Interactions between Microcystis and its associated bacterial community on electron transfer and transcriptomic processes.

Microcystis and bacteria always live together in the mucilage of Microcystis colonies. Extracellular electrons between Microcystis and bacteria can be translated from bioenergy to electric energy. Here, photosynthetic microbial fuel cells (PMFCs) were constructed to make clear the electron transfer mechanism between Microcystis and bacteria. A remarkable enhancement of current density with 2.5-fold change was detected in the coculture of Microcystis and bacteria than pure culture of Microcystis. Transcriptome analyses showed that photosynthesis efficiency of Microcystis was upregulated and may release more electron to improve extracellular electron transfer rate. Significant increase on oxidative phosphorylation of bacterial community was observed according to meta-transcriptome. Bacterial electrons were transferred out of cell membranes by enhancing VgrG and IcmF copies though the type II bacterial secretion system. Not only Microcystis and bacteria attached with each other tightly by filamentous, but also more gene copies relating to pilin and riboflavin production were detected from Microcystis culture. A confirmatory experiment found that riboflavin can upregulate the electron transfer and current density by adding riboflavin into cocultures. Thus, the direct contact and indirect interspecies electron transfer processes between Microcystis and bacteria were observed. Results enlarge knowledge for activities of Microcystis colonies in cyanobacterial blooms, and provide a better understanding for energy transformation.

Does Microbiome Contribute to Longevity? Compositional and Functional Differences in Gut Microbiota in Chinese Long-Living (>90 Years) and Elderly (65-74 Years) Adults.

The study of longevity and its determinants has been revitalized with the rise of microbiome scholarship. The gut microbiota have been established to play essential protective, metabolic, and physiological roles in human health and disease. The gut dysbiosis has been identified as an important factor contributing to the development of multiple diseases. Accordingly, it is reasonable to hypothesize that the gut microbiota of long-living individuals have healthy antiaging-associated gut microbes, which, by extension, might provide specific molecular targets for antiaging treatments and interventions. In the present study, we compared the gut microbiota of Chinese individuals in two different age groups, long-living adults (aged over 90 years) and elderly adults (aged 65-74 years) who were free of major diseases. We found significantly lower relative abundances of bacteria in the genera Sutterella and Megamonas in the long-living individuals. Furthermore, we established that while biological processes such as autophagy (GO:0006914) and telomere maintenance through semiconservative replication (GO:0032201) were enhanced in the long-living group, response to lipopolysaccharide (GO:0032496), nicotinamide adenine dinucleotide oxidation (GO:0006116), and S-adenosyl methionine metabolism (GO:0046500) were weakened. Moreover, the two groups were found to differ with respect to amino acid metabolism. We suggest that these compositional and functional differences in the gut microbiota may potentially be associated with mechanisms that contribute to determining longevity or aging.

Nanoparticle co-delivery of carboplatin and PF543 restores platinum sensitivity in ovarian cancer models through inhibiting platinum-induced pro-survival pathway activation.

Resistance to platinum-based chemotherapy is the major cause of poor prognosis and cancer-associated mortality in ovarian cancer patients, so novel therapeutic strategies to restore platinum sensitivity are needed to improve patient outcomes. Sphingosine Kinase (SphK) 1 is involved in regulating multiple pro-survival pathways, key mediators in the sensitivity of tumor cells toward platinum. By encapsulating CBP and the SphK1 inhibitor PF543 in PLGA (poly lactic-co-glycolic acid) nanoparticles, a dual-drug delivery system (C/PNPs) was formed to simultaneously deliver CBP and PF543. The physicochemical characteristics, cell uptake rate and biodistribution behavior of C/PNPs were evaluated. Then the anti-tumor ability of C/PNPs in vitro and in vivo was further investigated. The C/PNPs could deliver CBP and PF543 simultaneously to a platinum-insensitive cell line (SKOV3) both in vitro and in vivo. Furthermore, benefiting from the enhanced permeability and retention (EPR) effect of PLGA NPs, C/PNPs exhibited an improved tumor region accumulation. As a result, a synergistic anti-tumor effect was found in the SKOV3 tumor-bearing mice, with tumor volume inhibiting rates of 84.64% and no side effects in major organs. The mechanistic studies confirmed that the inhibition of SphK1 by PF543 sensitized SKOV3 cells to CBP chemotherapy, partly by inhibiting the CBP-induced activation of pro-survival pathways, including ERK, AKT and STAT3 signaling. Our study reveals that C/PNPs can serve as an efficient dual-drug delivery system to restore platinum sensitivity in ovarian cancer models partly through inhibiting platinum-induced pro-survival pathway activation.

Adsorption/desorption of enrofloxacin in farmland soil as the effect of pH and coexisting ions: implications for enrofloxacin fate and risk in loess soil.

Fluoroquinolone antibiotics have been extensively used in clinical treatments for human and animal diseases. However, their long-term presence in the environment increases the risk of producing resistance genes and creates a potential threat to ecosystems and the health of humans and animals. Batch equilibrium experiments were utilized to investigate the adsorption and retention behavior and mechanism of the quinolone antibiotic enrofloxacin (ENR) in farmland soil in North China. The adsorption and desorption kinetics of ENR in soil were best fitted by pseudo-second-order model (R2 > 0.999). Both the adsorption and desorption processes of ENR in soil reached equilibrium in 1 h. The desorption amounts of ENR were significantly lower than the adsorption amounts, with the hysteresis coefficient (HI) being less than 0.7. The adsorption thermodynamic process of ENR followed the Linear and Freundlich models (0.965 < R2 < 0.985). Hydrophobic distribution and heterogeneous multimolecular layer adsorption were identified as critical factors in the adsorption process. The adsorption amount of ENR gradually decreased with increasing temperature and the initial concentration of ENR. The adsorption rate of ENR was above 80%, while the desorption rate remained below 15%, indicating strong retention ability. The adsorption rate of ENR in soil decreased with increasing pH, the adsorption rate reached 98.3% at pH 3.0 but only 31.5% at pH 11. The influence of coexisting ions on adsorption primarily depended on their properties, such as ion radius, ionic strength, and hydrolysis properties, and the inhibition of adsorption increased with increasing ionic strength. These findings contribute to understanding the fate and risk of veterinary antibiotics in loess soil in North China.

Comprehensive analysis of B3 family genes in pearl millet (Pennisetum glaucum) and the negative regulator role of PgRAV-04 in drought tolerance.

Introduction: Members of the plant-specific B3 transcription factor superfamily play crucial roles in various plant growth and developmental processes. Despite numerous valuable studies on B3 genes in other species, little is known about the B3 superfamily in pearl millet. Methods and results: Here, through comparative genomic analysis, we identified 70 B3 proteins in pearl millet and categorized them into four subfamilies based on phylogenetic affiliations: ARF, RAV, LAV, and REM. We also mapped the chromosomal locations of these proteins and analyzed their gene structures, conserved motifs, and gene duplication events, providing new insights into their potential functional interactions. Using transcriptomic sequencing and real-time quantitative PCR, we determined that most PgB3 genes exhibit upregulated expression under drought and high-temperature stresses, indicating their involvement in stress response regulation. To delve deeper into the abiotic stress roles of the B3 family, we focused on a specific gene within the RAV subfamily, PgRAV-04, cloning it and overexpressing it in tobacco. PgRAV-04 overexpression led to increased drought sensitivity in the transgenic plants due to decreased proline levels and peroxidase activity. Discussion: This study not only adds to the existing body of knowledge on the B3 family's characteristics but also advances our functional understanding of the PgB3 genes in pearl millet, reinforcing the significance of these factors in stress adaptation mechanisms.

Novel fungal diphenyl ether biosynthetic gene clusters encode a promiscuous oxidase for elevated antibacterial activities.

Diphenyl ethers (DPEs) are produced by filamentous fungi using polyketide synthases (PKSs) directly, or via Cu oxidase-catalyzed oxidative rearrangements of benzophenone intermediates. Here, we use heterologous expression to reveal a third route towards DPEs in Preussia isomera that relies on an oxidative multienzyme cascade to convert a PKS-generated, ester-linked didepside to depsidones and further to DPEs, and apply comparative genomics to identify conserved biosynthetic gene clusters for this pathway in multiple fungi. The distribution of DPE products is modulated by the expression chassis upon pathway reconstitution. Among the post-PKS enzymes, the DpeH tyrosinase shows considerable substrate promiscuity towards synthetic DPE analogues. By creating hybrid enzymes with a DpeH orthologue from Aspergillus nidulans, we identify the C-terminal region of DpeH to alter substrate recognition. Our work highlights an evolutionarily conserved way to produce DPEs, and provides enzymatic tools to generate DPE analogues with broad spectrum antibiotic activity against multidrug-resistant human pathogens.

Multi-type maternal diabetes mellitus affects human placental villous geometric morphology: A three-dimensional imaging study.

INTRODUCTION: Diabetes mellitus leads to maldevelopment of the villous morphology in the human placenta, disrupting the exchange of materials between the maternal and fetal compartments, consequently compromising fetal development. This study aims to explore how different types of diabetes mellitus affect human placental villous geometric morphology including branching numbers and sizes (length, diameter). METHODS: Here an optical coherence tomography (OCT)-based 3D imaging platform was utilized to capture 3D images of placental villi from different types of diabetes, including type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), and gestational diabetes mellitus (GDM). RESULTS: Different types of diabetes mellitus exhibit different effects on human placental villous geometric morphological parameters: GDM had greater placenta villous parameters at intermediate villous diameter (IVD), terminal villous diameter (TVD), terminal villous length (TVL) compared to the healthy, T1DM, and T2DM, and these differences were statistically significant. The TVD of T1DM and T2DM had significantly greater sizes than the healthy. There was no statistically significant difference in the number of villous branches among the three types of diabetes, but T1DM and GDM had more villous branches than healthy individuals. DISCUSSION: Diabetes mellitus affects the geometric morphology of human placental villi, with varying effects observed in pregnancies of different diabetes types. These findings offer a novel avenue for exploring underlying pathophysiological mechanisms and enhancing the management of women with diabetes from preconception through pregnancy.

Carbon-Spaced Tandem-Disulfide Bond Bridge Design Addresses Limitations of Homodimer Prodrug Nanoassemblies: Enhancing Both Stability and Activatability.

Redox-responsive homodimer prodrug nanoassemblies (RHPNs) have emerged as a significant technology for overcoming chemotherapeutical limitations due to their high drug-loading capacity, low excipient-associated toxicity, and straightforward preparation method. Previous studies indicated that α-position disulfide bond bridged RHPNs exhibited rapid drug release rates but unsatisfactory assembly stability. In contrast, γ-disulfide bond bridged RHPNs showed better assembly stability but low drug release rates. Therefore, designing chemical linkages that ensure both stable assembly and rapid drug release remains challenging. To address this paradox of stable assembly and rapid drug release in RHPNs, we developed carbon-spaced double-disulfide bond (CSDD)-bridged RHPNs (CSDD-RHPNs) with two carbon-spaces. Pilot studies showed that CSDD-RHPNs with two carbon-spaces exhibited enhanced assembly stability, reduction-responsive drug release, and improved selective toxicity compared to α-/γ-position single disulfide bond bridged RHPNs. Based on these findings, CSDD-RHPNs with four and six carbon-spaces were designed to further investigate the properties of CSDD-RHPNs. These CSDD-RHPNs exhibited excellent assembly ability, safety, and prolonged circulation. Particularly, CSDD-RHPNs with two carbon-spaces displayed the best antitumor efficacy on 4T1 and B16-F10 tumor-bearing mice. CSDD chemical linkages offer novel perspectives on the rational design of RHPNs, potentially overcoming the design limitations regarding contradictory assembly ability and drug release rate.

Supercoiled DNA percentage: A key in-process control of linear DNA template for mRNA drug substance manufacturing.

The development of messenger RNA (mRNA) vaccines and therapeutics necessitates the production of high-quality in vitro-transcribed mRNA drug substance with specific critical quality attributes (CQAs), which are closely tied to the uniformity of linear DNA template. The supercoiled plasmid DNA is the precursor to the linear DNA template, and the supercoiled DNA percentage is commonly regarded as a key in-process control (IPC) during the manufacturing of linear DNA template. In this study, we investigate the influence of supercoiled DNA percentage on key mRNA CQAs, including purity, capping efficiency, double-stranded RNA (dsRNA), and distribution of poly(A) tail. Our findings reveal a significant impact of supercoiled DNA percentage on mRNA purity and in vitro transcription yield. Notably, we observe that the impact on mRNA purity can be mitigated through oligo-dT chromatography, alleviating the tight range of DNA supercoiled percentage to some extent. Overall, this study provides valuable insights into IPC strategies for DNA template chemistry, manufacturing, and controls (CMC) and process development for mRNA drug substance.

The p38/MAPK pathway as a therapeutic target to prevent therapeutic escape of breast cancer stem cells.

Cancer stem cells (CSCs) play an important role in metastasis development, tumor recurrence, and treatment resistance, and are essential for the eradication of cancer. Currently, therapies fail to eradicate CSCs due to their therapeutic stress-induced cellular escape, which leads to enhanced aggressive behaviors compared with CSCs that have never been treated. However, the underlying mechanisms regulating the therapeutic escape remain unknown. To this end, we established a model to isolate the therapeutic escaped CSCs (TSCSCs) from breast CSCs and performed the transcription profile to reveal the mechanism. Mechanistically, we demonstrated that the behavior of therapeutic escape was regulated through the p38/MAPK signaling pathway, resulting in TSCSCs exhibiting enhanced motility and metastasis. Notably, blocking the p38/MAPK signaling pathway effectively reduced motility and metastasis ability both in vitro and in vivo, which were further supported by downregulated motility-related genes and epithelial-mesenchymal transition (EMT)-related proteins vimentin and N-cadherin. The obtained findings reveal the p38/MAPK pathway as a potential therapeutic target for TSCSCs and would provide profound implications for cancer therapy.

MXene/Carbon Dots Nanozyme Composites for Glutathione Detection and Tumor Therapy.

Co-N-CDs-based MXene nanocomposites (MXene@PDA/Co-N-CDs) were constructed by decorating Co-N-CDs on polydopamine-functionalized MXene nanosheets. Both Co-N-CDs and MXene nanosheets have peroxidase-like activity; when the two materials are combined to form MXene@PDA/Co-N-CDs nanocomposites, the peroxide-like activity can be further enhanced. MXene@PDA/Co-N-CDs could oxidize the substrate 3,3'5,5'-tetramethylbenziline (TMB) to form ox-TMB, as confirmed by detecting the absorption of the blue products. A highly selective colorimetric biosensor was developed for the determination of glutathione (GSH) in the concentration range of 0.3 to 20 µM with a lower detection limit (LOD) of 0.12 µM, which realized the accurate detection of GSH in human serum and urine samples. Moreover, in the tumor microenvironment, MXene@PDA/Co-N-CDs could catalyze hydrogen peroxide to produce hydroxyl free radicals and produce a photothermal effect under the exposure of NIR-I irradiation. The catalytic activity of MXene@PDA/Co-N-CD nanocomposites was fully achieved for the death of cancer cells through photothermal/photodynamic synergistic therapy. The MXene@PDA/Co-N-CDs nanozyme offers multiple applications in GSH detection and tumor therapy.

Single-cell atlas of peripheral blood by CyTOF revealed peripheral blood immune cells metabolic alterations and neutrophil changes in intracranial aneurysm rupture.

Previous studies have found that the peripheral immune environment is closely related to the occurrence and development of intracranial aneurysms. However, it remains unclear how the metabolism of peripheral blood mononuclear cells (PBMCs) and the composition of polymorphonuclear leukocytes (PMNs) changes in the process of intracranial aneurysm rupture. This study utilized cytometry by time of flight technology to conduct single-cell profiling analysis of PBMCs and PMNs from 72 patients with IAs. By comparing the expression differences of key metabolic enzymes in PBMCs between patients with ruptured intracranial aneurysms (RIAs) and unruptured intracranial aneurysms, we found that most PBMCs subsets from RIA group showed upregulation of rate-limiting enzymes related to the glycolytic pathway. By comparing the composition of PMNs, it was found that the proinflammatory CD101+HLA DR+ subsets were increased in the RIA group, accompanied by a decrease in the anti-inflammatory polymorphonuclear myeloid-derived suppressor cells. In conclusion, this study showed the changes in the peripheral immune profile of RIAs, which is helpful for our understanding of the mechanisms underlying peripheral changes and provides a direction for future related research.

Retinoic acid generates a beneficial microenvironment for liver progenitor cell activation in acute liver failure.

BACKGROUND: When massive necrosis occurs in acute liver failure (ALF), rapid expansion of HSCs called liver progenitor cells (LPCs) in a process called ductular reaction is required for survival. The underlying mechanisms governing this process are not entirely known to date. In ALF, high levels of retinoic acid (RA), a molecule known for its pleiotropic roles in embryonic development, are secreted by activated HSCs. We hypothesized that RA plays a key role in ductular reaction during ALF. METHODS: RNAseq was performed to identify molecular signaling pathways affected by all-trans retinoid acid (atRA) treatment in HepaRG LPCs. Functional assays were performed in HepaRG cells treated with atRA or cocultured with LX-2 cells and in the liver tissue of patients suffering from ALF. RESULTS: Under ALF conditions, activated HSCs secreted RA, inducing RARα nuclear translocation in LPCs. RNAseq data and investigations in HepaRG cells revealed that atRA treatment activated the WNT-ß-Catenin pathway, enhanced stemness genes (SOX9, AFP, and others), increased energy storage, and elevated the expression of ATP-binding cassette transporters in a RARα nuclear translocation-dependent manner. Further, atRA treatment-induced pathways were confirmed in a coculture system of HepaRG with LX-2 cells. Patients suffering from ALF who displayed RARα nuclear translocation in the LPCs had significantly better MELD scores than those without. CONCLUSIONS: During ALF, RA secreted by activated HSCs promotes LPC activation, a prerequisite for subsequent LPC-mediated liver regeneration.

Caffeic acid inhibits the tumorigenicity of triple-negative breast cancer cells through the FOXO1/FIS pathway.

Triple-negative breast cancer (TNBC) still one of the most challenging sub-type in breast cancer clinical. Caffeic acid (CA) derived from effective components of traditional Chinese herbal medicine has been show potential against TNBCs. Our research has found that CA can inhibit the proliferation of TNBC cells while also suppressing the size of cancer stem cell spheres. Additionally, it reduces reactive oxygen species (ROS) levels and disruption of mitochondrial membrane potential. Simultaneously, CA influences the stemness of TNBC cells by reducing the expression of the stem cell marker protein CD44. Furthermore, we have observed that CA can modulate the FOXO1/FIS signaling pathway, disrupting mitochondrial function, inducing mitochondrial autophagy, and exerting anti-tumor activity. Additionally, changes in the immune microenvironment were detected using a mass cytometer, we found that CA can induce M1 polarization of macrophages, enhancing anti-tumor immune responses to exert anti-tumor activity. In summary, CA can be considered as a lead compound for further research in targeting TNBC.

P7C3 suppresses astrocytic senescence to protect dopaminergic neurons: Implication in the mouse model of Parkinson's disease.

AIMS: Astrocytic senescence is inextricably linked to aging and neurodegenerative disorders, including Parkinson's disease (PD). P7C3 is a small, neuroprotective aminopropyl carbazole compound that exhibits anti-inflammatory properties. However, the effects of P7C3 on astrocytic senescence in PD remain to be elucidated. METHODS: An in vitro, long culture-induced, replicative senescence cell model and a 1-methyl-4-phenylpyridinium (MPP+)/rotenone-induced premature senescence cell model were used to investigate the effects of P7C3 on astrocytic senescence. An in vivo, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse PD model was used to study the role of P7C3 in astrocytic senescence. Immunoblotting, real-time quantitative RT-PCR (qPCR), immunofluorescence, subcellular fractionation assays, and immunohistochemistry were utilized to confirm the effects of P7C3 on astrocytic senescence and elucidate its underlying mechanisms. RESULTS: This study determined that P7C3 suppressed the senescence-associated secretory phenotype (SASP) in both cell models, as demonstrated by the reduction in the critical senescence marker p16 and proinflammatory factors (IL-6, IL-1ß, CXCL10, and MMP9) and increased laminB1 levels, implying that P7C3 inhibited replicative astrocytic senescence and MPP+/rotenone-induced premature astrocytic senescence, Most importantly, we demonstrated that P7C3 prevented the death of dopamine (DA) neurons and reduced the behavioral deficits in the MPTP-induced mouse model of PD, which is accompanied by a decrease in senescent astrocytes in the substantia nigra compacta (SNc). Mechanistically, P7C3 promoted Nrf2/Sirt3-mediated mitophagy and reduced mitochondrial reactive oxygen species (mitoROS) generation, which contributed to the suppression of astrocytic senescence. Furthermore, Sirt3 deficiency obviously abolished the inhibitory effects of P7C3 on astrocytic senescence. CONCLUSION: This study revealed that P7C3 inhibited astrocytic senescence via increased Nrf2/Sirt3-mediated mitophagy and suppression of mitoROS, which further protected against DA neuronal loss. These observations provide a prospective theoretical basis for P7C3 in the treatment of age-associated neurodegenerative diseases, such as PD.

Gender Inequality is negatively associated with academic achievement for both boys and girls.

To examine the role of inequality in academic achievement, we analyse a cross-national dataset including data from three cycles from 2012 to 2018 from the PISA, an international assessment of 15-year-old students' math, reading, and science performance. The Gini coefficient and gender inequality index (GII) were used as metrics for a country's economic inequality and gender inequality, respectively. The results show that gender inequality has a negative association with academic achievement for both boys and girls. Moreover, gender inequality has a stronger association with academic achievement than does economic inequality. We also find that gender inequality in reproductive health may contribute substantially to the association between gender inequality and academic achievement. Despite substantial advances in gender equality worldwide, multisectoral and multilevel approaches from the community to the country level are needed to ensure substantial long-term reductions in economic, gender, and educational inequalities.

Isoporous Membranes by the Symmetric Triblock Copolymer: A Strategy to Improve the Mechanical Strength without Sharply Changing the Pore Size and Permselectivity.

Isoporous membranes produced from diblock copolymers commonly display a poor mechanical property that shows many negative impacts on their separation application. It is theoretically predicted that dense films produced from symmetric triblock copolymers show much stronger mechanical properties than those of homologous diblock copolymers. However, to the best of our knowledge, symmetric triblock copolymers have rarely been fabricated into isoporous membranes before, and a full understanding of separation as well as mechanical properties of membranes prepared from triblock copolymers and homologous diblock copolymers has not been conducted, either. In this work, a cleavable symmetric triblock copolymer with polystyrene as the side block and poly(4-vinylpyridine) (P4VP) as the middle block was synthesized and designed by the RAFT polymerization using the symmetric chain transfer agent, which located at the center of polymer chains and could be removed to produce homologous diblock copolymers with half-length while having the same composition as that found in triblock copolymers. The self-assembly of these two copolymers in thin films and casting solutions was first investigated, observing that they displayed similar self-organized structures under these two conditions. When fabricated into isoporous membranes, they showed similar pore sizes (5-7% difference) and comparable rejection performance (∼10% difference). However, isoporous membranes produced from triblock copolymers showed significantly improved mechanical strength and higher toughness (2-10 times larger) as evidenced by the compacting resistance, strain-stress determination, and nanoindentation testing, suggesting the unique and novel structure-performance relationship in the isoporous membranes produced from symmetric triblock copolymers. The above finding will guide the way to fabricate mechanically robust isoporous membranes without notably changing the separation performance from rarely used symmetric triblock copolymers, which can be synthesized by the controlled polymerization as facilely as that found for diblock copolymers.

Post-implantation analysis of genomic variations in the progeny from developing fetus to birth.

The analysis of genomic variations in offspring after implantation has been infrequently studied. In this study, we aim to investigate the extent of de novo mutations in humans from developing fetus to birth. Using high-depth whole-genome sequencing, 443 parent-offspring trios were studied to compare the results of de novo mutations (DNMs) between different groups. The focus was on fetuses and newborns, with DNA samples obtained from the families' blood and the aspirated embryonic tissues subjected to deep sequencing. It was observed that the average number of total DNMs in the newborns group was 56.26 (54.17-58.35), which appeared to be lower than that the multifetal reduction group, which was 76.05 (69.70-82.40) (F = 2.42, P = 0.12). However, after adjusting for parental age and maternal pre-pregnancy body mass index (BMI), significant differences were found between the two groups. The analysis was further divided into single nucleotide variants (SNVs) and insertion/deletion of a small number of bases (indels), and it was discovered that the average number of de novo SNVs associated with the multifetal reduction group and the newborn group was 49.89 (45.59-54.20) and 51.09 (49.22-52.96), respectively. No significant differences were noted between the groups (F = 1.01, P = 0.32). However, a significant difference was observed for de novo indels, with a higher average number found in the multifetal reduction group compared to the newborn group (F = 194.17, P < 0.001). The average number of de novo indels among the multifetal reduction group and the newborn group was 26.26 (23.27-29.05) and 5.17 (4.82-5.52), respectively. To conclude, it has been observed that the quantity of de novo indels in the newborns experiences a significant decrease when compared to that in the aspirated embryonic tissues (7-9 weeks). This phenomenon is evident across all genomic regions, highlighting the adverse effects of de novo indels on the fetus and emphasizing the significance of embryonic implantation and intrauterine growth in human genetic selection mechanisms.

Mitochondrial dysfunction-associated alveolar epithelial senescence is involved in CdCl2-induced COPD-like lung injury.

An earlier study found that respiratory cadmium chloride (CdCl2) exposure caused COPD-like lung injury. This study aimed to explore whether mitochondrial dysfunction-mediated alveolar epithelial senescence is involved in CdCl2-induced COPD-like lung injury. Adult C57BL/6 mice were exposed to CdCl2 (10 mg/L) aerosol for six months. Beta-galactosidase-positive cells, p21 and p16 were increased in CdCl2-exposed mouse lungs. The in vitro experiments showed that γ-H2AX was elevated in CdCl2-exposed alveolar epithelial cells. The cGAS-STING pathway was activated in CdCl2-exposed alveolar epithelial cells and mouse lungs. Cxcl1, Cxcl9, Il-10, Il-1ß and Mmp2, several senescence-associated secretory phenotypes (SASP), were upregulated in CdCl2-exposed alveolar epithelial cells. Mechanistically, CdCl2 exposure caused SIRT3 reduction and mitochondrial dysfunction in mouse lungs and alveolar epithelial cells. The in vitro experiment found that Sirt3 overexpression attenuated CdCl2-induced alveolar epithelial senescence and SASP. The in vivo experiments showed that Sirt3 gene knockout exacerbated CdCl2-induced alveolar epithelial senescence, alveolar structure damage, airway inflammation and pulmonary function decline. NMN, an NAD+ precursor, attenuated CdCl2-induced alveolar epithelial senescence and SASP in mouse lungs. Moreover, NMN supplementation prevented CdCl2-induced COPD-like alveolar structure damage, epithelial-mesenchymal transition and pulmonary function decline. These results suggest that mitochondrial dysfunction-associated alveolar epithelial senescence is involved in CdCl2-induced COPD-like lung injury.