Changes in the Non-targeted Metabolomic Profile of Three-year-old Toddlers with Elevated Exposure to Polycyclic Aromatic Hydrocarbons.

Objective: To investigate changes in the urinary metabolite profiles of children exposed to polycyclic aromatic hydrocarbons (PAHs) during critical brain development and explore their potential link with the intestinal microbiota. Methods: Liquid chromatography-tandem mass spectrometry was used to determine ten hydroxyl metabolites of PAHs (OH-PAHs) in 36-month-old children. Subsequently, 37 children were categorized into low- and high-exposure groups based on the sum of the ten OH-PAHs. Ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry was used to identify non-targeted metabolites in the urine samples. Furthermore, fecal flora abundance was assessed by 16S rRNA gene sequencing using Illumina MiSeq. Results: The concentrations of 21 metabolites were significantly higher in the high exposure group than in the low exposure group (variable importance for projection > 1, P < 0.05). Most of these metabolites were positively correlated with the hydroxyl metabolites of naphthalene, fluorine, and phenanthrene ( r = 0.336-0.531). The identified differential metabolites primarily belonged to pathways associated with inflammation or proinflammatory states, including amino acid, lipid, and nucleotide metabolism. Additionally, these distinct metabolites were significantly associated with specific intestinal flora abundances ( r = 0.34-0.55), which were mainly involved in neurodevelopment. Conclusion: Higher PAH exposure in young children affected metabolic homeostasis, particularly that of certain gut microbiota-derived metabolites. Further investigation is needed to explore the potential influence of PAHs on the gut microbiota and their possible association with neurodevelopmental outcomes.

Anterior chamber and angle characteristics in Chinese children (6-11 years old) with different refractive status using swept-source optical coherence tomography.

BACKGROUND: The anatomic structure of the anterior chamber (AC) helps to explain differences in refractive status in school-aged children and is closely associated with primary angle closure (PAC). The aim of this study was to quantify and analyze the anterior chamber and angle (ACA) characteristics in Chinese children with different refractive status by swept-source optical coherence tomography (SS-OCT). METHODS: In a cross-sectional observational study, 383 children from two primary schools in Shandong Province, China, underwent a complete ophthalmic examination. First, the anterior chamber depth (ACD), anterior chamber width (ACW), angle-opening distance (AOD), and trabecular-iris space area (TISA) were evaluated automatically using a CASIA2 imaging device. AOD and TISA were measured at 500, 750 µm nasal (N1 and N2, respectively), and temporal (T1 and T2, respectively) to the scleral spur (SS). Cycloplegic refraction and axial length (AL) were then measured. According to spherical equivalent refraction (SER), the children were assigned to hyperopic (SER > 0.50D), emmetropic (-0.50D < SER ≤ 0.50D), and myopic groups (SER ≤ -0.50D). RESULTS: Out of the 383 children, 349 healthy children (160 girls) with a mean age of 8.23 ± 1.06 years (range: 6-11 years) were included. The mean SER and AL were - 0.10 ± 1.57D and 23.44 ± 0.95 mm, respectively. The mean ACD and ACW were 3.17 ± 0.24 mm and 11.69 ± 0.43 mm. The mean AOD were 0.72 ± 0.25, 0.63 ± 0.22 mm at N1, T1, and 0.98 ± 0.30, 0.84 ± 0.27 mm at N2, T2. The mean TISA were 0.24 ± 0.09, 0.22 ± 0.09mm2 at N1, T1, and 0.46 ± 0.16, 0.40 ± 0.14mm2 at N2, T2. The myopic group had the deepest AC and the widest angle. Compared with boys, girls had shorter AL, shallower ACD, narrower ACW, and ACA (all p < 0.05). By Pearson's correlation analysis, SER was negatively associated with ACD, AOD, and TISA. AL was positively associated with ACD, ACW, AOD, and TISA. In the multiple regression analysis, AOD and TISA were associated with deeper ACD, narrower ACW, and longer AL. CONCLUSION: In primary school students, the myopic eyes have deeper AC and wider angle. ACD, ACW, AOD, and TISA all increase with axial elongation. ACA is highly correlated with deeper ACD.

The opposing effect of acute and chronic Toxoplasma gondii infection on tumor development.

BACKGROUND: The interplay between Toxoplasma gondii infection and tumor development is intriguing and not yet fully understood. Some studies showed that T. gondii reversed tumor immune suppression, while some reported the opposite, stating that T. gondii infection promoted tumor growth. METHODS: We created three mouse models to investigate the interplay between T. gondii and tumor. Model I aimed to study the effect of tumor growth on T. gondii infection by measuring cyst number and size. Models II and III were used to investigate the effect of different stages of T. gondii infection on tumor development via flow cytometry and bioluminescent imaging. Mouse strains (Kunming, BALB/c, and C57BL/6J) with varying susceptibilities to tumors were used in the study. RESULTS: The size and number of brain cysts in the tumor-infected group were significantly higher, indicating that tumor presence promotes T. gondii growth in the brain. Acute T. gondii infection, before or after tumor cell introduction, decreased tumor growth manifested by reduced bioluminescent signal and tumor size and weight. In the tumor microenvironment, CD4+ and CD8+ T cell number, including their subpopulations (cytotoxic CD8+ T cells and Th1 cells) had a time-dependent increase in the group with acute T. gondii infection compared with the group without infection. However, in the peripheral blood, the increase of T cells, including cytotoxic CD8+ T cells and Th1 cells, persisted 25 days after Lewis lung carcinoma (LLC) cell injection in the group with acute T. gondii. Chronic T. gondii infection enhanced tumor growth as reflected by increase in tumor size and weight. The LLC group with chronic T. gondii infection exhibited decreased percentages of cytotoxic CD8+ T cells and Th1 cells 25 days post-LLC injection as compared with the LLC group without T. gondii infection. At week 4 post-LLC injection, chronic T. gondii infection increased tumor formation rate [odds ratio (OR) 1.71] in both KM and BALB/c mice. CONCLUSIONS: Our research elucidates the dynamics between T. gondii infection and tumorigenesis. Tumor-induced immune suppression promoted T. gondii replication in the brain. Acute and chronic T. gondii infection had opposing effects on tumor development.

Characterization of a novel cold-adapted GH1 ß-glucosidase from Psychrobacillus glaciei and its application in the hydrolysis of soybean isoflavone glycosides.

The novel ß-glucosidase gene (pgbgl1) of glycoside hydrolase (GH) family 1 from the psychrotrophic bacterium Psychrobacillus glaciei sp. PB01 was successfully expressed in Escherichia coli BL21 (DE3). The deduced PgBgl1 contained 447 amino acid residues with a calculated molecular mass of 51.4 kDa. PgBgl1 showed its maximum activity at pH 7.0 and 40 °C, and still retained over 10% activity at 0 °C, suggesting that the recombinant PgBgl1 is a cold-adapted enzyme. The substrate specificity, Km, Vmax, and Kcat/Km for the p-Nitrophenyl-ß-D-glucopyranoside (pNPG) as the substrate were 1063.89 U/mg, 0.36 mM, 1208.31 U/mg and 3871.92/s, respectively. Furthermore, PgBgl1 demonstrated remarkable stimulation of monosaccharides such as glucose, xylose, and galactose, as well as NaCl. PgBgl1 also demonstrated a high capacity to convert the primary soybean isoflavone glycosides (daidzin, genistin, and glycitin) into their respective aglycones. Overall, PgBgl1 exhibited high catalytic activity towards aryl glycosides, suggesting promising application prospects in the food, animal feed, and pharmaceutical industries.

Metabolomics analysis reveals enhanced salt tolerance in maize through exogenous Valine-Threonine-Isoleucine-Aspartic acid application.

Salt stress is a well-known abiotic constraint that hampers crop productivity, affecting more than 424 million hectares of topsoil worldwide. Applying plant growth regulators externally has proven effective in enhancing crop resilience to salt stress. Previous metabolomics studies revealed an accumulation of Valine-Threonine-Isoleucine-Aspartic acid (VTID) in salt-stressed maize seedlings, suggesting its potential to assist maize adaptation to salt stress. To explore the effectiveness of VTID in enhancing salt tolerance in maize, 10 nM VTID was applied to salt-stressed maize seedlings. The results showed a remarkable 152.29% increase in plant height and a 122.40% increase in fresh weight compared to salt-stressed seedlings. Moreover, the addition of VTID enhanced the activity of antioxidant enzymes, specifically superoxide dismutase (SOD) and catalase (CAT), while reducing the level of malondialdehyde (MDA), a marker of oxidative stress. Additionally, VTID supplementation resulted in a significant increase in osmoregulatory substances such as proline. Metabolomic analysis revealed substantial changes in the metabolite profile of maize seedlings when treated with VTID during salt stress. Differential metabolites (DMs) analysis revealed that the identified DMs primarily belonged to lipids and lipid-like molecules. The receiver operating characteristic curve and linear regression analysis determined a correlation between isodolichantoside and the height of maize seedlings under salt-stress conditions. In conclusion, these findings validate that VTID effectively regulates tolerance in maize seedlings and offers valuable insights into the potential of short peptides for mitigating salt stress.

Differential transcriptome study on the damage of testicular tissues caused by chronic infection of T. gondii in mice.

BACKGROUND: Toxoplasma gondii is an intracellular protozoan parasite that is widely distributed in humans and warm-blooded animals. T. gondii chronic infections can cause toxoplasmic encephalopathy, adverse pregnancy, and male reproductive disorders. In male reproduction, the main function of the testis is to provide a stable place for spermatogenesis and immunological protection. The disorders affecting testis tissue encompass abnormalities in the germ cell cycle, spermatogenic retardation, or complete cessation of sperm development. However, the mechanisms of interaction between T. gondii and the reproductive system is unclear. The aims were to study the expression levels of genes related to spermatogenesis, following T. gondii infection, in mouse testicular tissue. METHODS: RNA-seq sequencing was carried out on mouse testicular tissues from mice infected or uninfected with the T. gondii type II Prugniaud (PRU) strain and validated in combination with real-time quantitative PCR and immunofluorescence assays. RESULTS: The results showed that there were 250 significant differentially expressed genes (DEGs) (P < 0.05, |log2fold change| â‰§ 1). Bioinformatics analysis showed that 101 DEGs were annotated to the 1696 gene ontology (GO) term. While there was a higher number of DEGs in the biological process classification as a whole, the GO enrichment revealed a significant presence of DEGs in the cellular component classification. The Arhgap18 and Syne1 genes undergo regulatory changes following T. gondii infection, and both were involved in shaping the cytoskeleton of the blood-testis barrier (BTB). The number of DEGs enriched in the MAPK signaling pathway, the ERK1/2 signaling pathway, and the JNK signaling pathway were significant. The PTGDS gene is located in the Arachidonic acid metabolism pathway, which plays an important role in the formation and maintenance of BTB in the testis. The expression of PTGDS is downregulated subsequent to T. gondii infection, potentially exerting deleterious effects on the integrity of the BTB and the spermatogenic microenvironment within the testes. CONCLUSIONS: Overall, our research provides in-depth insights into how chronic T. gondii infection might affect testicular tissue and potentially impact male fertility. These findings offer a new perspective on the impact of T. gondii infection on the male reproductive system.

Enhancement of microbial community dynamics and metabolism in compost through ammonifying cultures inoculation.

The efficient use of livestock and poultry manure waste has become a global challenge, with microorganisms playing an important role. To investigate the impact of novel ammonifying microorganism cultures (NAMC) on microbial community dynamics and carbon and nitrogen metabolism, five treatments [5% (v/w) sterilized distilled water, Amm-1, Amm-2, Amm-3, and Amm-4] were applied to cow manure compost. Inoculation with NAMC improved the structure of bacterial and fungal communities, enriched the populations of the functional microorganisms, enhanced the role of specific microorganisms, and promoted the formation of tight modularity within the microbial network. Further functional predictions indicated a significant increase in both carbon metabolism (CMB) and nitrogen metabolism (NMB). During the thermophilic phase, inoculated NAMC treatments boosted carbon metabolism annotation by 10.55%-33.87% and nitrogen metabolism annotation by 26.69%-63.11. Structural equation modeling supported the NAMC-mediated enhancement of NMB and CMB. In conclusion, NAMC inoculation, particularly with Amm-4, enhanced the synergistic interaction between bacteria and fungi. This collaboration promoted enzymatic catabolic and synthetic processes, resultng in positive feedback loops with the endogenous microbial community. Understanding these mechanisms not only unravels how ammonifying microorganisms influence microbial communities but also paves the way for the development of the composting industry and global waste management practices.

MCT1-mediated transport of valeric acid promotes porcine preimplantation embryo development by improving mitochondrial function and inhibiting the autophagic AMPK-ULK1 pathway.

Oocytes and embryos are highly sensitive to environmental stress in vivo and in vitro. During in vitro culture, many stressful conditions can affect embryo quality and viability, leading to adverse clinical outcomes such as abortion and congenital abnormalities. In this study, we found that valeric acid (VA) increased the mitochondrial membrane potential and ATP content, decreased the level of reactive oxygen species that the mitochondria generate, and thus improved mitochondrial function during early embryonic development in pigs. VA decreased expression of the autophagy-related factors LC3B and BECLIN1. Interestingly, VA inhibited expression of autophagy-associated phosphorylation-adenosine monophosphate-activated protein kinase (p-AMPK), phosphorylation-UNC-51-like autophagy-activated kinase 1 (p-ULK1, Ser555), and ATG13, which reduced apoptosis. Short-chain fatty acids (SCFAs) can signal through G-protein-coupled receptors on the cell membrane or enter the cell directly through transporters. We further show that the monocarboxylate transporter 1 (MCT1) was necessary for the effects of VA on embryo quality, which provides a new molecular perspective of the pathway by which SCFAs affect embryos. Importantly, VA significantly inhibited the AMPK-ULK1 autophagic signaling pathway through MCT1, decreased apoptosis, increased expression of embryonic pluripotency genes, and improved embryo quality.

Clinical implications and mechanism of CST1 in gastric carcinoma based on database screening.

Gastric cancer (GC) remains one of the most common malignant tumours worldwide, with extremely high morbidity and mortality rates. An in-depth understanding of the pathogenesis of GC is key to the future diagnosis and treatment of GC. In this study, we analysed the differentially expressed genes (DEGs) in gastric carcinoma (GC) through GEO database and their clinical implications, with the aim of providing clinical reference and guidance. We selected the GSE118916 dataset for bioinformatics analysis and identified a total of 3231 DEGs. Keywords, including extracellular region, vesicle, protein digestion and absorption, ECM-receptor interaction, etc., of DEGs can be seen by the GO and KEGG enrichment analysis. The online database determined up-regulated CST1 in GC and some other tumors, as well as a close connection between CST1 with patient prognosis. Subsequently, we collected a number of GC clinical cases and examined the expression of CST1, which was seen to be highly expressed in GC, with a favorable diagnostic effect on the occurrence of GC (P<0.05) and a strong correlation with TNM stage, tumor invasion, tumor diameter and differentiation (P<0.05). In other words, CST1 is closely related to the occurrence and development of GC, and has the potential to be a breakthrough in the diagnosis and treatment of GC in the future.

Calmodulin-like 5 promotes PEDV replication by regulating late-endosome synthesis and innate immune response.

The infection caused by porcine epidemic diarrhea virus (PEDV) is associated with high mortality in piglets worldwide. Host factors involved in the efficient replication of PEDV, however, remain largely unknown. Our recent proteomic study in the virus-host interaction network revealed a significant increase in the accumulation of CALML5 (EF-hand protein calmodulin-like 5) following PEDV infection. A further study unveiled a biphasic increase of CALML5 in 2 and 12 â€‹h after viral infection. Similar trends were observed in the intestines of piglets in the early and late stages of the PEDV challenge. Moreover, CALML5 depletion reduced PEDV mRNA and protein levels, leading to a one-order-of-magnitude decrease in virus titer. At the early stage of PEDV infection, CALML5 affected the endosomal trafficking pathway by regulating the expression of endosomal sorting complex related cellular proteins. CALML5 depletion also suppressed IFN-ß and IL-6 production in the PEDV-infected cells, thereby indicating its involvement in negatively regulating the innate immune response. Our study reveals the biological function of CALML5 in the virology field and offers new insights into the PEDV-host cell interaction.

Identification and validation of a prognostic anoikis-related gene signature in papillary thyroid carcinoma by integrated analysis of single-cell and bulk RNA-sequencing.

Papillary thyroid carcinoma (PTC) prognosis may be deteriorated due to the metastases, and anoikis palys an essential role in the tumor metastasis. However, the potential effect of anoikis-related genes on the prognosis of PTC was unclear. The mRNA and clinical information were obtained from the cancer genome atlas database. Hub genes were identified and risk model was constructed using Cox regression analysis. Kaplan-Meier (K-M) curve was applied for the survival analysis. Immune infiltration and immune therapy response were calculated using CIBERSORT and TIDE. The identification of cell types and cell interaction was performed by Seurat, SingleR and CellChat packages. GO, KEGG, and GSVA were applied for the enrichment analysis. Protein-protein interaction network was constructed in STRING and Cytoscape. Drug sensitivity was assessed in GSCA. Based on bulk RNA data, we identified 4 anoikis-related risk signatures, which were oncogenes, and constructed a risk model. The enrichment analysis found high risk group was enriched in some immune-related pathways. High risk group had higher infiltration of Tregs, higher TIDE score and lower levels of monocytes and CD8 T cells. Based on scRNA data, we found that 4 hub genes were mainly expressed in monocytes and macrophages, and they interacted with T cells. Hub genes were significantly related to immune escape-related genes. Drug sensitivity analysis suggested that cyclin dependent kinase inhibitor 2A may be a better chemotherapy target. We constructed a risk model which could effectively and steadily predict the prognosis of PTC. We inferred that the immune escape may be involved in the development of PTC.

Advances in myopia control strategies for children.

Myopia has long been a global threat to public health. Timely interventions are likely to reduce the risk of vision-threatening complications. There are both established and rapidly evolving therapeutic approaches to slow myopia progression and/or delay its onset. The effective methods for slowing myopia progression include atropine eye-drops, defocus incorporated multiple segments (DIMS) spectacle lenses, spectacle lenses with highly aspherical lenslets target (HALT), diffusion optics technology (DOT) spectacle lenses, red light therapy (RLT), multifocal soft contact lenses and orthokeratology. Among these, 0.05% atropine, HALT lenses, RLT and +3.00 peripheral addition soft contact lenses yield over 60% reduction in myopia progression, whereas DIMS, DOT and MiSight contact lenses demonstrate at least 50% myopia control efficacy. 0.05% atropine demonstrates a more optimal balance of efficacy and safety than 0.01%. The efficacy of 0.01% atropine has not been consistent and requires further validation across diverse ethnicities. Combining atropine 0.01% with orthokeratology or DIMS spectacles yields better outcomes than using these interventions as monotherapies. Increased outdoor time is an effective public health strategy for myopia prevention while recent studies suggest that 0.05% low-concentration atropine and RLT therapy have promising potential as clinical myopia prevention interventions for high-risk groups. Myopia control spectacle lenses, being the least invasive, are safe for long-term use. However, when considering other approaches, it is essential to ensure proper instruction and regular follow-ups to maintain safety and monitor any potential complications. Ultimately, significant advances have been made in myopia control strategies, many of which have shown meaningful clinical outcomes. However, regular use and adequate safety monitoring over extended durations are imperative to foster confidence that can only come from extensive clinical experience.

ZFYVE19 deficiency: a ciliopathy involving failure of cell division, with cell death.

BACKGROUND AND AIMS: Variants in ZFYVE19 underlie a disorder characterised by progressive portal fibrosis, portal hypertension and eventual liver decompensation. We aim to create an animal model to elucidate the pathogenic mechanism. METHODS: Zfyve19 knockout (Zfyve19-/- ) mice were generated and exposed to different liver toxins. Their livers were characterised at the tissue, cellular and molecular levels. Findings were compared with those in wild-type mice and in ZFYVE19-deficient patients. ZFYVE19 knockout and knockdown retinal pigment epithelial-1 cells and mouse embryonic fibroblasts were generated to study cell division and cell death. RESULTS: The Zfyve19-/- mice were normal overall, particularly with respect to hepatobiliary features. However, when challenged with α-naphthyl isothiocyanate, Zfyve19-/- mice developed changes resembling those in ZFYVE19-deficient patients, including elevated serum liver injury markers, increased numbers of bile duct profiles with abnormal cholangiocyte polarity and biliary fibrosis. Failure of cell division, centriole and cilia abnormalities, and increased cell death were observed in knockdown/knockout cells. Increased cell death and altered mRNA expression of cell death-related signalling pathways was demonstrated in livers from Zfyve19-/- mice and patients. Transforming growth factor-ß (TGF-ß) and Janus kinase-Signal Transducer and Activator of Transcription 3 (JAK-STAT3) signalling pathways were upregulated in vivo, as were chemokines such as C-X-C motif ligands 1, 10 and 12. CONCLUSIONS: Our findings demonstrated that ZFYVE19 deficiency is a ciliopathy with novel histological features. Failure of cell division with ciliary abnormalities and cell death activates macrophages and may thus lead to biliary fibrosis via TGF-ß pathway in the disease.

Progesterone Enhances Niraparib Efficacy in Ovarian Cancer by Promoting Palmitoleic-Acid-Mediated Ferroptosis.

Poly (adenosine 5'-diphosphate-ribose) polymerase inhibitors (PARPi) are increasingly important in the treatment of ovarian cancer. However, more than 40% of BRCA1/2-deficient patients do not respond to PARPi, and BRCA wild-type cases do not show obvious benefit. In this study, we demonstrated that progesterone acted synergistically with niraparib in ovarian cancer cells by enhancing niraparib-mediated DNA damage and death regardless of BRCA status. This synergy was validated in an ovarian cancer organoid model and in vivo experiments. Furthermore, we found that progesterone enhances the activity of niraparib in ovarian cancer through inducing ferroptosis by up-regulating palmitoleic acid and causing mitochondrial damage. In clinical cohort, it was observed that progesterone prolonged the survival of patients with ovarian cancer receiving PARPi as second-line maintenance therapy, and high progesterone receptor expression combined with low glutathione peroxidase 4 (GPX4) expression predicted better efficacy of PARPi in patients with ovarian cancer. These findings not only offer new therapeutic strategies for PARPi poor response ovarian cancer but also provide potential molecular markers for predicting the PARPi efficacy.

Prevotella copri promotes vascular calcification via lipopolysaccharide through activation of NF-κB signaling pathway.

Emerging evidence indicates that alteration of gut microbiota plays an important role in chronic kidney disease (CKD)-related vascular calcification (VC). We aimed to investigate the specific gut microbiota and the underlying mechanism involved in CKD-VC. We identified an increased abundance of Prevotella copri (P. copri) in the feces of CKD rats (induced by using 5/6 nephrectomy followed by a high calcium and phosphate diet) with aortic calcification via amplicon sequencing of 16S rRNA genes. In patients with CKD, we further confirmed a positive correlation between abundance of P. copri and aortic calcification scores. Moreover, oral administration of live P. copri aggravated CKD-related VC and osteogenic differentiation of vascular smooth muscle cells in vivo, accompanied by intestinal destruction, enhanced expression of Toll-like receptor-4 (TLR4), and elevated lipopolysaccharide (LPS) levels. In vitro and ex vivo experiments consistently demonstrated that P. copri-derived LPS (Pc-LPS) accelerated high phosphate-induced VC and VSMC osteogenic differentiation. Mechanistically, Pc-LPS bound to TLR4, then activated the nuclear factor κB (NF-κB) and nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome signals during VC. Inhibition of NF-κB reduced NLRP3 inflammasome and attenuated Pc-LPS-induced VSMC calcification. Our study clarifies a novel role of P. copri in CKD-related VC, by the mechanisms involving increased inflammation-regulating metabolites including Pc-LPS, and activation of the NF-κB/NLRP3 signaling pathway. These findings highlight P. copri and its-derived LPS as potential therapeutic targets for VC in CKD.

Improving the Prognostic Evaluation Precision of Hospital Outcomes for Heart Failure Using Admission Notes and Clinical Tabular Data: Multimodal Deep Learning Model.

BACKGROUND: Clinical notes contain contextualized information beyond structured data related to patients' past and current health status. OBJECTIVE: This study aimed to design a multimodal deep learning approach to improve the evaluation precision of hospital outcomes for heart failure (HF) using admission clinical notes and easily collected tabular data. METHODS: Data for the development and validation of the multimodal model were retrospectively derived from 3 open-access US databases, including the Medical Information Mart for Intensive Care III v1.4 (MIMIC-III) and MIMIC-IV v1.0, collected from a teaching hospital from 2001 to 2019, and the eICU Collaborative Research Database v1.2, collected from 208 hospitals from 2014 to 2015. The study cohorts consisted of all patients with critical HF. The clinical notes, including chief complaint, history of present illness, physical examination, medical history, and admission medication, as well as clinical variables recorded in electronic health records, were analyzed. We developed a deep learning mortality prediction model for in-hospital patients, which underwent complete internal, prospective, and external evaluation. The Integrated Gradients and SHapley Additive exPlanations (SHAP) methods were used to analyze the importance of risk factors. RESULTS: The study included 9989 (16.4%) patients in the development set, 2497 (14.1%) patients in the internal validation set, 1896 (18.3%) in the prospective validation set, and 7432 (15%) patients in the external validation set. The area under the receiver operating characteristic curve of the models was 0.838 (95% CI 0.827-0.851), 0.849 (95% CI 0.841-0.856), and 0.767 (95% CI 0.762-0.772), for the internal, prospective, and external validation sets, respectively. The area under the receiver operating characteristic curve of the multimodal model outperformed that of the unimodal models in all test sets, and tabular data contributed to higher discrimination. The medical history and physical examination were more useful than other factors in early assessments. CONCLUSIONS: The multimodal deep learning model for combining admission notes and clinical tabular data showed promising efficacy as a potentially novel method in evaluating the risk of mortality in patients with HF, providing more accurate and timely decision support.

Hydrogel-exosome system in tissue engineering: A promising therapeutic strategy.

Characterized by their pivotal roles in cell-to-cell communication, cell proliferation, and immune regulation during tissue repair, exosomes have emerged as a promising avenue for "cell-free therapy" in clinical applications. Hydrogels, possessing commendable biocompatibility, degradability, adjustability, and physical properties akin to biological tissues, have also found extensive utility in tissue engineering and regenerative repair. The synergistic combination of exosomes and hydrogels holds the potential not only to enhance the efficiency of exosomes but also to collaboratively advance the tissue repair process. This review has summarized the advancements made over the past decade in the research of hydrogel-exosome systems for regenerating various tissues including skin, bone, cartilage, nerves and tendons, with a focus on the methods for encapsulating and releasing exosomes within the hydrogels. It has also critically examined the gaps and limitations in current research, whilst proposed future directions and potential applications of this innovative approach.

Integration of transcriptome, gut microbiota, and physiology reveals toxic responses of the red claw crayfish (Cherax quadricarinatus) to imidacloprid.

Imidacloprid enters the water environment through rainfall and causes harm to aquatic crustaceans. However, the potential chronic toxicity mechanism of imidacloprid in crayfish has not been comprehensively studied. In this study, red claw crayfish (Cherax quadricarinatus) were exposed to 11.76, 35.27, or 88.17 µg/L imidacloprid for 30 days, and changes in the physiology and biochemistry, gut microbiota, and transcriptome of C. quadricarinatus and the interaction between imidacloprid, gut microbiota, and genes were studied. Imidacloprid induced oxidative stress and decreased growth performance in crayfish. Imidacloprid exposure caused hepatopancreas damage and decreased serum immune enzyme activity. Hepatopancreatic and plasma acetylcholine decreased significantly in the 88.17 µg/L group. Imidacloprid reduced the diversity of the intestinal flora, increased the abundance of harmful flora, and disrupted the microbiota function. Transcriptomic analysis showed that the number of up-and-down-regulated differentially expressed genes (DEGs) increased significantly with increasing concentrations of imidacloprid. DEG enrichment analyses indicated that imidacloprid inhibits neurotransmitter transduction and immune responses and disrupts energy metabolic processes. Crayfish could alleviate imidacloprid stress by regulating antioxidant and detoxification-related genes. A high correlation was revealed between GST, HSPA1s, and HSP90 and the composition of gut microorganisms in crayfish under imidacloprid stress. This study highlights the negative effects and provides detailed sequencing data from transcriptome and gut microbiota to enhance our understanding of the molecular toxicity of imidacloprid in crustaceans.

Epigenetic regulation of FOXI2 promotes clear cell renal cell carcinoma progression.

In recent decades, substantial advancements in epigenetics have unveiled a profound understanding of its mechanisms in tumorigenesis and have offered promising strategies for epigenetic therapy in cancer patients. In our study, through bioinformatics analysis, we discovered a significant downregulation and hypermethylation of FOXI2 in clear cell renal cell carcinoma (ccRCC), while the expression in chromophobe cell carcinoma (chRCC) exhibited the opposite trend. Moreover, we established a strong correlation between FOXI2 expression levels and the prognosis of ccRCC. Gene enrichment analysis and cell function experiments unequivocally demonstrate that FOXI2 possesses the capability to induce cell cycle arrest and inhibit cell proliferation. Our research findings demonstrate that the expression of FOXI2 in ccRCC is under the regulation of promoter hypermethylation. Furthermore, in vitro experiments have conclusively shown that the overexpression of FOXI2 induces cell cycle arrest and inhibits cell proliferation.