Faecal contamination in China: Trends, sources, and driving mechanisms.

Faecal contamination of surface waters is a global public health and economic burden. Here, we constructed a 30-year dataset to analyse the spatiotemporal trends and driving mechanisms of faecal coliforms (FCs) in China. We found that previous national policies to reduce water pollution have significantly improved the quality of surface water and, correspondingly, faecal contamination. However, the downward trend in FC levels has been more gradual than that for physico-chemical pollutants, and this trend may be exaggerated. Our results show that the driving mechanisms of faecal pollution were seasonal and complex. During the dry season, forests and grasslands were the source landscapes that exacerbated faecal pollution; during the wet season, urbanisation dominated, highlighting China's poorly designed drainage systems. Our projections revealed that faecal contamination will continue to worsen from 2022 to 2035, highlighting the need for pollution control. In the future, faecal indicators should be included in routine monitoring, evaluation, and assessment at the national level. Moreover, coordinated design of forest, grassland, and wetland landscapes is recommended for faecal pollution control at the regional level, whereas stormwater-related source control needs to be further strengthened at the urban level.

Immobilized NRG1 Accelerates Neural Crest like Cell Differentiation Toward Functional Schwann Cells Through Sustained Erk1/2 Activation and YAP/TAZ Nuclear Translocation.

Neural Crest cells (NC) are a multipotent cell population that give rise to a multitude of cell types including Schwann cells (SC) in the peripheral nervous system (PNS). Immature SC interact with neuronal axons via the neuregulin 1 (NRG1) ligand present on the neuronal surface and ultimately form the myelin sheath. Multiple attempts to derive functional SC from pluripotent stem cells have met challenges with respect to expression of mature markers and axonal sorting. Here, they hypothesized that sustained signaling from immobilized NRG1 (iNRG1) might enhance the differentiation of NC derived from glabrous neonatal epidermis towards a SC phenotype. Using this strategy, NC derived SC expressed mature markers to similar levels as compared to explanted rat sciatic SC. Signaling studies revealed that sustained NRG1 signaling led to yes-associated protein 1 (YAP) activation and nuclear translocation. Furthermore, NC derived SC on iNRG1 exhibited mature SC function as they aligned with rat dorsal root ganglia (DRG) neurons in an in vitro coculture model; and most notably, aligned on neuronal axons upon implantation in a chick embryo model in vivo. Taken together their work demonstrated the importance of signaling dynamics in SC differentiation, aiming towards development of drug testing platforms for de-myelinating disorders.

Inhibitors and PROTACs of CDK2: challenges and opportunities.

INTRODUCTION: Abundant evidence suggests that the overexpression of CDK2-cyclin A/E complex disrupts normal cell cycle regulation, leading to uncontrolled proliferation of cancer cells. Thus, CDK2 has become a promising therapeutic target for cancer treatment. In recent years, insights into the structures of the CDK2 catalytic site and allosteric pockets have provided notable opportunities for developing more effective clinical candidates of CDK2 inhibitors. AREA COVERED: This article reviews the latest CDK2 inhibitors that have entered clinical trials and discusses the design and discovery of the most promising new preclinical CDK2 inhibitors in recent years. Additionally, it summarizes the development of allosteric CDK2 inhibitors and CDK2-targeting PROTACs. The review encompasses strategies for inhibitor and PROTAC design, structure-activity relationships, as well as in vitro and in vivo biological assessments. EXPERT OPINION: Despite considerable effort, no CDK2 inhibitor has yet received FDA approval for marketing due to poor selectivity and observed toxicity in clinical settings. Future research must prioritize the optimization of the selectivity, potency, and pharmacokinetics of CDK2 inhibitors and PROTACs. Moreover, exploring combination therapies incorporating CDK2 inhibitors with other targeted agents, or the design of multi-target inhibitors, presents significant promise for advancing cancer treatment strategies.

Optimizing Soil Health and Sorghum Productivity through Crop Rotation with Quinoa.

Crop rotation has been considered a potential solution to mitigate the negative effects of the continuous cropping of sorghum, including soil quality issues, inadequate plant development, and diminished yield and quality. A two-year field experiment was conducted to compare the effects of sorghum-sorghum continuous cropping and quinoa-sorghum rotation on soil properties and sorghum yield. The treatments were arranged in a randomized complete block design with three replicates. Sorghum seeds (Jinza 22) and quinoa seeds ('Jiaqi 1' variety) were used. Soil samples were collected before and during the experiment for the analysis of physicochemical properties. The yield traits of sorghum were measured at maturity. The results showed that soil nutrients and organic matter were higher in the top 0-20 cm soil depth compared to 20-40 cm depth, with significant differences observed between cropping systems. Sorghum-quinoa cropping increased soil total N and organic matter, particularly at the jointing and maturity stages of sorghum. However, the available phosphorus was higher under continuous cropping at all growth stages. Crop rotation significantly improved sorghum yield traits, including spike fresh weight, spike dry weight, grain weight per spike, and grain yield per hectare. A correlation analysis revealed positive relationships between soil total N, organic matter, and sorghum yield. Overall, sorghum-quinoa rotation demonstrated potential for improving soil fertility and enhancing crop productivity compared to continuous cropping, although further studies are needed to explore the long-term effects and optimize management practices.

The Association of Infant Birth Sizes and Anemia under Five Years Old: A Population-Based Prospective Cohort Study in China.

Infant birth sizes are vital clinical parameters to predict poor growth and micronutrient deficiency in early life. However, their effects on childhood anemia remain unclear. We aimed to explore the associations between birth weight, crown-heel length, and head circumference with anemia in early childhood, as well as potential modification factors. This population-based prospective cohort study included 204,556 participants with singleton live births delivered at gestational ages of 28-42 weeks. A logistic regression model was used to estimate the associations of the measures of infant birth size and their Z-score with anemia under five years old. There were 26,802 (13.10%) children under five years old who were diagnosed has having anemia. Compared with children who did not have anemia, children who had anemia had a lower birth weight and smaller head circumference and a longer crown-heel length (all p-values < 0.05). After adjusting for confounders, not only birth weight (ß coefficient, -0.008; 95% CI, -0.011--0.004; p < 0.001) and head circumference (ß coefficient, -0.004; 95% CI, -0.007--0.001; p = 0.009), but also the related Z-scores were negatively associated with childhood anemia, while the trends for crown-heel length were the opposite. We further found significant interactions of folic acid use and maternal occupation with infant birth sizes. In conclusion, infants having abnormal sizes at birth are significantly associated with the risk for childhood anemia, which can be modified by folic acid use during pregnancy and maternal occupation.

Biomimetic Slippery Surface with Exclusive Liquid-Repellent and Self-Cleaning Properties for Antifouling.

The nature always offers amazing inspiration, where it is highly desirable to endow coatings on marine equipment with powerful functions. An excellent example is slippery zone of Nepenthes pitcher, which possesses novel liquid-repellent and self-cleaning performance. Therefore, this study presents an efficient fabrication method to prepare a novel coating. The coatings were fabricated by designing biomimetic textures extracted from the lunate bodies of slippery zone on polydimethylsiloxane (PDMS) and then grafting Dictyophora indusiata polysaccharide (DIP) modifier. The as-prepared slippery coatings exhibited outstanding antifouling properties against kinds of daily life pollutants such as Chlorella and coffee. This synergistic strategy was proposed combined with environmentally friendly modifier grafting and heterogeneous microstructure on the surface to broaden new probabilities for manufacturing slippery coatings with incredible protective functionality.

Social Exclusion and Short Video Addiction: The Mediating Role of Boredom and Self-Control.

Background: Short video apps are very popular among Chinese college students, and some students even rely on them. Most of the current research has focused only on Internet addiction and has seldom focused on the phenomenon of short video addiction. Its influencing factors and formation mechanism are worth exploring. Objective: This study aimed to explore the relationship between social exclusion and short video addiction among college students and the mediating roles of boredom and self-control. Methods: This study adopted a multistage investigation and investigated 532 college students (39% male; mean age 19.32 ± 1.23 years) with a social exclusion scale, boredom proneness scale, self-control scale, and short video addiction scale. The mediating effect was tested with Process 3.1. Results: The results showed that social exclusion has a positive predictive effect on college student's short video addiction. The impact of social exclusion on college student's short video addiction was mediated by boredom and self-control, and the chained mediation of boredom and self-control. Conclusion: Theoretically, this study modified the I-PACE model, indicating that personal and distant social factors should be considered in individuals with behavioral addictions, such as short video addiction. Practically, the results suggested that schools should reduce peer rejection and improve students' mental health literacy to reduce boredom and enhance self-control, thus effectively preventing short video addiction.

The role of small dense LDL-C/large buoyant LDL-C ratio as an independent risk factor in patients with type 2 diabetes mellitus and metabolic syndrome

Dyslipidemia plays a key role in metabolic syndrome (MS), intricately linked to type 2 diabetes mellitus (T2DM). This study aimed to investigate the differences in low-density lipoprotein cholesterol (LDL-C) subfraction levels between T2DM and T2DM with MS, and identify the risk factors associated with the disease. A total of 246 individuals diagnosed with T2DM, including 144 T2DM patients with MS, and 147 healthy subjects were recruited. All participants underwent a comprehensive clinical evaluation. Lipoprotein subfraction analysis was performed using the Lipoprint LDL system. Multivariate logistic regression analysis revealed that several lipid markers, including triglyceride (TG), LDL-C, large buoyant LDL-C (lbLDL-C), small dense LDL-C (sdLDL-C), LDLC2-5, and sdLDL-C/lbLDL-C ratio, were identified as independent risk factors for T2DM. Additionally, TG, sdLDL-C, LDLC-4, LDLC-5, and sdLDL-C/lbLDL-C ratio were found to be independent risk factors for T2DM with MS. Furthermore, the results of the receiver operating characteristic (ROC) curves demonstrated that sdLDL-C, LDLC-4, LDLC-3, and sdLDL-C/lbLDL-C ratio exhibited excellent predictive performance for the risk of T2DM (AUC > 0.9). The sdLDL-C/lbLDL-C ratio emerges as a shared independent risk factor for T2DM and MS complications. Furthermore, sdLDL-C/lbLDL-C ratio, along with LDL-4 and LDL-3, exhibits noteworthy predictive capabilities for T2DM.

Lycorine relieves the CCl4-induced liver fibrosis mainly via the JAK2/STAT3 and PI3K/AKT signaling pathways.

Liver fibrosis, a progressive process of fibrous scarring, results from the accumulation of extracellular matrix proteins (ECM). If left untreated, it often progresses to diseases such as cirrhosis and hepatocellular carcinoma. Lycorine, a natural alkaloid derived from medicinal plants, has shown diverse bioactivities by targeting JAK2/STAT3 signaling, but its pharmacological effects and potential molecular mechanisms in liver fibrosis remains largely unexplored. The purpose of this study is to elucidate the pharmacological activity and molecular mechanism of lycorine in anti-hepatic fibrosis. Findings indicate that lycorine significantly inhibited hepatic stellate cells (HSCs) activation by reducing the expression of α-SMA and collagen-1. In vivo, lycorine treatment alleviated carbon tetrachloride (CCl4) -induced mice liver fibrosis, improving liver function, decreasing ECM deposition, and inhibiting fibrosis-related markers' expression. Mechanistically, it was found that lycorine exerts protective activity through the JAK2/STAT3 and PI3K/AKT signaling pathways, as evidenced by transcriptome sequencing technology and small molecule inhibitors. These results underscore lycorine's potential as a therapeutic drug for liver fibrosis.

Laser-Induced Controllable Porosity in Additive Manufacturing Boosts Efficiency of Electrocatalytic Water Splitting.

In laser-based additive manufacturing (AM), porosity and unmelted metal powder are typically considered undesirable and harmful. Nevertheless in this work, precisely controlling laser parameters during printing can intentionally introduce controllable porosity, yielding a porous electrode with enhanced catalytic activity for the oxygen evolution reaction (OER). This study demonstrates that deliberate introduction of porosity, typically considered a defect, leads to improved gas molecule desorption, enhanced mass transfer, and increased catalytically active sites. The optimized P-93% electrode displays superior OER performance with an overpotential of 270 mV at 20 mA cm-2. Furthermore, it exhibits remarkable long-term stability, operating continuously for over 1000 h at 10 mA cm-2 and more than 500 h at 500 mA cm-2. This study not only provides a straightforward and mass-producible method for efficient, binder-free OER catalysts but also, if optimized, underscores the potential of laser-based AM driven defect engineering as a promising strategy for industrial water splitting.

Controllable non-uniformly distributed spiking cluster generation in broadband optoelectronic oscillator.

An approach to achieve controllable non-uniformly distributed spiking cluster generation is proposed and demonstrated based on an externally-triggered broadband optoelectronic oscillator (OEO). The theory of controlling the distribution of the spiking pulses in a spiking cluster is established. Based on the theory, the dynamic and the distribution characteristics are analyzed and revealed in the stable spiking oscillation state under different externally-injected trigger signal voltages. The peak-voltage envelop of the cluster and the interval of the spiking pulses are demonstrated to have an approximate negative linearity relationship with the externally-injected trigger signal voltage in both the numerical simulation and the experiment, where a square waveform, a trapezoidal waveform, a parabola waveform, and a half-sinusoidal waveform are used as the externally-injected trigger signals. The results indicate that the spiking pulse distribution in the generated spiking cluster can be well controlled through tuning the externally-injected trigger signal voltage. The proposed scheme can be utilized in spiking encoding and reservoir computing.

Phase-locked dual-frequency microwave signal generation in an optoelectronic oscillator based on frequency mixing mutual injection.

An approach to generating stable phase-locked dual-frequency microwave signals is proposed and demonstrated based on a dual-passband optoelectronic oscillator (OEO). Mode gain competition is broken by employing frequency mixing mutual injection effect to realize phase locking between the two oscillation signals, which is achieved by applying a single-tone signal to a microwave mixer in the OEO cavity. In addition, a dual-loop configuration with balanced detection is utilized to ensure a high side mode suppression ratio (SMSR) and ultra-low phase noise, which also enhances the stability of the generated signal. In the experiment, a phase-locked dual-frequency microwave signal at 9.9982 GHz and 10.1155 GHz is generated by using the proposed OEO scheme. The SMSR and the phase noise are 75 dB and -141 dBc/Hz@10 kHz, respectively. Additionally, the Allan deviation of the generated signal is in the order of 10-11@1 s. These parameters are superior to those based on the same OEO but with a single-loop configuration, which are also compared in detail.

The development of the biological soil crust regulates the fungal distribution and the stability of fungal networks.

The heterogeneous composition of fungi plays an indispensable role in the foundation of the multifunctionalities of ecosystems within drylands. The precise mechanisms that govern fluctuations in soil fungal assemblages in dryland ecosystems remain incompletely elucidated. In this study, biological soil crusts (biocrusts) at different successional stages in the Gurbantunggut Desert were used as substrates to examine the characteristics and driving factors that influence fungal abundance and community dynamics during biocrust development using qPCR and high-throughput sequencing of the ITS2 region. The findings showed that the physicochemical properties changed significantly with the development of biocrusts. In particular, total nitrogen increased 4.8 times, along with notable increases in ammonium, total phosphorus (2.1 times) and soil organic carbon (6.5 times). Initially, there was a rise in fungal abundance, which was subsequently followed by a decline as the biocrust developed, with the highest abundance detected in lichen crust (2.66 × 107 copies/g soil) and the lowest in bare sand (7.98 × 106 copies/g soil). Ascomycetes and Basidiomycetes emerged as dominant phyla, collectively forming 85% of the fungal community. As the biocrust developed, noticeable alterations occurred in fungal community compositions, resulting from changes in the relative proportions of Dothideomycetes, Lecanoromycetes and unclassified ascomycetes. Nitrogen, phosphorus, organic carbon content, and pH of biocrusts were identified as direct or indirect regulators of fungal abundance and community structure. The complexity of fungal networks increased as biocrusts developed as revealed by network analysis, but reduced in the stability of fungal communities within algal and lichen crusts. Keystone species within the fungal community also underwent changes as biocrust developed. These results suggested that shifts in interspecies relationships among fungi could further contribute to the variation in fungal communities during the development of biocrusts.

Outcomes of Human Leukocyte Antigen-Matched Related Donor and Haploidentical Allogeneic Hematopoietic Cell Transplantation Recipients by Immune Profiles of Recipients and Donors.

Haploidentical (Haplo) allogeneic HCTs (alloHCT) have been used more frequently over the last decade as survival is similar to HLA-matched related donor (MRD) alloHCTs. We aimed to identify donor and recipient immune signatures before alloHCT that are associated with clinically meaningful outcomes in MRD vs Haplo alloHCT recipients. This retrospective cohort study of 165 MRD (n = 132) and Haplo (n = 33) alloHCT recipients and their related donors between 2007-2019 with paired peripheral blood samples immunophenotyped for T-cell, B-cell, NK cell and dendritic cell (DC) subsets. Immune cells were quantified before alloHCT in donors and recipients; calculations of immune cell ratios were classified as high, intermediate, and low and analyzed with alloHCT outcomes. Haplo donors were younger than MRD donors (median: 35 vs 51 years), whereas Haplo recipients were older than MRD recipients (median: 68 vs 54 years), were more likely to have a Karnofsky Performance Score ≤ 70 (76% vs 57%), 3+ comorbidities (54% vs 47%), and were in complete remission prior to alloHCT (58% vs 42%). In MRD alloHCT, a lower ratio of CD4+ to CD8+ effector memory cells in the donor was associated with lower 4-yr overall survival (OS; 25% vs 61%; P = .009), lower 4-yr progression free survival (PFS; 25% vs 58%; P = .014) and higher incidence of 1-yr transplant-related mortality (TRM; 39% vs 7%; P = .009) in recipients. A higher ratio of CD8+ effector memory to total NK cells measured in MRD recipients was associated with a higher incidence of grade II-IV aGvHD (63% vs 37%; P = .004) but was not statistically significant for III-IV aGvHD (23% vs 12%). In Haplo alloHCT, a lower ratio of total T-regulatory to CD4+ central memory cells in the donor was associated with lower 4-yr PFS (22% vs 60%; P = .0091). A higher ratio of CD4+ effector memory to CD8+ effector memory cells measured in Haplo recipients pre-alloHCT was associated with lower 4-yr OS (25% vs 88%; P = .0039). In both MRD and Haplo recipients, a higher ratio of CD4+ naïve to CD4+ central memory cells was associated with a higher incidence of grade II-IV aGvHD (64% vs 38%; P = .04). Evaluation of pre-alloHCT immune signatures of the donor and recipient may influence clinically meaningful patient outcomes in both MRD and Haplo transplants.

Large-scale comparative analysis reveals phylogenomic preference of blaNDM-1 and blaKPC-2 transmission among Klebsiella pneumoniae.

blaNDM-1 and blaKPC-2 are responsible for the global increase in carbapenem-resistant Klebsiella pneumoniae, posing a great challenge to public health. However, the impact of phylogenetic factors on the dissemination of blaNDM-1 and blaKPC-2 is not yet fully understood. This study established a global dataset of 4051 blaNDM-1+ and 10,223 blaKPC-2+ K. pneumoniae genomes, and compared their transmission modes on a global scale. The results showed that blaNDM-1+ K. pneumoniae genomes exhibited a broader geographical distribution and higher sequence type (ST) richness than blaKPC-2+ genomes, indicating higher transmissibility of the blaNDM-1 gene. Furthermore, blaNDM-1+ genomes displayed significant differences in ST lineage, antibiotic resistance gene composition, virulence gene composition and genetic environments compared with blaKPC-2+ genomes, suggesting distinct dissemination mechanisms. blaNDM-1+ genomes were predominantly associated with ST147 and ST16, whereas blaKPC-2+ genomes were mainly found in ST11 and ST258. Significantly different accessory genes were identified between blaNDM-1+ and blaKPC-2+ genomes. The preference for blaKPC-2 distribution across certain countries, ST lineages and genetic environments underscores vertical spread as the primary mechanism driving the expansion of blaKPC-2. In contrast, blaNDM-1+ genomes did not display such a strong preference, confirming that the dissemination of blaNDM-1 mainly depends on horizontal gene transfer. Overall, this study demonstrates different phylogenetic drivers for the dissemination of blaNDM-1 and blaKPC-2, providing new insights into their global transmission dynamics.

MEF2D Functions as a Tumor Suppressor in Breast Cancer.

The myocyte enhancer factor 2 (MEF2) gene family play fundamental roles in the genetic programs that control cell differentiation, morphogenesis, proliferation, and survival in a wide range of cell types. More recently, these genes have also been implicated as drivers of carcinogenesis, by acting as oncogenes or tumor suppressors depending on the biological context. Nonetheless, the molecular programs they regulate and their roles in tumor development and progression remain incompletely understood. The present study evaluated whether the MEF2D transcription factor functions as a tumor suppressor in breast cancer. The knockout of the MEF2D gene in mouse mammary epithelial cells resulted in phenotypic changes characteristic of neoplastic transformation. These changes included enhanced cell proliferation, a loss of contact inhibition, and anchorage-independent growth in soft agar, as well as the capacity for tumor development in mice. Mechanistically, the knockout of MEF2D induced the epithelial-to-mesenchymal transition (EMT) and activated several oncogenic signaling pathways, including AKT, ERK, and Hippo-YAP. Correspondingly, a reduced expression of MEF2D was observed in human triple-negative breast cancer cell lines, and a low MEF2D expression in tissue samples was found to be correlated with a worse overall survival and relapse-free survival in breast cancer patients. MEF2D may, thus, be a putative tumor suppressor, acting through selective gene regulatory programs that have clinical and therapeutic significance.

Identification of a novel matrix metalloproteinases-related prognostic signature in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary liver cancer worldwide. Cancer cells' local infiltration, proliferation, and spread are mainly influenced by the protein hydrolyzing function of different matrix metalloproteinases (MMPs). However, no study has determined the relationship between MMPs and prognostic prediction in HCC. METHODS: Expression profiles of mRNA and MMPs-related genes were obtained from publicly available databases. Cox regression and LASSO Cox regression analysis were used to identify and predict MMPs-related prognostic signature and construct predictive models for overall survival (OS). A nomogram was used to validate the accuracy of the prediction model. Drug prediction was performed using the Genomics of Drug Sensitivity in Cancer (GDSC) dataset, and single-cell clustering analysis was performed to further understand the significance of the MMPs-related signature. RESULTS: A MMPs-related prognostic signature (including RNPEPL1, ADAM15, ADAM18, ADAMTS5, CAD, YME1L1, AMZ2, PSMD14, and COPS6) was identified. Using the median value, HCC patients in the high-risk group showed worse OS than those in the low-risk group. Immune microenvironment analysis showed that patients in the high-risk group had higher levels of M0 and M2 macrophages. Drug sensitivity analysis revealed that the IC50 values of sorafenib, cisplatin, and cytarabine were higher in the high-risk group. Finally, the single-cell cluster analysis results showed that YME1L1 and COPS6 were the major genes expressed in the monocyte cluster. CONCLUSIONS: A novel MMPs-related signature can be used to predict the prognosis of HCC. The findings of this research could potentially impact the predictability of the prognosis and treatment of HCC.

The effects of trade liberalization on inequality in nutrition intake: empirical evidence from Indian districts.

BACKGROUND: Despite the positive impact of trade liberalization on food availability in India, severe inequality in nutrition consumption at the district level persists. Empirical evidence on the relationship between trade liberalization and nutrition consumption inequality often offers a country-level perspective and generates disputed outcomes. The study aimed to explore the effects of trade liberalization on inequality in nutrition consumption at the district level in India and to examine the heterogeneity of the impact on different nutrition consumption. METHODS: Our study employed the Gini Index to measure nutrition consumption inequality of 2 macronutrients and 5 micronutrients at the district level in India during 2009-2011, utilizing the comprehensive FAO/WHO individual food consumption data. The import tariff was adopted as a proxy for trade liberalization, as its externally imposed nature facilitates a causal interpretation. We further identified the direct causal relationship between food trade liberalization and inequality in nutrition consumption using a fixed effects model. RESULTS: The results show that more than 50% of the individuals in the survey districts did not meet the dietary standards for both macronutrients and micronutrients. Food trade liberalization hindered the improvement of inequality in nutrition consumption. As import tariffs were reduced by 1%, the inequality in intake of calories, zinc, vitamin B1, and vitamin B2 increased significantly by 0.45, 0.56, 0.48, and 0.66, respectively, which might be related to food market performance. The results also highlight the positive role of the gender gap, female-headed households, and caste culture on inequality in nutrition consumption in India. CONCLUSIONS: To ease the shock of liberalization and minimize its inequality effects, complementary measures should be adopted, such as improving food logistic conditions in poor areas, and nutrition relief schemes.

Diversity and host interaction of the gut microbiota in specific pathogen-free pigs.

Pigs are widely used as animal models in various studies related to humans. The interaction between the gut microbiota and the host has significant effects on the host's health and disease status. However, although there have been many studies investigating the pig gut microbiota, the findings have been inconsistent due to variations in rearing conditions. Interactions between the gut microbiota and host have not been fully explored in pigs. Specific pathogen-free (SPF) pigs are ideal non-primate large animals to study the interactions between the gut microbiota and the host. In this study, we performed high-throughput sequencing analysis of the gut microbiota and the gut tissue transcriptome of six SPF pigs to provide a systematic understanding of the composition, function, and spatial distribution of gut microbiota in SPF pigs. We identified significant differences in microbial diversity and functionality among different gastrointestinal tract sites. Metagenomics data analysis revealed significant differences in alpha diversity and beta diversity of microbiota in different gastrointestinal sites of SPF pigs. Additionally, transcriptomic data indicated significant differences in gene expression as well as KEGG and GO functional enrichment between the small intestine and large intestine. Furthermore, by combining microbial metagenomics and host transcriptomics analyses, specific correlations were found between gut microbiota and host genes. These included a negative correlation between the TCN1 gene and Prevotella dentalis, possibly related to bacterial metabolic pathways involving vitamin B12, and a positive correlation between the BDH1 gene and Roseburia hominis, possibly because both are involved in fatty acid metabolism. These findings lay the groundwork for further exploration of the co-evolution between the microbiota and the host, specifically in relation to nutrition, metabolism, and immunity. In conclusion, we have elucidated the diversity of the gut microbiota in SPF pigs and conducted a detailed investigation into the interactions between the gut microbiota and host gene expression. These results contribute to our understanding of the intricate dynamics between the gut microbiota and the host, offering important references for advancements in life science research, bioproduct production, and sustainable development in animal husbandry.

Machine learning deciphers the significance of mitochondrial regulators on the diagnosis and subtype classification in non-alcoholic fatty liver disease.

Background: Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent liver disease worldwide and lack of research on the diagnostic utility of mitochondrial regulators in NAFLD. Mitochondrial dysfunction plays a pivotal role in the development and progression of NAFLD, especially oxidative stress and acidity ß-oxidative overload. Thus, we aimed to identify and validate a panel of mitochondrial gene expression biomarkers for detection of NAFLD. Methods: We selected the GSE89632 dataset and identified key mitochondrial regulators by intersecting DEGs, WGCNA modules, and MRGs. Classification of NAFLD subtypes based on these key mitochondrial regulatory factors was performed, and the pattern of immune system infiltration in different NAFLD subtypes were also investigated. RF, LASSO, and SVM-RFE were employed to identify possible diagnostic biomarkers from key mitochondrial regulatory factors and the predictive power was demonstrated through ROC curves. Finally, we validated these potential diagnostic biomarkers in human peripheral blood samples and a high-fat diet-induced NAFLD mouse model. Results: We identified 25 key regulators of mitochondria and two NAFLD subtypes with different immune infiltration patterns. Four potential diagnostic biomarkers (BCL2L11, NAGS, HDHD3, and RMND1) were screened by three machine learning methods thereby establishing the diagnostic model, which showed favorable predictive power and achieved significant clinical benefit at certain threshold probabilities. Then, through internal and external validation, we identified and confirmed that BCL2L11 was significantly downregulated in NAFLD, while the other three were significantly upregulated. Conclusion: The four MRGs, namely BCL2L11, NAGS, HDHD3, and RMND1, are novel potential biomarkers for diagnosing NAFLD. A diagnostic model constructed using the four MRGs may aid early diagnosis of NAFLD in clinics.