Bioinspired Three-Component System to Prepare Full-Color Functional Biomimetic Pigments.

Nature provides a great source of inspiration for the development of sustainable materials with excellent properties, among which melanin with optical, electronic, and radiation protection properties are considered to be promising coloring materials. However, compared to chemical pigments, the single color, complex oxidation process, and poor solubility of natural melanin strongly limit their further applications. Here, we introduce a series of melanin-like polymeric pigments with amino acid-encoded physicochemical properties by a simple three-component reaction system. Our protocol enables artificial control of the chromophore structures through the rational design of the substrates and dopants, thereby combining the safety and functionality of biopigments with the color richness of chemical dyes. Similar to the photoprotective effect of natural melanin, the polymeric pigments showed excellent antioxidant activity in reducing free radicals and have the advantages of iridescent color, strong tinting strength, stability, and affordability. Furthermore, due to their ability to dye substrates, these biomimetic are expected to become new low-cost bioactive chromophores and find various biochemical applications such as in clothing and hair dyeing, food addition, and anticounterfeiting detection.

Role of gut microbiota in doxorubicin-induced cardiotoxicity: from pathogenesis to related interventions.

Doxorubicin (DOX) is a broad-spectrum and highly efficient anticancer agent, but its clinical implication is limited by lethal cardiotoxicity. Growing evidences have shown that alterations in intestinal microbial composition and function, namely dysbiosis, are closely linked to the progression of DOX-induced cardiotoxicity (DIC) through regulating the gut-microbiota-heart (GMH) axis. The role of gut microbiota and its metabolites in DIC, however, is largely unelucidated. Our review will focus on the potential mechanism between gut microbiota dysbiosis and DIC, so as to provide novel insights into the pathophysiology of DIC. Furthermore, we summarize the underlying interventions of microbial-targeted therapeutics in DIC, encompassing dietary interventions, fecal microbiota transplantation (FMT), probiotics, antibiotics, and natural phytochemicals. Given the emergence of microbial investigation in DIC, finally we aim to point out a novel direction for future research and clinical intervention of DIC, which may be helpful for the DIC patients.

Clinical Activity of Selpercatinib in RET-mutant Pheochromocytoma.

INTRODUCTION: Activating RET alterations have been reported in a variety of solid tumors, including pheochromocytoma where they occur both sporadically and as part of familial multiple endocrine neoplasia type 2 (MEN2) syndromes. Selpercatinib is a first-in-class, highly selective, and potent small molecule RET kinase inhibitor that has demonstrated marked and durable anti-tumor activity in diverse RET-activated solid tumors in the LIBRETTO-001 study (NCT03157128). METHODS: We describe the first six pheochromocytoma cases treated with selpercatinib in the LIBRETTO-001 study. RESULTS: Of the six patients (one sporadic and five reported as part of MEN2 syndromes) in this case report, four had a partial response/complete response and two had stable disease per independent review committee. Treatment duration ranged from 9.2 months to more than 56.4 months. The safety profile of treatment was consistent with selpercatinib in other indications. CONCLUSION: These data support selpercatinib as an effective therapy against RET-mutant pheochromocytoma, adding to the diversity of RET-activated tumor types that may benefit from targeted RET inhibition.

Galvanic Replacement Synthesis of VOx@EGaIn-PEG Core-Shell Nanohybrids for Peroxidase Mimics.

The development of high-performance biosensors is a key focus in the nanozyme field, but the current limitations in biocompatibility and recyclability hinder their broader applications. Herein, we address these challenges by constructing core-shell nanohybrids with biocompatible poly(ethylene glycol) (PEG) modification using a galvanic replacement reaction between orthovanadate ions and liquid metal (LM) (VOx@EGaIn-PEG). By leveraging the excellent charge transfer properties and the low band gap of the LM surface oxide, the VOx@EGaIn-PEG heterojunction can effectively convert hydrogen peroxide into hydroxyl radicals, demonstrating excellent peroxidase-like activity and stability (Km = 490 µM, vmax = 1.206 µM/s). The unique self-healing characteristics of LM further enable the recovery and regeneration of VOx@EGaIn-PEG nanozymes, thereby significantly reducing the cost of biological detection. Building upon this, we developed a nanozyme colorimetric sensor suitable for biological systems and integrated it with a smartphone to create an efficient quantitative detection platform. This platform allows for the convenient and sensitive detection of glucose in serum samples, exhibiting a good linear relationship in the range of 10-500 µM and a detection limit of 2.35 µM. The remarkable catalytic potential of LM, combined with its biocompatibility and regenerative properties, offers valuable insights for applications in catalysis and biomedical fields.

Decoupling the mutual promotion of inflammation and oxidative stress mitigates cognitive decline and depression-like behavior in rmTBI mice by promoting myelin renewal and neuronal survival.

BACKGROUND: Repetitive mild traumatic brain injury (rmTBI) can lead to somatic, emotional, and cognitive symptoms that persist for years after the initial injury. Although the ability of various treatments to promote recovery after rmTBI has been explored, the optimal time window for early intervention after rmTBI is unclear. Previous research has shown that hydrogen-rich water (HRW) can diffuse through the blood-brain - barrier, attenuate local oxidative stress, and reduce neuronal apoptosis in patients with severe traumatic brain injury. However, research on the effect of HRW on rmTBI is scarce. AIMS: The objectives of this study were to explore the following changes after rmTBI and HRW treatment: (i) temporal changes in inflammasome activation and oxidative stress-related protein expression through immunoblotting, (ii) temporal changes in neuron/myelin-related metabolite concentrations in vivo through magnetic resonance spectroscopy, (iii) myelin structural changes in late-stage rmTBI via immunofluorescence, and (iv) postinjury anxiety/depression-like behaviors and spatial learning and memory impairment. RESULTS: NLRP-3 expression in the rmTBI group was elevated at 7 and 14 DPI, and inflammasome marker levels returned to normal at 30 DPI. Oxidative stress persisted throughout the first month postinjury. HRW replacement significantly decreased Nrf2 expression in the prefrontal cortex and hippocampal CA2 region at 14 and 30 DPI, respectively. Edema and local gliosis in the hippocampus and restricted diffusion in the thalamus were observed on MR-ADC images. The tCho/tCr ratio in the rmTBI group was elevated, and the tNAA/tCr ratio was decreased at 30 DPI. Compared with the mice in the other groups, the mice in the rmTBI group spent more time exploring the open arms in the elevated plus maze (P < 0.05) and were more active in the maze (longer total distance traveled). In the sucrose preference test, the rmTBI group exhibited anhedonia. In the Morris water maze test, the latency to find the hidden platform in the rmTBI group was longer than that in the sham and HRW groups (P < 0.05). CONCLUSION: Early intervention with HRW can attenuate inflammasome assembly and reduce oxidative stress after rmTBI. These changes may restore local oligodendrocyte function, promote myelin repair, prevent axonal damage and neuronal apoptosis, and alleviate depression-like behavior and cognitive impairment.

Comprehensive bioinformatics analysis and systems biology approaches to identify the interplay between COVID-19 and pericarditis.

Background: Increasing evidence indicating that coronavirus disease 2019 (COVID-19) increased the incidence and related risks of pericarditis and whether COVID-19 vaccine is related to pericarditis has triggered research and discussion. However, mechanisms behind the link between COVID-19 and pericarditis are still unknown. The objective of this study was to further elucidate the molecular mechanisms of COVID-19 with pericarditis at the gene level using bioinformatics analysis. Methods: Genes associated with COVID-19 and pericarditis were collected from databases using limited screening criteria and intersected to identify the common genes of COVID-19 and pericarditis. Subsequently, gene ontology, pathway enrichment, protein-protein interaction, and immune infiltration analyses were conducted. Finally, TF-gene, gene-miRNA, gene-disease, protein-chemical, and protein-drug interaction networks were constructed based on hub gene identification. Results: A total of 313 common genes were selected, and enrichment analyses were performed to determine their biological functions and signaling pathways. Eight hub genes (IL-1ß, CD8A, IL-10, CD4, IL-6, TLR4, CCL2, and PTPRC) were identified using the protein-protein interaction network, and immune infiltration analysis was then carried out to examine the functional relationship between the eight hub genes and immune cells as well as changes in immune cells in disease. Transcription factors, miRNAs, diseases, chemicals, and drugs with high correlation with hub genes were predicted using bioinformatics analysis. Conclusions: This study revealed a common gene interaction network between COVID-19 and pericarditis. The screened functional pathways, hub genes, potential compounds, and drugs provided new insights for further research on COVID-19 associated with pericarditis.

[Determination of nine aromatic amines in water by cloud point extraction-gas chromatography-mass spectrometry].

Aromatic amines are a class of compounds bearing amino groups on their benzene rings; these compounds are important raw materials for the industrial production of rubber chemicals, pesticides, dyes, pharmaceuticals, photosensitive chemicals, and agricultural chemicals. Research has revealed that some aromatic amines teratogenetic, carcinogenic, and mutagenic properties. Given the high toxicity and potential harm caused by aromatic amines, monitoring their levels in water sources is critical. Aromatic amines are among the 14 strategic environmental pollutants blacklisted in China, and assessing their exposure levels is essential for protecting human health and the environment. At present, the standard method for detecting aromatic amines in water is liquid-liquid extraction-gas chromatography-mass spectrometry (LLE-GC-MS). However, this method has the disadvantages of large sample size requirement, complex operation, long analysis time, and high reagent consumption. In this study, instead of traditional LLE technology, cloud point extraction (CPE) technology was used in combination with GC-MS to establish an efficient, sensitive, and environment-friendly method for the detection of nine aromatic amines, namely, 2-chloramine, 3-chloramine, 4-chloramine, 2-nitroaniline, 3-nitroaniline, 4-nitroaniline, 1-naphthylamine, 2-naphthylamine, and 4-aminobenzene, in water. Triton X-114 was used as the extraction agent. The main experimental parameters were optimized using a single-factor optimization method. The aromatic amines in various water samples were quantitatively analyzed using GC-MS. The nine aromatic amines were separated on a DB-35 MS capillary column (30 m×0.25 mm×0.25 µm). The mass spectrometer was operated in selected ion monitoring (SIM) mode, and quantitative analysis was performed using the internal standard method. The results demonstrated that all nine aromatic amines could be completely separated within 16 min and had good linearities within accurate mass concentration ranges, with correlation coefficients (R2) greater than 0.998. The limits of detection (LODs) and quantification (LOQs) of these aromatic amines in water were 0.12-0.48 and 0.40-1.60 µg/L, respectively. The accuracy and precision of the method were assessed via the determination of aromatic amines in surface water of drinking water sources, offshore seawater, wastewater of the typical printing and dyeing industry at levels of 2.0 and 10.0 µg/L. The recoveries of the aromatic amines in surface water of drinking water sources were 81.1%-109.8%, with intra-day and inter-day relative standard deviations (RSDs) of 0.7%-5.2% (n=6) and 1.6%-6.2% (n=3), respectively. The recoveries of the aromatic amines in offshore seawater were 83.0%-115.8%, with intra-day RSDs (n=6) of 1.5%-8.6% and inter-day RSDs (n=3) of 2.4%-12.2%. The recoveries of the nine aromatic amines in wastewater of the typical printing and dyeing industry were 91.0%-120.0%, with intra-day RSDs (n=6) of 2.9%-12.9% and inter-day RSDs (n=3) of 2.5%-13.1%. The established method was used to detect nine aromatic amines in actual water samples. No aromatic amines were detected in the surface water of drinking water sources or offshore seawater samples. However, 2-chloramine, 4-chloramine, and 4-aminobenzene, which are frequently used in the printing and dyeing industry, were detected in the wastewater of the typical printing and dyeing industry samples. The proposed method offers the advantages of simple operation, high sensitivity, low cost, low organic reagent requirement, and good repeatability. Thus, this method provides reliable technical support for studying the residual status and environmental behavior of aromatic amines in water.

Enhanced Artificial Intelligence Strategies in Renal Oncology: Iterative Optimization and Comparative Analysis of GPT 3.5 Versus 4.0.

BACKGROUND: The rise of artificial intelligence (AI) in medicine has revealed the potential of ChatGPT as a pivotal tool in medical diagnosis and treatment. This study assesses the efficacy of ChatGPT versions 3.5 and 4.0 in addressing renal cell carcinoma (RCC) clinical inquiries. Notably, fine-tuning and iterative optimization of the model corrected ChatGPT's limitations in this area. METHODS: In our study, 80 RCC-related clinical questions from urology experts were posed three times to both ChatGPT 3.5 and ChatGPT 4.0, seeking binary (yes/no) responses. We then statistically analyzed the answers. Finally, we fine-tuned the GPT-3.5 Turbo model using these questions, and assessed its training outcomes. RESULTS: We found that the average accuracy rates of answers provided by ChatGPT versions 3.5 and 4.0 were 67.08% and 77.50%, respectively. ChatGPT 4.0 outperformed ChatGPT 3.5, with a higher accuracy rate in responses (p < 0.05). By counting the number of correct responses to the 80 questions, we then found that although ChatGPT 4.0 performed better (p < 0.05), both versions were subject to instability in answering. Finally, by fine-tuning the GPT-3.5 Turbo model, we found that the correct rate of responses to these questions could be stabilized at 93.75%. Iterative optimization of the model can result in 100% response accuracy. CONCLUSION: We compared ChatGPT versions 3.5 and 4.0 in addressing clinical RCC questions, identifying their limitations. By applying the GPT-3.5 Turbo fine-tuned model iterative training method, we enhanced AI strategies in renal oncology. This approach is set to enhance ChatGPT's database and clinical guidance capabilities, optimizing AI in this field.

Analysis and Validation of Critical Signatures and Immune Cell Infiltration Characteristics in Doxorubicin-Induced Cardiotoxicity by Integrating Bioinformatics and Machine Learning.

Purpose: Doxorubicin-induced cardiotoxicity (DIC) is a severe side reaction in cancer chemotherapy that greatly impacts the well-being of cancer patients. Currently, there is still an insufficiency of effective and reliable biomarkers in the field of clinical practice for the early detection of DIC. This study aimed to determine and validate the potential diagnostic and predictive values of critical signatures in DIC. Methods: We obtained high-throughput sequencing data from the GEO database and performed data analysis and visualization using R software, GO, KEGG and Cytoscape. Machine learning methods and weighted gene coexpression network (WGCNA) were used to identify key genes for diagnostic model construction. Receiver operating characteristic (ROC) analysis and a nomogram were used to assess their diagnostic values. A multiregulatory network was built to reveal the possible regulatory relationships of critical signatures. Cell-type identification by estimating relative subsets of RNA transcript (CIBERSORT) analysis was used to investigate differential immune cell infiltration. Additionally, a cell and animal model were constructed to investigate the relationship between the identified genes and DIC. Results: Among the 3713 differentially expressed genes, three key genes (CSGALNACT1, ZNF296 and FANCB) were identified. A nomogram and ROC curves based on three key genes showed excellent diagnostic predictive performance. The regulatory network analysis showed that the TFs CREB1, EP300, FLI1, FOXA1, MAX, and MAZ modulated three key genes. An analysis of immune cell infiltration indicated that many immune cells (activated NK cells, M0 macrophages, activated dendritic cells and neutrophils) might be related to the progression of DIC. Furthermore, there may be various degrees of correlation between the three critical signatures and immune cells. RT‒qPCR demonstrated that the mRNA expression of CSGALNACT1 and ZNF296 was significantly upregulated, while FANCB was significantly downregulated in DOX-treated cardiomyocytes in vitro and in vivo. Conclusion: Our study suggested that the differential expression of CSGALNACT1, ZNF296 and FANCB is associated with cardiotoxicity and is also involved in immune cell infiltration in DIC. They might be potential biomarkers for the early occurrence of DIC.

A Phase I Dose-Escalation Study of LY3405105, a Covalent Inhibitor of Cyclin-Dependent Kinase 7, Administered to Patients With Advanced Solid Tumors.

BACKGROUND: This study aimed to evaluate the safety, pharmacokinetics (PKs), and preliminary activity of LY3405105, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7), in patients with advanced solid tumors. MATERIALS AND METHODS: LY3405105 monotherapy was given once daily (QD; part A1) or thrice weekly (TIW; part A2) starting at 1 and 2 mg orally, respectively, and escalated per a Bayesian design in adult patients. The primary endpoint was safety, and secondary endpoints included PKs and antitumor activity. RESULTS: Fifty-four patients were enrolled: 43 in part A1 and 11 in part A2. Seven patients had dose-limiting toxicities, all in part A1 (45 mg: n = 3; 35 mg: n = 3; 25 mg: n = 1). Thirty-five patients (64.8%) reported at least one treatment-related adverse event (TRAE). TRAEs (≥10%) were diarrhea, nausea, fatigue, vomiting, abdominal pain, anemia, asthenia, and decreased platelet count. QD dosing showed sustained exposure with less peak-trough fluctuation compared to TIW dosing. Median time to maximum concentration was 1-2 hours and half-life was 15-19 hours. CDK7-target occupancy in skin and peripheral blood on day 15 was dose-dependent and reached near maximal occupancy of 75% at ≥15 mg QD. The maximum tolerated dose (MTD) was 20 mg QD. Twelve patients in part A1 (27.9%) and 5 patients in part A2 (45.5%) had a best overall response of stable disease. No complete response or partial response was observed. CONCLUSION: The MTD of LY3405105 monotherapy was 20 mg QD. The most common toxicities were gastrointestinal adverse events, myelosuppression, fatigue, and asthenia. Limited clinical activity was observed in this phase I trial, and there are no plans for further development. CLINICALTRIALS.GOV IDENTIFIER: NCT03770494.

MINOCA biomarkers: Non-atherosclerotic aspects.

Myocardial infarction in the absence of obstructive coronary artery disease (MINOCA) is an important subtype of myocardial infarction. Although comprising less than 50% stenosis in the main epicardial coronary arteries, it constitutes a severe health risk. A variety of approaches have been recommended, but definitive diagnosis remains elusive. In addition, the lack of a comprehensive understanding of underlying pathophysiology makes clinical management difficult and unpredictable. This review highlights ongoing efforts to identify relevant biomarkers in MINOCA to improve diagnosis, individualize treatment and better predict outcomes.

The value of Computed Tomography in the Diagnostic and Prognostic Prediction of Renal Epithelioid Angiomyolipoma.

PURPOSE: This study aimed to assess the importance of computed tomography (CT) imaging in the diagnostic and prognostic evaluation of renal epithelioid angiomyolipoma (EAML). MATERIALS AND METHODS: This study comprised 63 patients diagnosed with renal EAML in the First Affiliated Hospital of Soochow University during 2010-2021, who met the inclusion criteria. The clinical, pathological, and therapeutic features were analyzed to determine the optimum diagnostic and therapeutic approaches. RESULTS: Of the 63 participants, 20 were men and 43 women aged 24-74 years (average, 45.5 years). In 35 and 28 participants, the tumor was located on the left and right sides, respectively. All the patients underwent CT scanning. Most of the patients (54/63) with EAMLs demonstrated hyperattenuation, one showed isoattenuation, and eight showed hypoattenuation compared with renal parenchyma on unenhanced CT images. The diameter of each tumor was 2-25 cm (average, 5.6 cm). All the participants underwent surgical treatment. Of these, 53 were followed up for 4-128 months (median, 64 months). Among the followed-up patients, one died of the tumor, one died due to acute severe pancreatitis, and two had an ipsilateral recurrence. CONCLUSION: EAML is a relatively rare renal angiomyolipoma depleted in fat. A characteristic of hyperattenuation on unenhanced CT images in EAML can help distinguish this tumor from clear cell renal cell carcinoma. Surgical resection is the main treatment. Most EAMLs are benign, and only a few have malignant potential. However, post-surgery recurrence and metastasis may occur, especially in elderly patients, and thus close follow-up is recommended.

Application of Lineage Tracing in Central Nervous System Development and Regeneration.

The central nervous system (CNS) is a complicated neural network. The origin and evolution of functional neurons and glia cells remain unclear, as do the cellular alterations that occur during the course of cerebral disease rehabilitation. Lineage tracing is a valuable method for tracing specific cells and achieving a better understanding of the CNS. Recently, various technological breakthroughs have been made in lineage tracing, such as the application of various combinations of fluorescent reporters and advances in barcode technology. The development of lineage tracing has given us a deeper understanding of the normal physiology of the CNS, especially the pathological processes. In this review, we summarize these advances of lineage tracing and their applications in CNS. We focus on the use of lineage tracing techniques to elucidate the process CNS development and especially the mechanism of injury repair. Deep understanding of the central nervous system will help us to use existing technologies to diagnose and treat diseases.

Enzymatic polymerization of enantiomeric L-3,4-dihydroxyphenylalanine into films with enhanced rigidity and stability.

L-3,4-dihydroxyphenylalanine is an important molecule in the adhesion of mussels, and as an oxidative precursor of natural melanin, it plays an important role in living system. Here, we investigate the effect of the molecular chirality of 3,4-dihydroxyphenylalanine on the properties of the self-assembled films by tyrosinase-induced oxidative polymerization. The kinetics and morphology of pure enantiomers are completely altered upon their co-assembly, allowing the fabrication of layer-to-layer stacked nanostructures and films with improved structural and thermal stability. The different molecular arrangements and self-assembly mechanisms of the L+D-racemic mixtures, whose oxidation products have increased binding energy, resulting in stronger intermolecular forces, which significantly increases the elastic modulus. This study provides a simple pathway for the fabrication of biomimetic polymeric materials with enhanced physicochemical properties by controlling the chirality of monomers.

Gut microbiota-derived 3-phenylpropionic acid promotes intestinal epithelial barrier function via AhR signaling.

BACKGROUND: The intestinal epithelial barrier confers protection against the intestinal invasion by pathogens and exposure to food antigens and toxins. Growing studies have linked the gut microbiota to the intestinal epithelial barrier function. The mining of the gut microbes that facilitate the function of intestinal epithelial barrier is urgently needed. RESULTS: Here, we studied a landscape of the gut microbiome of seven pig breeds using metagenomics and 16S rDNA gene amplicon sequencing. The results indicated an obvious difference in the gut microbiome between Congjiang miniature (CM) pigs (a native Chinese breed) and commercial Duroc × [Landrace × Yorkshire] (DLY) pigs. CM finishing pigs had stronger intestinal epithelial barrier function than the DLY finishing pigs. Fecal microbiota transplantation from CM and DLY finishing pigs to germ-free (GF) mice transferred the intestinal epithelial barrier characteristics. By comparing the gut microbiome of the recipient GF mice, we identified and validated Bacteroides fragilis as a microbial species that contributes to the intestinal epithelial barrier. B. fragilis-derived 3-phenylpropionic acid metabolite had an important function on the enhancement of intestinal epithelial barrier. Furthermore, 3-phenylpropionic acid facilitated the intestinal epithelial barrier by activating aryl hydrocarbon receptor (AhR) signaling. CONCLUSIONS: These findings suggest that manipulation of B. fragilis and 3-phenylpropionic acid is a promising strategy for improving intestinal epithelial barrier. Video Abstract.

Megf10-related engulfment of excitatory postsynapses by astrocytes following severe brain injury.

AIMS: To investigate astrocyte-related phagocytosis of synapses in the ipsilateral hippocampus after traumatic brain injury (TBI). METHODS: We performed controlled cortical impact to simulate TBI in mice. Seven days postinjury, we performed cognitive tests, synapse quantification, and examination of astrocytic phagocytosis in association with Megf10 expression. RESULTS: During the subacute stage post-TBI, we found a reduction in excitatory postsynaptic materials in the ipsilateral hippocampus, which was consistent with poor performance in the cognitive test. The transcriptome data suggested that robust phagocytosis was responsible for this process. Coincidently, we identified phagocytic astrocytes containing secondary lysosomes that were wrapped around the synapses in the ipsilateral hippocampus. Moreover, a significant increase in the co-location of GFAP and PSD-95 in the CA1 region suggested astrocytic engulfment of excitatory postsynaptic proteins. After examining the reported phagocytic pathways, we found that both the transcription level and protein expression of Megf10 were elevated. Co-immunofluorescence of GFAP and Megf10 demonstrated that the expression of Megf10 was spatially upregulated in astrocytes, exclusively in the CA1 region, and was related to the astrocytic engulfment of PSD-95. CONCLUSION: Our study elaborated that the Megf10-related astrocytic engulfment of PSD-95 in the CA1 region of the ipsilateral hippocampus aggravated cognitive dysfunction following severe TBI.

Core-predominant gut fungus Kazachstania slooffiae promotes intestinal epithelial glycolysis via lysine desuccinylation in pigs.

BACKGROUND: Gut fungi are increasingly recognized as important contributors to host physiology, although most studies have focused on gut bacteria. Post-translational modifications (PTMs) of proteins play vital roles in cell metabolism. However, the contribution of gut fungi to host protein PTMs remains unclear. Mining gut fungi that mediate host protein PTMs and dissecting their mechanism are urgently needed. RESULTS: We studied the gut fungal communities of 56 weaned piglets and 56 finishing pigs from seven pig breeds using internal transcribed spacer (ITS) gene amplicon sequencing and metagenomics. The results showed that Kazachstania slooffiae was the most abundant gut fungal species in the seven breeds of weaned piglets. K. slooffiae decreased intestinal epithelial lysine succinylation levels, and these proteins were especially enriched in the glycolysis pathway. We demonstrated that K. slooffiae promoted intestinal epithelial glycolysis by decreasing lysine succinylation by activating sirtuin 5 (SIRT5). Furthermore, K. slooffiae-derived 5'-methylthioadenosine metabolite promoted the SIRT5 activity. CONCLUSIONS: These findings provide a landscape of gut fungal communities of pigs and suggest that K. slooffiae plays a crucial role in intestinal glycolysis metabolism through lysine desuccinylation. Our data also suggest a potential protective strategy for pigs with an insufficient intestinal energy supply. Video Abstract.

HIF-1α participates in secondary brain injury through regulating neuroinflammation.

A deeper understanding of the underlying biological mechanisms of secondary brain injury induced by traumatic brain injury (TBI) will greatly advance the development of effective treatments for patients with TBI. Hypoxia-inducible factor-1 alpha (HIF-1α) is a central regulator of cellular response to hypoxia. In addition, growing evidence shows that HIF-1α plays the important role in TBI-induced changes in biological processes; however, detailed functional mechanisms are not completely known. The aim of the present work was to further explore HIF-1α-mediated events after TBI. To this end, next-generation sequencing, coupled with cellular and molecular analysis, was adopted to interrogate vulnerable events in a rat controlled cortical impact model of TBI. The results demonstrated that TBI induced accumulation of HIF-1α at the peri-injury site at 24 h post-injury, which was associated with neuronal loss. Moreover, gene set enrichment analysis unveiled that neuroinflammation, especially an innate inflammatory response, was significantly evoked by TBI, which could be attenuated by the inhibition of HIF-1α. Furthermore, the inhibition of HIF-1α could mitigate the activation of microglia and astrocytes. Taken together, all these data implied that HIF-1α might contribute to secondary brain injury through regulating neuroinflammation.