Gene Co-Expression and miRNA Regulation: A Path to Early Intervention in Colorectal Cancer.

Early diagnosis and intervention are pivotal in reducing colorectal cancer (CRC) incidence and enhancing patient outcomes. In this study, we focused on three genes, AQP8, GUCA2B, and SPIB, which exhibit high co-expression and play crucial roles in suppressing early-stage CRC. Our objective was to identify key miRNAs that can mitigate CRC tumorigenesis and modulate the co-expression network involving these genes. We conducted a comprehensive analysis using large-scale tissue mRNA data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus to validate the co-expression of AQP8, GUCA2B, and SPIB, and to assess their diagnostic and prognostic significance in CRC. mRNA-miRNA interactions were examined using MiRNet and the Encyclopedia of RNA Interactomes. Furthermore, using various molecular techniques, we conducted miRNA inhibitor transfection experiments in HCT116 cells to evaluate their effects on cell growth, migration, and gene/protein expression. Our findings revealed that, compared to normal tissues, AQP8, GUCA2B, and SPIB exhibited high co-expression and were downregulated in CRC, particularly during tumorigenesis. OncoMirs, hsa-miR-182-5p, and hsa-miR-27a-3p, were predicted to regulate these genes. MiRNA inhibition experiments in HCT116 cells demonstrated the inhibitory effects of miR-27a-3p and miR-182-5p on GUCA2B mRNA and protein expression. These miRNAs promoted the proliferation of CRC cells, possibly through their involvement in the GUCA2B-GUCY2C axis, which is known to promote tumor growth. While the expressions of AQP8 and SPIB were barely detectable, their regulatory relationship with hsa-miR-182-5p remained inconclusive. Our study confirms that hsa-miR-27a-3p and hsa-miR-182-5p are oncomiRs in CRC. These miRNAs may contribute to GUCY2C dysregulation by downregulating GUCA2B, which encodes uroguanylin. Consequently, hsa-miR-182-5p and hsa-miR-27a-3p show promise as potential targets for early intervention and treatment in the early stages of CRC.

Transformer with difference convolutional network for lightweight universal boundary detection.

Although deep-learning methods can achieve human-level performance in boundary detection, their improvements mostly rely on larger models and specific datasets, leading to significant computational power consumption. As a fundamental low-level vision task, a single model with fewer parameters to achieve cross-dataset boundary detection merits further investigation. In this study, a lightweight universal boundary detection method was developed based on convolution and a transformer. The network is called a "transformer with difference convolutional network" (TDCN), which implies the introduction of a difference convolutional network rather than a pure transformer. The TDCN structure consists of three parts: convolution, transformer, and head function. First, a convolution network fused with edge operators is used to extract multiscale difference features. These pixel difference features are then fed to the hierarchical transformer as tokens. Considering the intrinsic characteristics of the boundary detection task, a new boundary-aware self-attention structure was designed in the transformer to provide inductive bias. By incorporating the proposed attention loss function, it introduces the direction of the boundary as strongly supervised information to improve the detection ability of the model. Finally, several head functions with multiscale feature inputs were trained using a bidirectional additive strategy. In the experiments, the proposed method achieved competitive performance on multiple public datasets with fewer model parameters. A single model was obtained to realize universal prediction even for different datasets without retraining, demonstrating the effectiveness of the method. The code is available at https://github.com/neulmc/TDCN.

A cucurbit[8]uril based supramolecular assembly and its potential applications for the removal of dye and antibiotic from an aqueous medium.

CB[8]-based supramolecular assembly, i.e., 2CB[8]·[ZnCl4]·4H2O (1) (CB[8] = cucurbit[8]uril), was synthesized under solvothermal condition in the presence of [ZnCl4]2- anions as a structure inducer. 1 was applied as a high-efficiency absorbent to remove the commonly used dye amaranth (AMR) and an antibacterial drug of broad-spectrum sulfadiazine sodium (SFZ) from the aqueous solution. It showed an excellent removal rate and could remove 96.08% and 96.21% for AMR and SMZ, respectively. The adsorption behaviors were investigated using FT-IR. The differences in IR spectra revealed that the formation of inclusion complexes is the main driving force of adsorption. The phenyl and sulfonyl or sulfone moieties of AMR and SFZ entered the cavity of CB[8] in 1, and the adsorption mechanism could be due to the formation of inclusion complexes of AMR and SFZ in the CB[8] cavities of 1. This work illustrates the application prospects of CB[8]-based supramolecular assembly in environmental protection.

Preparation of biguanidine quaternary ammonium salts grafted chitosan with enhanced antibacterial and antibiofilm activities.

N-(4-N'-pyridine-benzylcarbonyl chloride) chitosan (CBPyC), N-p-biguanidine benzoyl chitosan (CSBG), and N-(p-biguanidine -1-pyridine-4-benzylcarbonyl chloride) chitosan (CSQPG) were synthesized. The structures of prepared chitosan derivatives were characterized using nuclear magnetic resonance spectroscopy (NMR) and ultraviolet-visible (UV-vis) spectroscopy, and the degree of substitution was determined through elemental analysis (EA) and evaluated on the basis of the integral values in 1H NMR. The antibacterial activities of chitosan derivatives against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) were investigated in vitro using antibacterial rate, minimal inhibitory concentration and minimum bacterial concentration assays. The antibiofilm activity was also assessed using the crystal violet assay. CSQPC exhibited higher antibacterial and antibiofilm activities against E. coli and S. aureus compared to CBPyC and CSBG. The antibacterial rate of CSQPG against E. coli and S. aureus at a concentration of 0.5 mg/mL was 43.3% and 100%, respectively. The biofilm inhibition rate of CSQPG at 0.5 MIC against E. coli and S. aureus was 56.5% and 69.1%, respectively. At a concentration of 2.5 mg/mL, the biofilm removal rates of E. coli and S. aureus were 72.9% and 90.1%, respectively. The antibacterial and antibiofilm activities of CSQPG were better than CSBG and CBPyC, and the combination of guanidine and quaternary ammonium further improved the positive charge density of chitosan and enhanced its antibacterial activity.

Regional population and social welfare from the perspective of sustainability: Evaluation indicator, level measurement, and interaction mechanism.

Key to regional sustainable development are the development and interplay of population dynamics and social welfare, each playing a significant role. As a representative region with demographic characteristics such as negative population growth and large labor outflow, the development and interaction between population and social welfare in Nanchong deserve in-depth exploration. This article takes the development of population and social welfare in Nanchong as the research object, and constructs an evaluation indicator system of population and social welfare through research backtracking, and uses entropy method and coupling coordination model to measure the development level and interactive effect of population and social welfare in Nanchong from 2010 to 2021. The research results show that: Firstly, the comprehensive evaluation results of population in Nanchong shows a linear upward trend, which indicates the stable positive effect of population structure and distribution, the gradual improvement effect of population quality effectively compensate for the weakening effect of population quantity, thus achieving the positive development of population. Secondly, the comprehensive evaluation results of social welfare in Nanchong shows an exponential upward trend, which indicates the social welfare has maintained a rapid growth momentum in various dimensions and the long-term positive effects have completely absorbed the negative effects, thus achieving the positive development of social welfare. Thirdly, during the sample period, the population and social welfare in Nanchong consistently maintained a high level of interaction strength, with factors diffusing and integrating. On this basis, the diffusion theory is used as an empirical reference to construct three interactive mechanisms between the population and social welfare in Nanchong and the implications are inferred from the empirical results.

The Endoplasmic Reticulum-Plasma Membrane Tethering Protein Ice2 Controls Lipid Droplet Size via the Regulation of Phosphatidylcholine in Candida albicans.

Lipid droplets (LDs) are intracellular organelles that play important roles in cellular lipid metabolism; they change their sizes and numbers in response to both intracellular and extracellular signals. Changes in LD size reflect lipid synthesis and degradation and affect many cellular activities, including energy supply and membrane synthesis. Here, we focused on the function of the endoplasmic reticulum-plasma membrane tethering protein Ice2 in LD dynamics in the fungal pathogen Candida albicans (C. albicans). Nile red staining and size quantification showed that the LD size increased in the ice2Δ/Δ mutant, indicating the critical role of Ice2 in the regulation of LD dynamics. A lipid content analysis further demonstrated that the mutant had lower phosphatidylcholine levels. As revealed with GFP labeling and fluorescence microscopy, the methyltransferase Cho2, which is involved in phosphatidylcholine synthesis, had poorer localization in the plasma membrane in the mutant than in the wild-type strain. Interestingly, the addition of the phosphatidylcholine precursor choline led to the recovery of normal-sized LDs in the mutant. These results indicated that Ice2 regulates LD size by controlling intracellular phosphatidylcholine levels and that endoplasmic reticulum-plasma membrane tethering proteins play a role in lipid metabolism regulation in C. albicans. This study provides significant findings for further investigation of the lipid metabolism in fungi.

Reduction of histone proteins dosages increases CFW sensitivity and attenuates virulence of Candida albicans.

Histone proteins are important components of nucleosomes, which play an important role in regulating the accessibility of DNA and the function of genomes. However, the effect of histone proteins dosages on physiological processes is not clear in the human fungal pathogen Candida albicans. In this study, we found that the deletion of the histone protein H3 coding gene HHT21 and the histone protein H4 coding gene HHF1 resulted in a significant decrease in the expression dosage of the histone proteins H3 and H4, which had a significant impact on the localization of the histone protein H2A and plasmid maintenance. Stress sensitivity experiments showed that the mutants hht21Δ/Δ, hhf1Δ/Δ and hht21Δ/Δhhf1Δ/Δ were more sensitive to cell wall stress induced by Calcofluor White (CFW) than the wild-type strain. Further studies showed that the decrease in the dosage of the histone proteins H3 and H4 led to the change of cell wall components, increased chitin contents, and down-regulated expression of the SAP9, KAR2, and CRH11 genes involved in the cell wall integrity (CWI) pathway. Overexpression of SAP9 could rescue the sensitivity of the mutants to CFW. Moreover, the decrease in the histone protein s dosages affected the FAD-catalyzed oxidation of Ero1 protein, resulting in the obstruction of protein folding in the ER, and thus reduced resistance to CFW. It was also found that CFW induced a large amount of ROS accumulation in the mutants, and the addition of ROS scavengers could restore the growth of the mutants under CFW treatment. In addition, the reduction of the histone proteins dosages greatly weakened systemic infection and kidney fungal burden in mice, and hyphal development was significantly impaired in the mutants under macrophage treatment, indicating that the histone proteins dosages is very important for the virulence of C. albicans. This study revealed that histone proteins dosages play a key role in the cell wall stress response and pathogenicity in C. albicans.

Mec1-Rad53 Signaling Regulates DNA Damage-Induced Autophagy and Pathogenicity in Candida albicans.

DNA damage activates the DNA damage response and autophagy in C. albicans; however, the relationship between the DNA damage response and DNA damage-induced autophagy in C. albicans remains unclear. Mec1-Rad53 signaling is a critical pathway in the DNA damage response, but its role in DNA damage-induced autophagy and pathogenicity in C. albicans remains to be further explored. In this study, we compared the function of autophagy-related (Atg) proteins in DNA damage-induced autophagy and traditional macroautophagy and explored the role of Mec1-Rad53 signaling in regulating DNA damage-induced autophagy and pathogenicity. We found that core Atg proteins are required for these two types of autophagy, while the function of Atg17 is slightly different. Our results showed that Mec1-Rad53 signaling specifically regulates DNA damage-induced autophagy but has no effect on macroautophagy. The recruitment of Atg1 and Atg13 to phagophore assembly sites (PAS) was significantly inhibited in the mec1Δ/Δ and rad53Δ/Δ strains. The formation of autophagic bodies was obviously affected in the mec1Δ/Δ and rad53Δ/Δ strains. We found that DNA damage does not induce mitophagy and ER autophagy. We also identified two regulators of DNA damage-induced autophagy, Psp2 and Dcp2, which regulate DNA damage-induced autophagy by affecting the protein levels of Atg1, Atg13, Mec1, and Rad53. The deletion of Mec1 or Rad53 significantly reduces the ability of C. albicans to systematically infect mice and colonize the kidneys, and it makes C. albicans more susceptible to being killed by macrophages.

Construction of Candida albicans Adhesin-Exposed Synthetic Cells for Preventing Systemic Fungal Infection.

The development of efficient fungal vaccines is urgent for preventing life-threatening systemic fungal infections. In this study, we prepared a synthetic, cell-based fungal vaccine for preventing systemic fungal infections using synthetic biology techniques. The synthetic cell EmEAP1 was constructed by transforming the Escherichia coli chassis using a de novo synthetic fragment encoding the protein mChEap1 that was composed of the E. coli OmpA peptide, the fluorescence protein mCherry, the Candida albicans adhesin Eap1, and the C-terminally transmembrane region. The EmEAP1 cells highly exposed the mChEap1 on the cell surface under IPTG induction. The fungal vaccine was then prepared by mixing the EmEAP1 cells with aluminum hydroxide gel and CpG. Fluorescence quantification revealed that the fungal vaccine was stable even after 112 days of storage. After immunization in mice, the vaccine resided in the lymph nodes, inducing the recruitment of CD11c+ dendritic cells. Moreover, the vaccine strongly activated the CD4+ T splenocytes and elicited high levels of anti-Eap1 IgG. By the prime-boost immunization, the vaccine prolonged the survival time of the mice infected by the C. albicans cells and attenuated fungal colonization together with inflammation in the kidneys. This study sheds light on the development of synthetic biology-based fungal vaccines for the prevention of life-threatening fungal infections.

Gallium-based metal-organic frameworks loaded with antimicrobial peptides for synergistic killing of drug-resistant bacteria.

Increased antibiotic resistance has made bacterial infections a global concern, which requires novel non-antibiotic-dependent antibacterial strategies to address the menace. Antimicrobial peptides (AMPs) are a promising antibiotic alternative, whose antibacterial mechanism is mainly to destroy the membrane of bacteria. Gallium ions exhibit an antibacterial effect by interfering with the iron metabolism of bacteria. With the rapid development of nanotechnology, it is worth studying the potential of gallium-AMP-based nanocomposites for treating bacterial infections. Herein, novel gallium-based metal-organic frameworks (MOFs) were synthesized at room temperature, followed by in situ loading of the model AMP melittin. The obtained nanocomposites exhibited stronger antibacterial activity than pure MEL and gallium ions, achieving the effects of "one plus one is greater than two". Moreover, the nanocomposites showed favorable biocompatibility and accelerated healing of a wound infected by methicillin-resistant Staphylococcus aureus by down-regulation of inflammatory cytokines IL-6 and TNF-α. This work presents an innovative antibacterial strategy to overcome the antibiotic resistance crisis and expand the application of AMPs.

Treatment options for stage III-N2 pulmonary lymphoepithelioma-like carcinoma: A retrospective cohort study.

BACKGROUND AND PURPOSE: Pulmonary lymphoepithelioma-like carcinoma (PLELC) is a rare form of non-small cell lung carcinoma (NSCLC) that shares similarities with nasopharyngeal carcinoma. The optimal treatment for stage III-N2 PLELC remains controversial. METHODS AND MATERIALS: We conducted a retrospective analysis from stage III-N2 PLELC patients between 2009 and 2022 in our center. The patients were categorized into three groups: Group 1 (G1, definitive chemoradiotherapy), Group 2 (G2, radical surgery plus adjuvant chemoradiotherapy), and Group 3 (G3, radical surgery plus adjuvant chemotherapy). RESULTS: A total of 103 patients were included in the study, with 34, 25, and 44 patients in G1, G2, and G3, respectively. The median follow-up time was 47.4 months. The overall median PFS was 66.6 months, with 3-year PFS and 3-year OS rates of 66.0% and 92.4%, respectively, for all patients. Multivariate analysis revealed no significant difference in PFS between G1 and G2 (p = 0.354), while both groups exhibited significantly longer PFS than G3 (p < 0.001; p = 0.039). Similarly, no significant difference in OS was observed between G1 and G2 (p = 0.649), but both tended to demonstrate improved OS compared to G3 (p = 0.081; p = 0.092). Only one case of grade 3 radiation esophagitis was observed in G1, and no grade 3 or higher radiation pneumonitis were reported. CONCLUSIONS: Patients with stage III-N2 PLELC have a favorable prognosis, with radiotherapy playing a crucial role in treatment. Both definitive chemoradiotherapy and radical surgery followed by chemoradiotherapy demonstrate favorable efficacy and manageable toxicity.

Analysis of the Potassium-Solubilizing Priestia megaterium Strain NK851 and Its Potassium Feldspar-Binding Proteins.

Potassium-solubilizing bacteria are an important microbial group that play a critical role in releasing mineral potassium from potassium-containing minerals, e.g., potassium feldspar. Their application may reduce eutrophication caused by overused potassium fertilizers and facilitate plants to utilize environmental potassium. In this study, a high-efficiency potassium-solubilizing bacterium, named NK851, was isolated from the Astragalus sinicus rhizosphere soil. This bacterium can grow in the medium with potassium feldspar as the sole potassium source, releasing 157 mg/L and 222 mg/L potassium after 3 days and 5 days of incubation, respectively. 16S rDNA sequencing and cluster analysis showed that this strain belongs to Priestia megaterium. Genome sequencing further revealed that this strain has a genome length of 5,305,142 bp, encoding 5473 genes. Among them, abundant genes are related to potassium decomposition and utilization, e.g., the genes involved in adherence to mineral potassium, potassium release, and intracellular trafficking. Moreover, the strong potassium-releasing capacity of NK851 is not attributed to the acidic pH but is attributed to the extracellular potassium feldspar-binding proteins, such as the elongation factor TU and the enolase that contains potassium feldspar-binding cavities. This study provides new information for exploration of the bacterium-mediated potassium solubilization mechanisms.

Effect of the structure of chitosan quaternary phosphonium salt and chitosan quaternary ammonium salt on the antibacterial and antibiofilm activity.

N-(4-N', N', N'-trimethylphosphonium chloride) benzoyl chitosan (TMPCS), N-(4-N', N', N'-triphenylphosphonium chloride) benzoyl chitosan (TPPCS), and N-(4-N', N', N'-trimethylmethanaminium chloride) benzoyl chitosan (TMACS) were synthesized. The structures of the products were characterized by Fourier transform infrared spectroscopy, Nuclear magnetic resonance spectroscopy and ultraviolet-visible spectroscopy. Their antibacterial activities against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) were investigated in vitro using the antibacterial rate, minimal inhibitory concentration (MIC) and minimum bactericidal concentration (MBC), the antibiofilm activity was investigated by crystal violet assay. The antibacterial assessment revealed that the chitosan quaternary phosphonium salts of similar structure had superior antibacterial activity than chitosan quaternary ammonium salt. The antibacterial rate of CS, TMPCS, TPPCS and TMACS against E. coli at 0.5 mg/mL was 10.4 %, 42.0 %, 58.5 % and 21.6 % respectively. At the same concentration, the antibacterial rate of TMPCS, TPPCS and TMACS against S.aureus was all up to 100 %. The biofilm inhibition rate of CS, TMPCS, TPPCS and TMACS at a half of MIC against E.coli was 28.4 %, 33.9 %, 56.6 % and 57.6 % respectively, and against S.aureus was 30.8 %, 53.8 %, 62.2 % and 58.5 % respectively. The biofilm removal rate of CS, TMPCS, TPPCS, TMACS against E.coli at 2.5 mg/mL was 20.6 %, 46.4 %, 48.9 % and 41.6 % respectively, and against S.aureus at 2.5 mg/mL was 41.5 %, 60.4 %, 69.9 % and 59.01 % respectively.

Oncogenic zinc finger protein ZNF687 accelerates lung adenocarcinoma cell proliferation and tumor progression by activating the PI3K/AKT signaling pathway.

BACKGROUND: Zinc finger protein 687 (ZNF687) has previously been discovered as a potential oncogene in individuals with giant cell tumors of the bone, acute myeloid leukemia, and hepatocellular carcinoma. However, its role and mechanism in lung adenocarcinoma (LUAD) remain unclear. METHODS: In LUAD cells, tumor, and matched adjacent tissue specimens, quantitative real-time RT- polymerase chain reaction (qRT-PCR), western blotting analyses, and immunohistochemistry staining (IHC) were conducted. Cell counting kit-8 (CCK8) assay, clonogenicity analysis, flow cytometry, and transwell assays were utilized to detect ZNF687 overexpression and knockdown impacts on cell growth, colony formation, cell cycle, migration, and invasion. Bioinformatic studies, qRT-PCR and western blotting studies were employed to validate the underlying mechanisms and signaling pathways implicated in the oncogenic effect of ZNF687. RESULTS: This study demonstrated that ZNF687 expression was elevated in LUAD cells and tissues. Individuals with upregulated ZNF687 had a poorer prognosis than those with downregulatedZNF687 (p < 0.001). ZNF687 overexpression enhanced LUAD growth, migration, invasion and colony formation, and the cell cycle G1-S transition; additionally, it promoted the epithelial-mesenchymal transition (EMT). In contrast, knocking down ZNF687 showed to have the opposite impact. Moreover, these effects were associated with the activity of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling mechanism. CONCLUSION: ZNF687 was upregulated in LUAD, and high ZNF687 expression levels are associated with poor prognoses. The activation of the PI3K/AKT signaling pathway by upregulated ZNF687 increased the proliferation of LUAD cells and tumor progression. ZNF687 may be a beneficial predictive marker and a therapeutic target in LUAD.

Identification of key surfactant in municipal solid waste leachate foaming and its influence mechanism.

Serious foaming problems and the excessive consumption of defoamer have undoubtedly become one of the most critical problems that hinder municipal solid waste (MSW) leachate treatment efficiency and industry development. Since there is limited research penetrating the foaming mechanism and identification of the key surfactants, current defoaming and surfactant removal techniques lack pertinence and orientation. In this study, a foaming characterization device was developed and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC/MS/MS) was optimized to accurately identify the key surfactants affecting leachate foaming and offer a glimpse into their interaction mechanisms. This study collected leachate samples from 9 typical landfills and waste-to-energy facilities of various waste compositions, climatic conditions, ages, and geographical locations. The foaming problem of leachate was mainly centered on raw leachate and nanofiltration membrane concentrate (NFC). Fresh leachate performed with relatively low foaming capacity and foam stability, associated with low surfactant concentration. The pH value of the system was positively correlated with the concentration of anionic surfactants, indicating significant impacts on surfactant release in MSW. Since the distribution characteristics of linear alkylbenzene sulfonate (LAS) in leachate were consistent with the variety of foaming performances, LAS proved to be an indispensable surfactant in the leachate involved in this study, and its content proportion escalated to 92.87% in aged leachate.

A Survey of Optimization Methods for Independent Vector Analysis in Audio Source Separation.

With the advent of the era of big data information, artificial intelligence (AI) methods have become extremely promising and attractive. It has become extremely important to extract useful signals by decomposing various mixed signals through blind source separation (BSS). BSS has been proven to have prominent applications in multichannel audio processing. For multichannel speech signals, independent component analysis (ICA) requires a certain statistical independence of source signals and other conditions to allow blind separation. independent vector analysis (IVA) is an extension of ICA for the simultaneous separation of multiple parallel mixed signals. IVA solves the problem of arrangement ambiguity caused by independent component analysis by exploiting the dependencies between source signal components and plays a crucial role in dealing with the problem of convolutional blind signal separation. So far, many researchers have made great contributions to the improvement of this algorithm by adopting different methods to optimize the update rules of the algorithm, accelerate the convergence speed of the algorithm, enhance the separation performance of the algorithm, and adapt to different application scenarios. This meaningful and attractive research work prompted us to conduct a comprehensive survey of this field. This paper briefly reviews the basic principles of the BSS problem, ICA, and IVA and focuses on the existing IVA-based optimization update rule techniques. Additionally, the experimental results show that the AuxIVA-IPA method has the best performance in the deterministic environment, followed by AuxIVA-IP2, and the OverIVA-IP2 has the best performance in the overdetermined environment. The performance of the IVA-NG method is not very optimistic in all environments.

Atg8 and Ire1 in combination regulate the autophagy-related endoplasmic reticulum stress response in Candida albicans.

The unfolded protein response (UPR) is an important pathway to prevent endoplasmic reticulum (ER) stress in eukaryotic cells. In Saccharomyces cerevisiae, Ire1 is a key regulatory factor required for HAC1 gene splicing for further production of functional Hac1 and activation of UPR gene expression. Autophagy is another mechanism involved in the attenuation of ER stress by ER-phagy, and Atg8 is a core protein in autophagy. Both autophagy and UPR are critical for ER stress response, but whether they act individually or in combination in Candida albicans is unknown. In this study, we explored the interaction between Ire1 and the autophagy protein Atg8 for the ER stress response by constructing the atg8Δ/Δire1Δ/Δ double mutant in the pathogenic fungus C. albicans. Compared to the single mutants atg8Δ/Δ or ire1Δ/Δ, atg8Δ/Δire1Δ/Δ exhibited much higher sensitivity to various ER stress-inducing agents and more severe attenuation of UPR gene expression under ER stress. Further investigations showed that the double mutant had a defect in ER-phagy, which was associated with attenuated vacuolar fusion under ER stress. This study revealed that Ire1 and Atg8 in combination function in the activation of the UPR and ER-phagy to maintain ER homeostasis under ER stress in C. albicans.

Transcriptional regulation of autophagy, cell wall stress response and pathogenicity by Pho23 in C. albicans.

The modification of chromatin by histone deacetylases (HDACs) has critical roles in transcriptional regulation. In this study, we identified the Rpd3 HDAC complex component Pho23 in Candida albicans and explored its role in the transcriptional regulation of physiological processes. PHO23 deletion increased autophagic activity and upregulated the transcription of ATG genes. Moreover, the deletion of PHO23 severely impaired cell wall stress resistance and reduced the cell wall integrity (CWI) pathway in response to cell wall stress. Furthermore, the pho23Δ/Δ mutant had partial defects in hyphal development and protease secretion, which were associated with the downregulation of genes involved in hyphal development (e.g. HWP1, ALS3 and ECE1) and genes encoding secreted aspartic proteases (e.g. SAP4, SAP5, SAP6 and SAP9). In addition, the deletion of PHO23 strongly attenuated systemic infection and kidney fungal burden in mice, demonstrating that Pho23 is required for the virulence of C. albicans. Together, our results revealed that Pho23 regulates many key physiological processes in C. albicans at the transcriptional level. These data also shed light on the potential for exploiting Rpd3 HDAC complex-related proteins as antifungal targets.

Semisupervised Boundary Detection for Aluminum Grains Combined With Transfer Learning and Region Growing.

In the manufacturing process of aluminum alloy, the size, distribution, and shape of microscopic grains indicate the mechanical characteristics and product quality. However, for metallographic images that can reveal microstructures, the cost of expert labeling at pixel level is high. To solve the problem, we propose a semisupervised learning strategy for grain boundary detection with a few labeled images and abundant unlabeled samples. To expand the helpful information, transfer learning and rule-based region growing are considered. Specifically, a deep network used for extracting multiscale features is designed. With constant training, through a few labeled metallographic images and abundant transferred natural images, pseudo annotations are generated gradually for unlabeled metallographic images iteratively by feature similarity and boundary region growing. The increased unlabeled samples with their pseudo annotations would be involved in the following training process in semisupervised self-training mode to improve the generalization ability of model, together with the domain adaptation block. In experiments, the proposed two methods named semiricher convolutional features-generative adversarial networks (SemiRCF-GAN) and semiricher convolutional features-maximum mean discrepancy (SemiRCF-MMD) can effectively detect grain boundaries with only one labeled metallographic image, and achieve F1 scores of 0.73 and 0.72, respectively, which surpass typical methods.

Xuebijing injection inhibited neutrophil extracellular traps to reverse lung injury in sepsis mice via reducing Gasdermin D.

The mortality of sepsis and septic shock remains high worldwide. Neutrophil extracellular traps (NETs) release is a major cause of organ failure and mortality in sepsis. Targeting Gasdermin D (GSDMD) can restrain NETs formation, which is promising for sepsis management. However, no medicine is identified without severe safety concerns for this purpose. Xuebijing injection (XBJ) has been demonstrated to alleviate the clinical symptoms of COVID-19 and sepsis patients, but there are not enough animal studies to reveal its mechanisms in depth. Therefore, we wondered whether XBJ relieved pulmonary damage in sepsis by suppressing NETs formation and adopted a clinically relevant polymicrobial infection model to test this hypothesis. Firstly, XBJ effectively reversed lung injury caused by sepsis and restrained neutrophils recruitment to lung by down-regulating proinflammatory chemokines, such as CSF-3, CXCL-2, and CXCR-2. Strikingly, we found that XBJ significantly reduced the expressions of NETs component proteins, including citrullinated histone H3 (CitH3), myeloperoxidase (MPO), and neutrophil elastase (NE). GSDMD contributes to the production of NETs in sepsis. Notably, XBJ exhibited a reduced effect on the expressions of GSDMD and its upstream regulators. Besides, we also revealed that XBJ reversed NETs formation by inhibiting the expressions of GSDMD-related genes. Collectively, we demonstrated XBJ protected against sepsis-induced lung injury by reversing GSDMD-related pathway to inhibit NETs formation.