions experienced in their invasive range, but there are few studies on the speed of adaptation and its genomic basis. Here, we examine a small insect pest, Thrips palmi, following its contemporary range expansion across a sharp climate gradient from the subtropics to temperate areas. We first found a geographically associated population genetic structure and inferred a stepping-stone dispersal pattern in this pest from the open fields of southern China to greenhouse environments of northern regions, with limited gene flow after colonization. In common garden experiments, both the field and greenhouse groups exhibited clinal patterns in thermal tolerance as measured by critical thermal maximum (CTmax) closely linked with latitude and temperature variables. A selection experiment reinforced the evolutionary potential of CTmax with an estimated h2 of 6.8% for the trait. We identified 3 inversions in the genome that were closely associated with CTmax, accounting for 49.9%, 19.6%, and 8.6% of the variance in CTmax among populations. Other genomic variations in CTmax outside the inversion region were specific to certain populations but functionally conserved. These findings highlight rapid adaptation to CTmax in both open field and greenhouse populations and reiterate the importance of inversions behaving as large-effect alleles in climate adaptation.

Molecular interactions of the chaperone CcmS and carboxysome shell protein CcmK1 that mediate ß-carboxysome assembly.

The carboxysome is a natural proteinaceous organelle for carbon fixation in cyanobacteria and chemoautotrophs. It comprises hundreds of protein homologs that self-assemble to form a polyhedral shell structure to sequester cargo enzymes, ribulose 1,5-bisphosphate carboxylase/oxygenase (Rubisco) and carbonic anhydrases. How these protein components assemble to construct a functional carboxysome is a central question in not only understanding carboxysome structure and function but also synthetic engineering of carboxysomes for biotechnological applications. Here, we determined the structure of the chaperone protein CcmS, which has recently been identified to be involved in ß-carboxysome assembly, and its interactions with ß-carboxysome proteins. The crystal structure at 1.99 Å resolution reveals CcmS from Nostoc sp. PCC 7120 forms a homodimer, and each CcmS monomer consists of five α-helices and four ß-sheets. Biochemical assays indicate that CcmS specifically interacts with the C-terminal extension of the carboxysome shell protein CcmK1, but not the shell protein homolog CcmK2 or the carboxysome scaffolding protein CcmM. Moreover, we solved the structure of a stable complex of CcmS and the C-terminus of CcmK1 at 1.67 Å resolution and unveiled how the CcmS dimer interacts with the C-terminus of CcmK1. These findings allowed us to propose a model to illustrate CcmS-mediated ß-carboxysome assembly by interacting with CcmK1 at the outer shell surface. Collectively, our study provides detailed insights into the accessory factors that drive and regulate carboxysome assembly, thereby improving our knowledge of carboxysome structure, function, and bioengineering.

The correlation between the level of cellular classification in bronchoalveolar lavage fluid of children with severe Mycoplasma pneumoniae and clinical characteristics.

Mycoplasma pneumoniae pneumonia (MPP) is a common respiratory tract infection disease in children. To date, there have been few studies on the relationship between cytological changes in bronchoalveolar lavage fluid (BALF) and clinical features. The objective of this study is to investigate the correlation between changes in the proportion of cell classifications in BALF and the clinical features in children with severe MPP (SMPP). In total, the study included 64 children with SMPP requiring bronchoalveolar lavage who were admitted to our hospital between March and September 2022 (study group) and 11 children with bronchial foreign bodies without co-infection (control group), who were admitted during the same period. The proportion of cell classifications in BALF was determined by microscopic examination after performing Wright-Giemsa staining. Patients were grouped according to different clinical characteristics, and between-group comparisons were made regarding the variations in the proportion of cell classifications in BALF. The levels of blood routine neutrophil percentage (GRA%), C-reactive protein, D-dimer and lactate dehydrogenase in the study group were higher than those in the control group (P < 0.05). There were differences in the GRA% and macrophage percentage in the BALF between the two groups (P < 0.05). The GRA% and blood lymphocyte percentage were associated with pleural effusion. Multiple indicators correlated with extrapulmonary manifestations (P < 0.05). Moreover, the percentage of lymphocytes in the BALF correlated with pleural effusion, extrapulmonary manifestations and refractory MPP (RMPP) (P < 0.05). Logistic regression showed that BALF lymphocytes were protective factors for RMPP, while serum amyloid A and extrapulmonary manifestations were risk factors (P < 0.05). CONCLUSION: The BALF of children with SMPP is predominantly neutrophilic. A lower percentage of lymphocytes is related to a higher incidence of pleural effusion, extrapulmonary manifestations and progression to RMPP, as well as a longer length of hospitalisation. WHAT IS KNOWN: • Mycoplasma pneumonia in children is relatively common in clinical practice. Bronchoalveolar lavage (BAL) is a routine clinical procedure. WHAT IS NEW: However, there are relatively few studies focusing on the cytomorphological analysis of cells in BAL fluid.

Increased serum extrachromosomal circular DNA SORBS1circle level is associated with insulin resistance in patients with newly diagnosed type 2 diabetes mellitus.

BACKGROUND: Extrachromosomal circular DNAs (eccDNAs) exist in human blood and somatic cells, and are essential for oncogene plasticity and drug resistance. However, the presence and impact of eccDNAs in type 2 diabetes mellitus (T2DM) remains inadequately understood. METHODS: We purified and sequenced the serum eccDNAs obtained from newly diagnosed T2DM patients and normal control (NC) subjects using Circle-sequencing. We validated the level of a novel circulating eccDNA named sorbin and SH3-domain- containing-1circle97206791-97208025 (SORBS1circle) in 106 newly diagnosed T2DM patients. The relationship between eccDNA SORBS1circle and clinical data was analyzed. Furthermore, we explored the source and expression level of eccDNA SORBS1circle in the high glucose and palmitate (HG/PA)-induced hepatocyte (HepG2 cell) insulin resistance model. RESULTS: A total of 22,543 and 19,195 eccDNAs were found in serum samples obtained from newly diagnosed T2DM patients and NC subjects, respectively. The T2DM patients had a greater distribution of eccDNA on chromosomes 1, 14, 16, 17, 18, 19, 20 and X. Additionally, 598 serum eccDNAs were found to be upregulated, while 856 eccDNAs were downregulated in T2DM patients compared with NC subjects. KEGG analysis demonstrated that the genes carried by eccDNAs were mainly associated with insulin resistance. Moreover, it was validated that the eccDNA SORBS1circle was significantly increased in serum of newly diagnosed T2DM patients (106 T2DM patients vs. 40 NC subjects). The serum eccDNA SORBS1circle content was positively correlated with the levels of glycosylated hemoglobin A1C (HbA1C) and homeostasis model assessment of insulin resistance (HOMA-IR) in T2DM patients. Intracellular eccDNA SORBS1circle expression was significantly enhanced in the high glucose and palmitate (HG/PA)-induced hepatocyte (HepG2 cell) insulin resistance model. Moreover, the upregulation of eccDNA SORBS1circle in the HG/PA-treated HepG2 cells was dependent on generation of apoptotic DNA fragmentation. CONCLUSIONS: These results provide a preliminary understanding of the circulating eccDNA patterns at the early stage of T2DM and suggest that eccDNA SORBS1circle may be involved in the development of insulin resistance.

The potential health risks of N,N-dimethylformamide: An updated review.

N,N-dimethylformamide (DMF) is a universally used industrial material with exponential growth in production and consumption worldwide. The frequently reported occupational DMF poisoning cases in some countries and the gradually recognized unavoidable health risks to the general population highlight that DMF should still be a matter of concern. Previous studies have demonstrated that the liver is the primary target organ of DMF exposure and multiple mechanisms have been revealed. However, most of these studies investigate the detrimental effects of acute and subacute DMF exposure, while the effects of chronic DMF exposure are rarely studied. Furthermore, the key mechanism for the acute hepatotoxicity of DMF remains to be elucidated. Future research may focus on the identification of efficient preventive measures against the toxicity of DMF to occupational workers, the investigation of the detrimental effects of DMF at environmentally relevant doses, and the studies on the elimination and recycling of DMF in industrial wastes. Herein, we present an updated review of the metabolism of DMF, the biomarker of DMF exposure, underlying molecular mechanisms of DMF-induced hepatotoxicity, and the toxicity of DMF to both occupational workers and general populations and discuss the possible directions in future studies.

Treatment of low-C/N nitrate wastewater using a partial denitrification-anammox granule system: Granule reconstruction, stability, and microbial structure analyses.

Industrial wastewater discharged into sewer systems is often characterized by high nitrate contents and low C/N ratios, resulting in high treatment costs when using conventional activated sludge methods. This study introduces a partial denitrification-anammox (PD/A) granular process to address this challenge. The PD/A granular process achieved an effluent TN level of 3.7 mg/L at a low C/N ratio of 2.3. Analysis of a typical cycle showed that the partial denitrification peaked within 15 min and achieved a nitrate-to-nitrite transformation ratio of 86.9%. Anammox, which was activated from 15 to 120 min, contributed 86.2% of the TN removal. The system exhibited rapid recovery from post-organic shock, which was attributed to significant increases in protein content within TB-EPS. Microbial dispersion and reassembly were observed after coexistence of the granules, with Thauera (39.12%) and Candidatus Brocadia (1.25%) identified as key functional microorganisms. This study underscores the efficacy of PD/A granular sludge technology for treating low-C/N nitrate wastewater.

CDK5RAP3 Inhibition by Hypoxia Activates P38MAPK to Facilitate Angiogenesis.

CDK5RAP3 is a recognized tumor suppressor that inhibits Chk1 and Chk2 and activates p53, all of which are involved with mediating toxin-induced apoptosis of cancer cells. CDK5RAP3 also inhibits p38MAPK phosphorylation and activity via mediating a p38 interaction with wild-type p53-induced phosphatase 1. This study aimed to investigate the antiangiogenic activity of CDK5RAP3 and its molecular mechanisms in human umbilical vein endothelial cells (HUVECs) under conditions of hypoxic conditions. Angiogenesis was induced in HUVECs mainly by vascular endothelial growth factor (VEGF). The CDK5RAP3 levels of HUVECs were reduced in a time-dependent manner in response to hypoxic treatment at 2% O2. The reduction of CDK5RAP3 was accompanied with increased p38MAPK phosphorylation and activation. Moderate hypoxia was found to significantly increase secreted VEGF concentrations, and the hypoxic conditioned medium (HCM) markedly enhanced proliferation, migration, and tube formation. Our findings indicate that moderate hypoxia facilitates angiogenesis by inhibiting CDK5RAP3. CDK5RAP3 exhibits a clear regulatory role in vascular regeneration, as downregulating its expression in endothelial cells enhances VEGF synthesis and subsequently improves cell migration and lumen formation capability. This study presents evidence indicating that moderate hypoxia facilitates angiogenesis by inhibiting CDK5RAP3, demonstrating the potential for CKD5RAP3 to be a potent antiangiogenic agent in angiogenesis regulation of cancer, ischemic diseases, and wound healing.

Innovative Clinical Scenario Simulator for Step-by-Step Microsurgical Training.

BACKGROUND: Microsurgical training should be implemented with consideration of operative difficulties that occur in actual clinical situations. We evaluated the effectiveness of a novel clinical scenario simulator for step-by-step microsurgical training that progressed from conventional training to escalated training with additional obstacles. METHODS: A training device was designed according to multiple and intricate clinical microsurgery scenarios. Twenty surgical residents with no experience in microsurgery were randomly assigned to either the control group (conventional training curricula, n = 10) or the experimental group (step-by-step training courses, n = 10). After 4 weeks of laboratory practice, the participants were scheduled to perform their first microvascular anastomoses on patients in an operating room. The Global Rating Scale (GRS) scores and operative duration were used to compare microsurgical skills between the two groups. RESULTS: There were no significant differences in the participants' baseline characteristics before microsurgical training between the groups with respect to age, sex, postgraduate year, surgical specialty, or mean GRS score (p < 0.05). There were also no significant differences in recipient sites between the two groups (p = 0.735). After training, the GRS scores in both groups were significantly improved (p = 0.000). However, in the actual microsurgical situations, the GRS scores were significantly higher in the experimental than control group (p < 0.05). There was no significant difference in the operative duration between the two groups (p < 0.13). CONCLUSION: Compared with a traditional training program, this step-by-step microsurgical curriculum based on our clinical scenario simulator results in significant improvement in acquisition of microsurgical skills.

A Cyclometalated Ruthenium(II) Complex Induces Oncosis for Synergistic Activation of Innate and Adaptive Immunity.

An optimal cancer chemotherapy regimen should effectively address the drug resistance of tumors while eliciting antitumor-immune responses. Research has shown that non-apoptotic cell death, such as pyroptosis and ferroptosis, can enhance the immune response. Despite this, there has been limited investigation and reporting on the mechanisms of oncosis and its correlation with immune response. Herein, we designed and synthesized a Ru(II) complex that targeted the nucleus and mitochondria to induce cell oncosis. Briefly, the Ru(II) complex disrupts the nucleus and mitochondria DNA, which active polyADP-ribose polymerase 1, accompanied by ATP consumption and porimin activation. Concurrently, mitochondrial damage and endoplasmic reticulum stress result in the release of Ca2+ ions and increased expression of Calpain 1. Subsequently, specific pore proteins porimin and Calpain 1 promote cristae destruction or vacuolation, ultimately leading to cell membrane rupture. The analysis of RNA sequencing demonstrates that the Ru(II) complex can initiate the oncosis-associated pathway and activate both innate and adaptive immunity. In vivo experiments have confirmed that oncosis promotes dendritic cell maturation and awakens adaptive cytotoxic T lymphocytes but also activates the innate immune by inducing the polarization of macrophages towards an M1 phenotype.

MUMA: a multi-omics meta-learning algorithm for data interpretation and classification.

Multi-omics data integration is a promising field combining various types of omics data, such as genomics, transcriptomics, and proteomics, to comprehensively understand the molecular mechanisms underlying life and disease. However, the inherent noise, heterogeneity, and high dimensionality of multi-omics data present challenges for existing methods to extract meaningful biological information without overfitting. This paper introduces a novel Multi-Omics Meta-learning Algorithm (MUMA) that employs self-adaptive sample weighting and interaction-based regularization for enhanced diagnostic performance and interpretability in multi-omics data analysis. Specifically, MUMA captures crucial biological processes across different omics layers by learning a flexible sample reweighting function adaptable to various noise scenarios. Additionally, MUMA incorporates an interaction-based regularization term, encouraging the model to learn from the relationships among different omics modalities. We evaluate MUMA using simulations and eighteen real datasets, demonstrating its superior performance compared to state-of-the-art methods in classifying biological samples (e.g., cancer subtypes) and selecting relevant biomarkers from noisy multi-omics data. As a powerful tool for multi-omics data integration, MUMA can assist researchers in achieving a deeper understanding of the biological systems involved. The source code for MUMA is available at https://github.com/bio-ai-source/MUMA.

Cancer cell response to extrinsic and intrinsic mechanical cue: opportunities for tumor apoptosis strategies.

Increasing studies have revealed the importance of mechanical cues in tumor progression, invasiveness and drug resistance. During malignant transformation, changes manifest in either the mechanical properties of the tissue or the cellular ability to sense and respond to mechanical signals. The major focus of the review is the subtle correlation between mechanical cues and apoptosis in tumor cells from a mechanobiology perspective. To begin, we focus on the intracellular force, examining the mechanical properties of the cell interior, and outlining the role that the cytoskeleton and intracellular organelle-mediated intracellular forces play in tumor cell apoptosis. This article also elucidates the mechanisms by which extracellular forces guide tumor cell mechanosensing, ultimately triggering the activation of the mechanotransduction pathway and impacting tumor cell apoptosis. Finally, a comprehensive examination of the present status of the design and development of anti-cancer materials targeting mechanotransduction is presented, emphasizing the underlying design principles. Furthermore, the article underscores the need to address several unresolved inquiries to enhance our comprehension of cancer therapeutics that target mechanotransduction.

Exosomes derived from miR-146a-overexpressing fibroblast-like synoviocytes in cartilage degradation and macrophage M1 polarization: a novel protective agent for osteoarthritis?

Introduction: Pathological changes in the articular cartilage (AC) and synovium are major manifestations of osteoarthritis (OA) and are strongly associated with pain and functional limitations. Exosome-derived microRNAs (miRNAs) are crucial regulatory factors in intercellular communication and can influence the progression of OA by participating in the degradation of chondrocytes and the phenotypic transformation in the polarization of synovial macrophages. However, the specific relationships and pathways of action of exosomal miRNAs in the pathological progression of OA in both cartilage and synovium remain unclear. Methods: This study evaluates the effects of fibroblast-like synoviocyte (FLS)-derived exosomes (FLS-Exos), influenced by miR-146a, on AC degradation and synovial macrophage polarization. We investigated the targeted relationship between miR-146a and TRAF6, both in vivo and in vitro, along with the involvement of the NF-κB signaling pathway. Results: The expression of miR-146a in the synovial exosomes of OA rats was significantly higher than in healthy rats. In vitro, the upregulation of miR-146a reduced chondrocyte apoptosis, whereas its downregulation had the opposite effect. In vivo, exosomes derived from miR-146a-overexpressing FLSs (miR-146a-FLS-Exos) reduced AC injury and chondrocyte apoptosis in OA. Furthermore, synovial proliferation was reduced, and the polarization of synovial macrophages shifted from M1 to M2. Mechanistically, the expression of TRAF6 was inhibited by targeting miR-146a, thereby modulating the Toll-like receptor 4/TRAF6/NF-κB pathway in the innate immune response. Discussion: These findings suggest that miR-146a, mediated through FLS-Exos, may alleviate OA progression by modulating cartilage degradation and macrophage polarization, implicating the NF-κB pathway in the innate immune response. These insights highlight the therapeutic potential of miR-146a as a protective agent in OA, underscoring the importance of exosomal miRNAs in the pathogenesis and potential treatment of the disease.

Long-term water demand forecasting using artificial intelligence models in the Tuojiang River basin, China.

Accurate forecasts of water demand are a crucial factor in the strategic planning and judicious use of finite water resources within a region, underpinning sustainable socio-economic development. This study aims to compare the applicability of various artificial intelligence models for long-term water demand forecasting across different water use sectors. We utilized the Tuojiang River basin in Sichuan Province as our case study, comparing the performance of five artificial intelligence models: Genetic Algorithm optimized Back Propagation Neural Network (GA-BP), Extreme Learning Machine (ELM), Gaussian Process Regression (GPR), Support Vector Regression (SVR), and Random Forest (RF). These models were employed to predict water demand in the agricultural, industrial, domestic, and ecological sectors using actual water demand data and relevant influential factors from 2005 to 2020. Model performance was evaluated based on the Root Mean Square Error (RMSE), Mean Absolute Error (MAE), and Mean Absolute Percentage Error (MAPE), with the most effective model used for 2025 water demand projections for each sector within the study area. Our findings reveal that the GPR model demonstrated superior results in predicting water demand for the agricultural, domestic, and ecological sectors, attaining R2 values of 0.9811, 0.9338, and 0.9142 for the respective test sets. Also, the GA-BP model performed optimally in predicting industrial water demand, with an R2 of 0.8580. The identified optimal prediction model provides a useful tool for future long-term water demand forecasting, promoting sustainable water resource management.

Fructose-mineralized black phosphorus for syncretic bone regeneration and tumor suppression.

Black phosphorus (BPs) nanosheets with their inherent and selective chemotherapeutic effects have recently been identified as promising cancer therapeutic agents, but challenges in surface functionalization hinder satisfactory enhancement of their selectivity between tumors and normal cells. To address this issue, we developed a novel biomineralization-inspired strategy to synthesize CaBPs-Na2FDP@CaCl2 nanosheets, aiming to achieve enhanced and selective anticancer bioactivity along with accelerated osteoblast activity. Benefiting from the in situ mineralization and fructose modification, CaBPs-Na2FDP@CaCl2 exhibited improved pH-responsive degradation behavior and targeted therapy for osteosarcoma. The in vitro results indicated that CaBPs-Na2FDP@CaCl2 exhibited efficient uptake and quick degradation by GLUT5-positive 143B osteosarcoma cells, enhancing BPs-driven chemotherapeutic effects through ATP level disturbance-mediated apoptosis of tumor cells. Moreover, CaBPs-Na2FDP@CaCl2 underwent gradual degradation into PO43-, Ca2+ and fructose in MC3T3-E1 cells, eliminating systemic toxicity. Intracellular Ca2+ bound to calmodulin (CaM), activating Ca2+/CaM-dependent signaling cascades, thereby enhancing osteoblast differentiation and mineralization in pro-osteoblastic cells. In vivo experiments affirmed the anti-tumor capability, inhibition of tumor recurrence and bone repair promotion of CaBPs-Na2FDP@CaCl2. This study not only broadens the application of BPs in bone tumor therapy but also provides a versatile surface functionalization strategy for nanotherapeutic agents.

Enzyme-Mineralized PVASA Hydrogels with Combined Toughness and Strength for Bone Tissue Engineering.

Enzymatic mineralization is an advanced mineralization method that is often used to enhance the stiffness and strength of hydrogels, but often accompanied by brittle behavior. Moreover, the hydrogel systems with dense networks currently used for enzymatic mineralization are not ideal materials for bone repair applications. To address these issues, two usual bone repair hydrogels, poly(vinyl alcohol) (PVA) and sodium alginate (SA), were selected to form a double-network structure through repeated freeze-thawing and ionic cross-linking, followed by enzyme mineralization. The results demonstrated that both enzymatic mineralization and double-network structure improved the mechanical and biological properties and even exhibited synergistic effects. The mineralized PVASA hydrogels exhibited superior comprehensive mechanical properties, with a Young's modulus of 1.03 MPa, a storage modulus of 103 kPa, and an equilibrium swelling ratio of 132%. In particular, the PVASA hydrogel did not suffer toughness loss after mineralization, with a high toughness value of 1.86 MJ/m3. The prepared hydrogels also exhibited superior biocompatibility with a cell spreading area about 13 times that of mineralized PVA. It also effectively promoted cellular osteogenic differentiation in vitro and further promoted the formation of new bone in the femur defect region in vivo. Overall, the enzyme-mineralized PVASA hydrogel demonstrated combined strength and toughness and great potential for bone tissue engineering applications.

Mitochondrial genome rearrangements and phylogenomics of the Hymenoptera (Insecta) using an expanded taxon sample.

The order Hymenoptera is one of the most species-rich insect orders, with more than 150,000 described extant species. Many hymenopteran insects have very different mitochondrial genome (mitogenome) organizations compared to the putative ancestral organization of insects. In this study, we sequenced 18 mitogenomes of representatives in the order Hymenoptera to increase taxonomic sampling. A total of 475 species were used in phylogenetic analyses, including 18 new mitogenomes and 457 existing mitogenomes. Using a site-heterogeneous model, Bayesian's inference from amino acid data yielded more resolved relationships among Hymenoptera than maximum-likelihood analysis and coalescent-based species analyses. The monophyly of Symphyta was not supported. The Xyeloidea was the earliest branching clade in the Hymenoptera. The Orussoidea was closely related to Apocrita. Within Apocrita, the Parasitoida was non-monophyletic. The monophyly of most Parasitoida superfamilies received strong support. The Proctotrupomorpha clade was supported in Bayesian's analysis. The Apoidea was monophyletic when excluding Ampulex compressa from consideration. The superfamilies Vespoidea and Chrysidoidea were found to be non-monophyletic. Comparisons of mitochondrial gene order revealed a higher frequency of gene rearrangement among lineages with a parasitoid lifestyle, particularly prominent in Chalcidoidea. The degree of gene rearrangement ranked second in specific taxa of Cynipoidea and Ichneumonoidea.

Synthesis of Ottonia anisum Extract Mediated ZnO NPs and Their Local Anesthetic, Analgesic and HCl­induced Acute Lung Injury Activities.

In this study, we outlined the green synthesis of Zinc oxide nanoparticles (ZnO NPs) using the plant-mediated method. Employing the nitrate derivative of Zinc and the extract from the native medicinal plant, Ottonia anisum, the nanoparticles were effectively produced. After obtaining a yellow-colored paste, it was meticulously dried, gathered, and set aside for subsequent examination. The UV-visible spectrometry analysis indicated an absorption peak at 320 nm, which is indicative of ZnO NPs. Characterization techniques, such as XRD and HR-TEM, confirmed the existence of agglomerated ZnO NPs with an average diameter of 40 nm. Through EDS analysis, distinct energy signals for both Zinc and Oxygen were observed, confirming their composition. Furthermore, FT-IR spectroscopy highlighted an absorption peak for Zn-O bonding in the range of 400 to 600 cm -1 . Further, we employed three distinct pain models in mice to evaluate the influence of ZnO NPs on the nociceptive threshold. Our findings revealed that, when orally administered, ZnO NPs at concentrations ranging from 5-20 mg/kg exerted a dose-dependent analgesic effect in both the hot-plate and the acetic acid-induced writhing tests. Moreover, when ZnO NPs were administered at doses between 2.5-10 mg/kg, there was a notable reduction in pain responses during both the initial and subsequent phases of the formalin test, but no change in PGE 2 production within the mice's hind paw was found. On the other hand, acute lung injury studies revealed that the administration of ZnO NPs orally 90 minutes prior to HCl instillation decreased the neutrophil infiltration into the lungs in a doseresponsive manner. This reduction in pulmonary inflammation was paralleled by a significant decrease in lung edema, as evidenced by the reduced total protein content in the BALF. Additionally, the ZnO NPs appeared to recalibrate the lung's redox equilibrium following HCl exposure, which was determined through measurements of ROS, malondialdehyde, glutathione, and catalase activity. All these results further indicated the potential of biofabricated ZnO NPs for future applications in analgesics and acute lung injury treatments.

HOXA5-induced lncRNA DNM3OS promotes human embryo lung fibroblast fibrosis via recruiting EZH2 to epigenetically suppress TSC2 expression.

Background: Idiopathic pulmonary fibrosis (IPF) is an unrepairable disease that results in lung dysfunction and decreased quality of life. Prevention of pulmonary fibrosis is challenging, while its pathogenesis remains largely unknown. Herein, we investigated the effect and mechanism of long non-coding RNA (lncRNA) DNM3OS/Antisense RNA in the pathogenesis of pulmonary fibrosis. Methods: EdU (5-ethynyl-2'-deoxyuridine) and wound healing assays were employed to evaluate the role of DNM3OS on cell proliferation and migration. Western blot detected the proteins expressions of alpha-smooth muscle actin (α-SMA), vimentin, and fibronectin. The interactions among genes were evaluated by RNA pull-down, luciferase reporter, RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP) and chromatin Isolation by RNA purification (ChIRP) assays. Results: DNM3OS was upregulated by transforming growth factor beta 1 (TGF-ß1) in a dose- and time-dependent manner. DNM3OS knockdown repressed the growth and migration of lung fibroblast, and fibrotic gene expression (CoL1α1, CoL3α1, α-SMA, vimentin, and fibronectin), while suppression of TSC2 accelerated the above process. DNM3OS recruited EZH2 to the promoter region of TSC2, increased the occupancy of EZH2 and H3K27me3, and thereby suppressed the expression of TSC2. HOXA5 promoted the transcription of DNM3OS. Conclusions: HOXA5-induced DNM3OS promoted the proliferation, migration, and expression of fibrosis-related genes in human embryo lung fibroblast via recruiting EZH2 to epigenetically suppress the expression of TSC2.

USP7 upregulated by TGF-ß1 promotes ferroptosis via inhibiting LATS1-YAP axis in sepsis-induced acute lung injury.

Our work aimed to investigate the interactive roles of transforming growth factor ß1 (TGF-ß1), ubiquitin-specific-processing protease 7 (USP7), and Yes-associated protein (YAP) in ferroptosis during sepsis-secondary acute lung injury (ALI). Our study demonstrated that ferroptosis was aggravated by TGF-ß1 in both cellular and animal models of acute lung injury. Additionally, YAP upregulated glutathione peroxidase 4 (GPX4) and SLC7A11 by regulating the binding of TEAD4 to GPX4/SLC7A11 promoters. Furthermore, large tumor suppressor kinase 1 (LATS1) knockdown resulted in YAP expression stimulation, while USP7 downregulated YAP via deubiquitinating and stabilizing LATS1/2. YAP overexpression or USP7/LATS1 silencing reduced ferroptosis process, which regulated YAP through a feedback loop. However, TGF-ß1 annulled the repression of ferroptosis by YAP overexpression or LATS1/USP7 knockdown. By elucidating the molecular interactions between TGF-ß1, USP7, LATS1/2, and YAP, we identified a new regulatory axis of ferroptosis in sepsis-secondary ALI. Our study sheds light on the pathophysiology of ferroptosis and proposes a potential therapeutic approach for sepsis-induced ALI.