Identification and validation of mitophagy-related signatures as a novel prognostic model for colorectal cancer.

Background: Colorectal cancer (CRC) is one of the most commonly diagnosed cancers in the world. Mitophagy is associated with tumorigenesis and development of malignancy. However, the specific role of mitophagy has yet not been systematically explored in CRC. Methods: The RNA-sequencing dataset of CRC from The Cancer Genome Atlas (TCGA) and microarray data of gene expression profiles of CRC from Gene Expression Omnibus (GEO) were downloaded. Mitophagy-related gene sets were obtained from the Pathway Unification database. The package "limma" was used for differential gene expression analysis. Kaplan-Meier (KM) survival analyses were utilized to evaluate the prognostic value of the mitophagy regulators. Single-sample gene set enrichment analysis (ssGSEA) was used to estimate the infiltrating immune cells and the activity of immune response. The ConsensusClusterPlus algorithm was used to determine mitophagy-related subtypes. Principal component analysis (PCA) was used to create composite measurement of mitophagy scores. The R packages "survminer" and "ReGlot" were used to plot the nomogram and calibration curves. Results: Integrated analysis of the GEO and TCGA databases revealed some common differentially expressed genes (DEGs) in CRC. MFN2, UBB, PINK1, and PRKN were significantly downregulated in CRC samples as compared to normal samples, and other genes were significantly upregulated in CRC samples. KM survival analyses showed that high expression of ATG12 and MAP1LC3B predicted a poor prognosis, whereas high expression of TOMM22 and TOMM40 predicted a better prognosis. Mitophagy showed significant correlation with immune-related pathways in CRC samples. We identified 2 distinct CRC subtypes with different mitophagy accumulation, of which subtype B had better prognosis and immune activity. The mitophagy score may be employed as a new and efficient clinical predictor in conjunction with other clinical indicators to predict the prognosis of CRC patients. Conclusions: We systematically investigated the CRC heterogeneity with reference to mitophagy based on bioinformatics analyses, and the findings of this study might provide some guidance for future research into potential biomarkers for diagnosis and prognosis prediction of CRC patients.

Formation mechanism of persistent free radicals during pyrolysis of Fenton-conditioned sewage sludge: Influence of NOM and iron.

The present study provided an innovative insight into the formation mechanism of persistent free radicals (PFRs) during the pyrolysis of Fenton-conditioned sludge. Fenton conditioners simultaneously improve the dewatering performance of sewage sludge and catalyze the pyrolysis of sewage sludge for the formation of PFRs. In this process, PFRs with a total number of spins of 9.533×1019 spins/g DS could be generated by pyrolysis of Fenton-conditioned sludge at 400°C. The direct thermal decomposition of natural organic matter (NOM) fractions contributed to the formation of carbon-centered radicals, while the Maillard reaction produced phenols precursors. Additionally, the reaction between aromatic proteins and iron played a crucial role in the formation of phenoxyl or semiquinone-type radicals. Kinetics analysis using discrete distributed activation energy model (DAEM) demonstrated that the average activation energy for pyrolysis was reduced from 178.28 kJ/mol for raw sludge to 164.53 KJ/mol for Fenton conditioned sludge. The reaction factor (fi) indicated that the primary reaction in Fenton-conditioned sludge comprised of 27 parallel first-order reactions, resulting from pyrolysis cleavage of the NOM fractions, the Maillard reaction, and iron catalysis. These findings are significant for understanding the formation process of PFRs from NOM in Fenton-conditioned sludge and provide valuable insight for controlling PFRs formation in practical applications.

Flexible wide-range multidimensional force sensors inspired by bones embedded in muscle.

Flexible sensors have been widely studied for use in motion monitoring, human‒machine interactions (HMIs), personalized medicine, and soft intelligent robots. However, their practical application is limited by their low output performance, narrow measuring range, and unidirectional force detection. Here, to achieve flexibility and high performance simultaneously, we developed a flexible wide-range multidimensional force sensor (FWMFS) similar to bones embedded in muscle structures. The adjustable magnetic field endows the FWMFS with multidimensional perception for detecting forces in different directions. The multilayer stacked coils significantly improved the output from the µV to the mV level while ensuring FWMFS miniaturization. The optimized FWMFS exhibited a high voltage sensitivity of 0.227 mV/N (0.5-8.4 N) and 0.047 mV/N (8.4-60 N) in response to normal forces ranging from 0.5 N to 60 N and could detect lateral forces ranging from 0.2-1.1 N and voltage sensitivities of 1.039 mV/N (0.2-0.5 N) and 0.194 mV/N (0.5-1.1 N). In terms of normal force measurements, the FWMFS can monitor finger pressure and sliding trajectories in response to finger taps, as well as measure plantar pressure for assessing human movement. The plantar pressure signals of five human movements collected by the FWMFS were analyzed using the k-nearest neighbors classification algorithm, which achieved a recognition accuracy of 92%. Additionally, an artificial intelligence biometric authentication system is being developed that classifies and recognizes user passwords. Based on the lateral force measurement ability of the FWMFS, the direction of ball movement can be distinguished, and communication systems such as Morse Code can be expanded. This research has significant potential in intelligent sensing and personalized spatial recognition.

Coupled microscale zero valent iron-autotrophic hydrogen bacteria dechlorination system is not always superior to its standalone counterparts: A sustainable remediation perspective.

The coupling of microscale zero-valent iron with autotrophic hydrogen bacteria (mZVI-AHB) are often believed to show greater potential than the single abiotic or biotic systems in remediating chlorinated aliphatic hydrocarbon-contaminated groundwater. However, our understanding of the remediation performance of this system under real field conditions, especially by incorporating the concept of sustainable remediation, remains limited. In this study, the performances of the mZVI, H2-AHB, and mZVI-AHB systems in dechlorinating groundwater containing complex electron acceptors were compared by evaluating their removal efficiency (RE), reaction products, and electron efficiency (EE), using trichloroethylene (TCE) as the target contaminant and NO3- and SO42- as the coexisting natural electron acceptors. Ultimately, which of these systems had TCE removal superiority was dependent on the coexisting electron acceptor. mZVI-AHB and mZVI resulted in more complete dechlorination, whereas H2-AHB exhibited higher N2 selectivity in reducing NO3-. Regardless of the coexisting electron acceptor, the mZVI-alone system showed the highest EE. Finally, the sustainability concerns and applicability of the three systems were evaluated on the basis of their TCE RE, complete dechlorination ratio, N2 selectivity, EE, and cost, which were integrated into a comparison of overall benefits. Our findings provide comprehensive and insightful information on the factors that determine remediation scheme selection in real practice.

Revealing the roles of chemical communication in restoring the formation and electroactivity of electrogenic biofilm under electrical signaling disruption.

Electrogenic biofilms in microbial electrochemical systems have played significant roles in simultaneous wastewater treatment and energy recovery owing to their unique extracellular electron transfer. Their formation has been shown to be regulated by electrical and chemical communication, but the interaction between these signal communication pathways has not been studied. This research investigated the coordination between intracellular c-di-GMP signaling and reinforced quorum sensing with or without exogenous HSL (a common quorum sensing molecule), on the formation of mixed-cultured electrogenic biofilm under electrical signaling disruption by tetraethylammonium (TEA, a broad-range potassium channel blocker). Intracellular c-di-GMP was spontaneously reinforced in response to TEA stress, and metagenomic analysis revealed that the dominant DGC (the genes for producing c-di-GMP) induced the eventual biofilm formation by mediating exopolysaccharide synthesis. Meanwhile, reinforced quorum sensing by exogenous HSL could also benefit the biofilm restoration, however, it alleviated the TEA-induced communication stress, resulting in the weakening of c-di-GMP dominance. Interestingly, suppressing electrical communication with or without HSL addition both induced selective enrichment of Geobacter of 85.5% or 30.1% respectively. Functional contribution analysis revealed the significant roles of Geobacter and Thauera in c-di-GMP signaling, especially Thauera in resistance to TEA stress. This study proposed a potential strategy for electrogenic biofilm regulation from the perspectives of cell-to-cell communication.

Full-Length Transcriptome and Gene Expression Analysis of Different Ovis aries Adipose Tissues Reveals Transcript Variants Involved in Lipid Biosynthesis.

Sheep have historically been bred globally as a vital food source. To explore the transcriptome of adipose tissue and investigate key genes regulating adipose metabolism in sheep, adipose tissue samples were obtained from F1 Dorper × Hu sheep. High-throughput sequencing libraries for second- and third-generation sequencing were constructed using extracted total RNA. Functional annotation of differentially expressed genes and isoforms facilitated the identification of key regulatory genes and isoforms associated with sheep fat metabolism. SMRT-seq generated 919,259 high-accuracy cDNA sequences after filtering. Full-length sequences were corrected using RNA-seq sequences, and 699,680 high-quality full-length non-chimeric (FLNC) reads were obtained. Upon evaluating the ratio of total lengths based on FLNC sequencing, it was determined that 36,909 out of 56,316 multiple-exon isoforms met the criteria for full-length status. This indicates the identification of 330,375 full-length FLNC transcripts among the 370,114 multiple-exon FLNC transcripts. By comparing the reference genomes, 60,276 loci and 111,302 isoforms were identified. In addition, 43,423 new genes and 44,563 new isoforms were identified. The results identified 185 (3198), 394 (3592), and 83 (3286) differentially expressed genes (transcripts) between tail and subcutaneous, tail and visceral, and subcutaneous and visceral adipose tissues, respectively. Functional annotation and pathway analysis revealed the following observations. (1) Among the differentially expressed genes (DEGs) of TF and SF tissues, the downregulation of ACADL, ACSL6, and NC_056060.1.2536 was observed in SF, while FFAR4 exhibited upregulation. (2) Among the DEGs of TF and VF tissues, expressions of ACADL, ACSL6, COL1A1, COL1A2, and SCD were downregulated in VF, with upregulation of FFAR4. (3) Among SF and VF expressions of COL1A1, COL1A2, and NC_056060.1.2536 were downregulated in VF. Specific differentially expressed genes (ACADL, ACSL6, COL1A1, COL1A2, FFAR4, NC_056060.1.2536, and SCD) and transcripts (NC_056066.1.1866.16 and NC_056066.1.1866.22) were identified as relevant to fat metabolism. These results provide a dataset for further verification of the regulatory pathway associated with fat metabolism in sheep.

Coupling microscale zero-valent iron and autotrophic hydrogen-bacteria provides a sustainable remediation solution for trichloroethylene-contaminated groundwater: Mechanisms, regulation, and engineering implications.

Coupling microscale zero-valent iron (mZVI) and autotrophic hydrogen bacteria (AHB) has gained increasing attention owing to its potential to improve dechlorination performance by bridging H2 donors and acceptors. However, few studies have attempted to test its sustainable remediation performance and to comprehensively unveil the governing mechanisms. This study systematically compared the performances of different systems (mZVI, H2-AHB, and mZVI-AHB) for trichloroethylene (TCE) removal, and further optimized dechlorination and H2 evolution of mZVI-AHB synchronously by regulating the mZVI particle size and dosage to achieve a win-win remediation solution. The final removal efficiency and removal rate of TCE by mZVI-AHB were 1.67-fold and 5.30-fold of those by mZVI alone respectively, and mZVI-AHB resulted in more complete dechlorination than H2-AHB alone. Combining H2 evolution kinetics, material characterization data, and bacterial community analysis results, the improved dechlorination performance of mZVI-AHB was mainly due to the following mechanisms: H2 generated by mZVI corrosion was efficiently utilized by AHB, lasting corrosion of mZVI was facilitated by AHB, and dechlorination functional bacteria were highly enriched by mZVI. Finally, the remediation performance of mZVI-AHB with different mZVI particle sizes and dosages was evaluated comprehensively in terms of dechlorination reactivity, H2 utilization efficiency and chemical cost, and suggestions for possible engineering applications are provided.

Electrical Modeling and Characterization of Graphene-Based On-Chip Spiral Inductors.

This paper investigates the electrical performance of graphene-based on-chip spiral inductors by virtue of a physics-based equivalent circuit model. The skin and proximity effects, as well as the substrate loss effect, are considered and treated appropriately. The graphene resistance and inductance are combined into the circuit model. It is demonstrated that the electrical characteristics of the on-chip square spiral inductor can be improved by replacing copper with graphene. Moreover, graphene exhibits more effectiveness in improving the inductance in tapered inductors than uniform ones.

Three Potential Tumor Markers Promote Metastasis and Recurrence of Colorectal Cancer by Regulating the Inflammatory Response: ADAM8, LYN, and S100A9.

Metastasis and recurrence are major causes of colorectal cancer (CRC) death, but their molecular mechanisms are unclear. In this study, genes associated with CRC metastasis and recurrence were identified by weighted gene coexpression network analysis, selecting the top 25% most variant genes in the dataset GSE33113. By average linkage hierarchical clustering, a total of 21 modules were generated. One key module was identified as the most relevant to the prognosis of CRC. Gene Ontology analysis indicated that genes associated with tumor metastasis and recurrence in this module were significantly enriched in inflammatory biological functions. Functional analysis was performed on the key module, and candidate hub genes (ADAM8, LYN, and S100A9) were screened out by expression and survival analysis. In summary, the three core genes identified in this study could greatly improve our understanding of CRC metastasis and recurrence. The results also provide a theoretical basis for the use of three core genes (ADAM8, LYN, and S100A9) as a combined marker for early diagnosis, which could benefit CRC patients.

A critical review of existing mechanisms and strategies to enhance N2 selectivity in groundwater nitrate reduction.

The pollution of nitrate (NO3-) in groundwater has become an environmental problem of general concern and requires immediate remediation because of adverse human and ecological impacts. NO3- removal from groundwater is conducted mainly by chemical, biological, and coupled methods, with the removal efficiency of NO3- considered the sole performance indicator. However, in addition to the harmless form of N2, the reduced NO3- could be transformed into other intermediates, such as nitrite (NO2-), nitrous oxide (N2O), and ammonia (NH4+), which may have direct or indirect negative impacts on the environment. Therefore, increasing N2 selectivity is a significant challenge in reducing NO3- in groundwater, which seriously impedes the large-scale implementation of available remediation technologies. In this work, we comprehensively overview the most recent advances in N2 selectivity regarding the understanding of emerging groundwater NO3- removal technologies. Mechanisms of by-product production and strategies to enhance the selective reduction of NO3- to N2 are discussed in detail. Furthermore, we proposed topics for further research and hope that the total environmental impacts of remediation schemes should be evaluated comprehensively by quantifying all potential intermediate products, and promising strategies should be further developed to enhance N2 selectivity, to improve the feasibility of related technologies in actual remediation.

Proteomic screening of potential N-glycoprotein biomarkers for colorectal cancer by TMT labeling combined with LC-MS/MS.

BACKGROUND AND AIMS: Colorectal cancer (CRC) is part of the most widespread malignant tumors. At present, colonoscopy is a routine procedure in the diagnosis of CRC, but it is traumatic. Carcinoembryonic antigen, CA199, and CA242 are common serum markers for the diagnosis of CRC; however, they do not demonstrate satisfactory specificity and sensitivity for the diagnosis of CRC. Hence, Now it is necessary to screen many valuable serum biomarkers for CRC, proteomics methods have been used to investigate PTMs such as glycosylation of proteins with prominent roles in the occurrence and development of tumors. METHODS: This study screens altering glycosylated proteins of CRC tissues using LC-MS/MS quantitative glycoproteomics, and then these candidate biomarkers for CRC are further validated by serum glycoproteomics. RESULTS: The results of glycoproteomics in CRC tissues show that the abundance of 160 and 79 glycerogelatin proteins was obviously upregulated and downregulated compared with their adjacent tissues(P < 0.05). Bioinformatics analysis suggests that these molecules are mainly involved in many biological processes, including skeletal system development, collagen fibril organization, and receptor-mediated endocytosis. Results of serum glycoproteomics show that the changing trends of 2 protein glycosylation were consistent with MS results of CRC tissues, including ICAM1and APMAP. Areas under the ROC curve (AUC) results confirm that ICAM1and APMAP as early immune diagnosis markers of CRC has excellent sensitivity and specificity. CONCLUSION: The ICAM1 and APMAP may serve as a potential tumor marker for CRC.

BDNF expression in GISTs predicts poor prognosis when associated with PD-L1 positive tumor-infiltrating lymphocytes.

Substantial evidence indicates that brain-derived neurotrophic factor (BDNF) plays an important role in tumorigenesis, in addition to its primary role in neuronal activity. Gastrointestinal stromal tumors (GISTs), which are the most common mesenchymal neoplasms of the gastrointestinal tract, contain multiple types of tumor-infiltrating lymphocytes (TILs) that express relevant immune checkpoint proteins. However, no data have been reported on the role of BDNF in GISTs. This study aimed to investigate the expression pattern and prognostic value of BDNF in GIST patients with different degrees of risk, as well as the relationship between BDNF expression and immune checkpoints. Immunohistochemistry (IHC) demonstrated that higher BDNF expression was more likely to be present in high-risk patients and suggested a poor prognosis. A similar phenomenon was demonstrated in plasma. Even more interesting was that a positive correlation was present between BDNF and PD-L1+ expression on TILs. Moreover, high BDNF expression levels in combination with a high PD-L1+ TIL count predict extremely poor survival. The combination of BDNF expression and TIL PD-L1+ expression as a single biomarker was a powerful significant independent predictor of prognosis. Taken together, BDNF expression may serve as a significant prognostic factor, as the combination of BDNF expression and the PD-L1+ TIL subset led to superior prediction of GIST prognosis. Furthermore, our research coupled a neurotrophin with immunity, which provides novel evidence of neural and immune regulation in a clinical study of GIST.

Electron competition and electron selectivity in abiotic, biotic, and coupled systems for dechlorinating chlorinated aliphatic hydrocarbons in groundwater: A review.

Chlorinated aliphatic hydrocarbons (CAHs) have been frequently detected in aquifers in recent years. Owing to the bioaccumulation and toxicity of CAHs, it is essential to explore high-efficiency technologies for their complete dechlorination in groundwater. At present, the most widely used abiotic and biotic remediation technologies are based on zero-valent iron (ZVI) and functional anaerobic bacteria (FAB), respectively. However, the main obstacles to the full potential of both technologies in the field include their lowered efficiencies and increased economic costs due to the co-existence of a variety of natural electron acceptors in the environment, such as dissolved oxygen (DO), nitrate (NO3-), sulfate (SO42-), ferric iron (Fe (III)), bicarbonate (HCO3-), and even water, which compete for electrons with the target contaminants. Therefore, a clear understanding of the mechanisms governing electron competition and electron selectivity is significant for the accurate evaluation of the effectiveness of both technologies under natural hydrochemical conditions. We collected data from both abiotic and biotic CAH-remediation systems, summarized the dechlorination and undesired reactions in groundwater, discussed the characterization methods and general principles of electron competition, and described strategies to improve electron selectivity in both systems. Furthermore, we reviewed the emerging ZVI-FAB coupled system, which integrates abiotic and biotic processes to enhance dechlorination performance and electron utilization efficiency. Lastly, we propose future research needs to quantitatively understand the electron competition in abiotic, biotic, and coupled systems in more detail and to promote improved electron selectivity in groundwater remediation.

Effects of co-existing nitrate on TCE removal by mZVI under different pollution load scenarios: Kinetics, electron efficiency and mechanisms.

Microscale zero-valent iron in situ reaction zone (mZVI-IRZ) has proved to be effective and efficient for the removal of chlorinated aliphatic hydrocarbons (CAHs) from groundwater. However, nitrate (NO3-), which is ubiquitous in groundwater, affects the mZVI-based attenuation of CAHs in a complicated manner. Both the reaction rate constant (k) and electron efficiency (EE) of mZVI must be considered to comprehensively reflect the effects of NO3- on the short and long-term remediation performances of mZVI. Therefore, the influence of NO3- on trichloroethylene (TCE) removal under high-pollution-load (iron limited) and low-pollution-load (iron excess) conditions was investigated. Low concentrations of NO3- (10 and 50 mg N L-1) were found to enhance the TCE removal rate and efficiency, whereas high concentrations of NO3- (100 mg N L-1) inhibited the reaction. Although TCE removal was increased at low concentrations of NO3-, the EE of mZVI was dramatically decreased in the presence of NO3- at all concentration levels. Therefore, both the short-term TCE removal characteristics and the EE of mZVI should be considered when evaluating the long-term remediation effectiveness of mZVI-IRZ technology. The effects of NO3- on the TCE removal trends under high- and low-pollution-load scenarios were similar, but had different magnitudes. NO3- affected the TCE removal mainly by promoting mZVI corrosion, competing for electrons and affecting passivation product evolution. Our results provide guidance for the practical application of mZVI-IRZ technology.

Human liver chimeric mouse model based on diphtheria toxin-induced liver injury.

AIM: To establish an inducible liver injury mouse model and transplant human hepatocytes to obtain liver-humanized mice. METHODS: We crossed three mouse strains, including albumin (Alb)-cre transgenic mice, inducible diphtheria toxin receptor (DTR) transgenic mice and severe combined immune deficient (SCID)-beige mice, to create Alb-cre/DTR/SCID-beige (ADSB) mice, which coincidentally harbor Alb-cre and DTR transgenes and are immunodeficient. As the Cre expression is driven by the liver-specific promoter Alb (encoding ALB), the DTR stop signal flanked by two loxP sites can be deleted in the ADSB mice, resulting in DTR expression in the liver. ADSB mice aged 8-10 wk were injected intraperitoneally (i.p.) with diphtheria toxin (DT) and liver damage was assessed by serum alanine aminotransferase (ALT) level. Two days later, mouse livers were sampled for histological analysis, and human hepatocytes were transplanted into the livers on the same day. A human ALB enzyme-linked immunosorbent assay was performed 7, 14, 21 and 28 d after transplantation. Human CD68 immunohistochemistry was performed 30 and 90 d after transplantation. RESULTS: We crossed Alb-cre with DTR and SCID-beige mice to obtain ADSB mice. These mice were found to have liver damage 4 d after i.p. injection of 2.5 ng/g bodyweight DT. Bodyweight began to decrease on day 2, increased on day 7, and was lowest on day 4 (range, 10.5%-13.4%). Serum ALT activity began to increase on day 2 and reached a peak value of 289.7 ± 16.2 IU/mL on day 4, then returned to background values on day 7. After transplantation of human liver cells, peripheral blood human ALB level was 1580 ± 454.8 ng/mL (range, 750.2-3064.9 ng/mL) after 28 d and Kupffer cells were present in the liver at 30 d in ADSB mice. CONCLUSION: Human hepatocytes were successfully repopulated in the livers of ADSB mice. The inducible mouse model of humanized liver in ADSB mice may have functional applications, such as hepatocyte transplantation, hepatic regeneration and drug metabolism.

Neutralization of Zika virus by germline-like human monoclonal antibodies targeting cryptic epitopes on envelope domain III.

The Zika virus (ZIKV), a flavivirus transmitted by Aedes mosquitoes, has emerged as a global public health concern. Pre-existing cross-reactive antibodies against other flaviviruses could modulate immune responses to ZIKV infection by antibody-dependent enhancement, highlighting the importance of understanding the immunogenicity of the ZIKV envelope protein. In this study, we identified a panel of human monoclonal antibodies (mAbs) that target domain III (DIII) of the ZIKV envelope protein from a very large phage-display naive antibody library. These germline-like antibodies, sharing 98%-100% hoLogy with their corresponding germline IGHV genes, bound ZIKV DIII specifically with high affinities. One mAb, m301, broadly neutralized the currently circulating ZIKV strains and showed a synergistic effect with another mAb, m302, in neutralizing ZIKV in vitro and in a mouse model of ZIKV infection. Interestingly, epitope mapping and competitive binding studies suggest that m301 and m302 bind adjacent regions of the DIII C-C' loop, which represents a recently identified cryptic epitope that is intermittently exposed in an uncharacterized virus conformation. This study extended our understanding of antigenic epitopes of ZIKV antibodies and has direct implications for the design of ZIKV vaccines.