RNA-binding protein Trx regulates alternative splicing and promotes metastasis of HCC via interacting with LINC00152.

BACKGROUND: Epithelial-mesenchymal transition (EMT) is central to HCC metastasis, in which RNA-binding proteins (RBPs) play a key role. METHODS: To explore the role of RBPs in metastasis of hepatocellular carcinoma (HCC), whole transcriptome sequencing was conducted to identify differential RBPs between HCC with metastasis and HCC without metastasis. The influence of RBPs on metastasis of HCC was verified by in vitro and in vivo experiments. The interaction of RBPs with non-coding RNAs was evaluated by RNA immunoprecipitation and pull-down assays. RNA sequencing, whole-genome sequencing, and alternative splicing analysis were further performed to clarify post-transcriptional regulation mechanisms. RESULTS: Whole transcriptome sequencing results showed that expression of thioredoxin (Trx) was significantly upregulated in HCC patients with metastasis. Trx was also found to be associated with poor prognosis in HCC patients. Overexpression of Trx could promote migration and invasion of HCC cells in vitro and increase the rate of lung metastasis of HCC cells in vivo. Moreover, binding assays showed that Trx could bind to LINC00152. As a result, LINC00152 was verified to determine the pro-metastasis function of Trx by knockdown assay. Furthermore, we revealed that Trx could regulate metastasis-associated alternative splicing program. Specifically, angiopoietin 1 (ANGPT1) was the splicing target; the splicing isoform switching of ANGPT1 could activate the PI3K-Akt pathway, upregulate EMT-associated proteins, and promote migration and invasion of HCC cells. CONCLUSIONS: We found that Trx could interact with LINC00152 and promote HCC metastasis via regulating alternative splicing, indicating that Trx may serve as a novel therapeutic target for HCC treatment.

Comparative Analysis of Phytohormone Biosynthesis Genes Responses to Long-Term High Light in Tolerant and Sensitive Wheat Cultivars.

Phytohormones are vital for developmental processes, from organ initiation to senescence, and are key regulators of growth, development, and photosynthesis. In natural environments, plants often experience high light (HL) intensities coupled with elevated temperatures, which pose significant threats to agricultural production. However, the response of phytohormone-related genes to long-term HL exposure remains unclear. Here, we examined the expression levels of genes involved in the biosynthesis of ten phytohormones, including gibberellins, cytokinins, salicylic acid, jasmonic acid, abscisic acid, brassinosteroids, indole-3-acetic acid, strigolactones, nitric oxide, and ethylene, in two winter wheat cultivars, Xiaoyan 54 (XY54, HL tolerant) and Jing 411 (J411, HL sensitive), when transferred from low light to HL for 2-8 days. Under HL, most genes were markedly inhibited, while a few, such as TaGA2ox, TaAAO3, TaLOG1, and TaPAL2, were induced in both varieties. Interestingly, TaGA2ox2 and TaAAO3 expression positively correlated with sugar content but negatively with chlorophyll content and TaAGP expression. In addition, we observed that both varieties experienced a sharp decline in chlorophyll content and photosynthesis performance after prolonged HL exposure, with J411 showing significantly more sensitivity than XY54. Hierarchical clustering analysis classified the phytohormone genes into the following three groups: Group 1 included six genes highly expressed in J411; Group 2 contained 25 genes drastically suppressed by HL in both varieties; and Group 3 contained three genes highly expressed in XY54. Notably, abscisic acid (ABA), and jasmonic acid (JA) biosynthesis genes and their content were significantly higher, while gibberellins (GA) content was lower in XY54 than J411. Together, these results suggest that the differential expression and content of GA, ABA, and JA play crucial roles in the contrasting responses of tolerant and sensitive wheat cultivars to leaf senescence induced by long-term HL. This study enhances our understanding of the mechanisms underlying HL tolerance in wheat and can guide the development of more resilient wheat varieties.

Organoid modeling meets cancers of female reproductive tract.

Diseases of the female reproductive system, especially malignant tumors, pose a serious threat to women's health worldwide. One of the key factors limiting research progress in this area is the lack of representative models. Organoid technology, especially tumor organoids, has been increasingly applied in the study of female reproductive system tumors due to their high heterogeneity, close resemblance to the physiological state, easy acquisition and cultivation advantages. They play a significant role in understanding the origin and causes of tumors, drug screening, and personalized treatment and more. This article reviews the organoid models for the female reproductive system, focusing on the cancer research advancements. It discusses the methods for constructing tumor organoids of the female reproductive tract and summarizes the limitations of current research. The aim is to offer a reference for future development and application of these organoid models, contributing to the advancement of anti-tumor drugs and treatment strategies for female reproductive tract cancer patients.

Lysosomal dysfunction in α-synuclein pathology: molecular mechanisms and therapeutic strategies.

In orchestrating cell signaling, facilitating plasma membrane repair, supervising protein secretion, managing waste elimination, and regulating energy consumption, lysosomes are indispensable guardians that play a crucial role in preserving intracellular homeostasis. Neurons are terminally differentiated post-mitotic cells. Neuronal function and waste elimination depend on normal lysosomal function. Converging data suggest that lysosomal dysfunction is a critical event in the etiology of Parkinson's disease (PD). Mutations in Glucosylceramidase Beta 1 (GBA1) and leucine-rich repeat kinase 2 (LRRK2) confer an increased risk for the development of parkinsonism. Furthermore, lysosomal dysfunction has been observed in the affected neurons of sporadic PD (sPD) patients. Given that lysosomal hydrolases actively contribute to the breakdown of impaired organelles and misfolded proteins, any compromise in lysosomal integrity could incite abnormal accumulation of proteins, including α-synuclein, the major component of Lewy bodies in PD. Clinical observations have shown that lysosomal protein levels in cerebrospinal fluid may serve as potential biomarkers for PD diagnosis and as signs of lysosomal dysfunction. In this review, we summarize the current evidence regarding lysosomal dysfunction in PD and discuss the intimate relationship between lysosomal dysfunction and pathological α-synuclein. In addition, we discuss therapeutic strategies that target lysosomes to treat PD.

Correlations among parameters of pentacam, iTrace, and LOCS III in assessing lens opacity.

OBJECTIVES: To investigate the diagnostic value of iTrace visual function analyzer, Pentacam 3D anterior segment analysis system and Lens Opacities Classification System III (LOCS III) in assessing lens opacity in patients with age-related cataract (ARC). METHODS: A total of 129 patients with ARC admitted to Anonymized from May 2019 to April 2021 were selected as the research objects. The degree of lens opacity was evaluated by LOCS III classification, iTrace and anterior segment analysis. RESULTS: The Pentacam nucleus staging (PNS) grade was strongly correlated with nuclear color (NC) (r = 0.537, p < 0.05) and moderately correlated with nuclear opalescence (NO) (r = 0.473, p < 0.05). The integrated density (IntDen) in 3-mm nuclear region was strongly correlated with NC (r = 0.548, p < 0.05) and NO (r = 0.539, p < 0.05). The dysfunctional lens index (DLI) in 3-mm area was negatively correlated with NC (r=-0.252, p < 0.05), NO (r=-0.239, p < 0.05) and posterior subcapsular cataract (r=-0.271, p < 0.05). PNS was weakly negatively correlated with the DLI in 3-mm area (r=-0.219, p < 0.05), and IntDen in 3-mm core area was weakly negatively correlated with the DLI in 3-mm area (r=-0.291, p < 0.05). CONCLUSION: A combination of iTrace, anterior segment analysis and LOCS III may be beneficial in objectively assessing the opacity of different regions of the lens.

GPTFF: A high-accuracy out-of-the-box universal AI force field for arbitrary inorganic materials.

This study introduces a novel artificial intelligence (AI) force field, namely a graph-based pre-trained transformer force field (GPTFF), which can simulate arbitrary inorganic systems with good precision and generalizability. Harnessing a large trove of the data and the attention mechanism of transformer algorithms, the model can accurately predict energy, atomic force, and stress with mean absolute error (MAE) values of 32 meV/atom, 71 meV/Å, and 0.365 GPa, respectively. The dataset used to train the model includes 37.8 million single-point energies, 11.7 billion force pairs, and 340.2 million stresses. We also demonstrated that the GPTFF can be universally used to simulate various physical systems, such as crystal structure optimization, phase transition simulations, and mass transport. The model is publicly released with this paper, enabling anyone to use it immediately without needing to train it.

Sleep status of centenarians and its association with death in the China Hainan Centenarian Cohort Study.

OBJECTIVE: This study investigated the associations of sleep status (duration and quality) with all-cause death among centenarians, using data from the China Hainan Centenarians Cohort Study. METHOD: The epidemiological distribution of sleep duration and sleep quality (estimated using the Pittsburgh Sleep Quality Index) was described based on the data from the China Hainan Centenarians Cohort Study. Cox regression was used to analyze the association between sleep status and all-cause mortality. RESULTS: A total of 994 centenarians, with an average age of 102.77 ± 2.75years, were included. The median (Q1, Q3) daytime sleep duration was 1.00 (0.50, 1.50) hour, while nighttime sleep duration and total sleep duration were 8.00 (7.00, 9.00) hours and 9.00 (8.00, 10.50) hours, respectively. By the end of the follow-up period, 517 centenarians had died, with a median follow-up time of 4.2 (1.3-5.0) years. A noteworthy finding emerged: male centenarians with a daytime sleep duration of at least 2 hours had a 97% greater risk of all-cause mortality (HR=1.97, 95%CI: 1.07-3.62, P = .039) than those who got less daytime sleep, after adjusting for potential confounders. CONCLUSION: The sleep duration patterns of centenarians in Hainan were comparable to those in other provinces of China. Centenarians who sleep longer had a higher risk of all-cause mortality. This risk plateaued after more than 9 hours of sleep, with no gender differences observed. Furthermore, the duration of daytime sleep was significantly associated with all-cause mortality among male centenarians.

Multi-omic analysis identifies metabolic biomarkers for the early detection of breast cancer and therapeutic response prediction.

Reliable blood-based tests for identifying early-stage breast cancer remain elusive. Employing single-cell transcriptomic sequencing analysis, we illustrate a close correlation between nucleotide metabolism in the breast cancer and activation of regulatory T cells (Tregs) in the tumor microenvironment, which shows distinctions between subtypes of patients with triple-negative breast cancer (TNBC) and non-TNBC, and is likely to impact cancer prognosis through the A2AR-Treg pathway. Combining machine learning with absolute quantitative metabolomics, we have established an effective approach to the early detection of breast cancer, utilizing a four-metabolite panel including inosine and uridine. This metabolomics study, involving 1111 participants, demonstrates high accuracy across the training, test, and independent validation cohorts. Inosine and uridine prove predictive of the response to neoadjuvant chemotherapy (NAC) in patients with TNBC. This study deepens our understanding of nucleotide metabolism in breast cancer development and introduces a promising non-invasive method for early breast cancer detection and predicting NAC response in patients with TNBC.

Causal Relationship Between Gut Microbiota and Leukemia: Future Perspectives.

The gut microbiota plays a crucial role in maintaining homeostasis in the human gastrointestinal tract. Numerous studies have shown a strong association between the gut microbiota and the emergence and progression of various diseases. Leukemia is one of the most common hematologic malignancies. Although standardized protocols and expert consensus have been developed for routine diagnosis and treatment, limitations remain due to individual differences. Nevertheless, a large number of studies have established a link between the gut microbiota and leukemia, with disturbances in the gut microbiota directly or indirectly affecting the development of leukemia. However, the causal relationship between the two remains unclear, and studying and exploring the causal relationship may open up entirely new avenues and protocols for use in the prevention and/or treatment of leukemia, offering new insights into diagnosis and treatment. In this review, the intricate relationship between the gut microbiota and leukemia is explored in depth, including causal associations, metabolite effects, therapeutic applications, and complications. Based on the characteristics of the gut microbiota, the future applications and prospects of gut microbiota are discussed to provide useful information for clinical treatment of leukemia.

Precisely Tunable Instantaneous Carbon Rearrangement Enables Low-Working-Potential Hard Carbon Toward Sodium-Ion Batteries with Enhanced Energy Density.

As the preferred anode material for sodium-ion batteries, hard carbon (HC) confronts significant obstacles in providing a long and dominant low-voltage plateau to boost the output energy density of full batteries. The critical challenge lies in precisely enhancing the local graphitization degree to minimize Na+ ad-/chemisorption, while effectively controlling the growth of internal closed nanopores to maximize Na+ filling. Unfortunately, traditional high-temperature preparation methods struggle to achieve both objectives simultaneously. Herein, a transient sintering-involved kinetically-controlled synthesis strategy is proposed that enables the creation of metastable HCs with precisely tunable carbon phases and low discharge/charge voltage plateaus. By optimizing the temperature and width of thermal pulses, the high-throughput screened HCs are characterized by short-range ordered graphitic micro-domains that possess accurate crystallite width and height, as well as appropriately-sized closed nanopores. This advancement realizes HC anodes with significantly prolonged low-voltage plateaus below 0.1 V, with the best sample exhibiting a high plateau capacity of up to 325 mAh g-1. The energy density of the HC||Na3V2(PO4)3 full battery can therefore be increased by 20.7%. Machine learning study explicitly unveils the "carbon phase evolution-electrochemistry" relationship. This work promises disruptive changes to the synthesis, optimization, and commercialization of HC anodes for high-energy-density sodium-ion batteries.

Comparison of Serum Vitamin D Levels in Obese Subjects with and without Type 2 Diabetes Mellitus.

Background: Although observational studies have reported a correlation between vitamin D deficiency and type 2 diabetes mellitus (T2DM), epidemiological evidence on the risk of obese subjects suffering T2DM due to a vitamin D deficiency is limited. Therefore, we investigated the correlation between T2DM and serum vitamin D, lipids, blood pressure, insulin indexes in an obese population. Methods: A total of 1440 participants including 450 healthy controls and 990 obese subjects, 470 without T2DM and 520 with T2DM. Serum vitamin D levels were measured, and the association between low levels and T2DM in obese subjects was examined using multinomial and linear regression analyses. Results: Of the participants, 35% had deficient or insufficient vitamin D levels (ie, <20 ng/mL). Compared with healthy controls, obese subjects, particularly those with T2DM had lower vitamin D levels. Multinomial logistic regression analysis showed that obese subjects with T2DM had a gradually increasing risk for desirable (RO = 1.41, 95% CI 1.06-1.93, P = 0.027), insufficient (RO = 1.83, 95% CI 1.27-2.84, P < 0.001), or deficient ((RO = 2.14, 95% CI 1.15-3.75, P = 0.014) vitamin D levels. In obese subjects with T2DM, vitamin D levels correlated inversely with the risk indicators for diabetes, such as the levels of HbA1c (ß = -0.16, P = 0.002), fasting insulin (Fins; ß = -0.31, P = 0.008), and HOMA-IR (ß = -0.19, P < 0.001). In obese subjects without T2DM, vitamin D was associated negatively with the risk of having T2DM at five-year follow-up (relative risk = 0.93, 95% CI 0.79-0.97, P = 0.037). Conclusion: This study demonstrates that low vitamin D levels correlate with the presence of T2DM in the obese population. This finding indicates that hypovitaminosis D may be a potential biological vulnerability factor for the development of T2DM in obese subjects.

Breast cancer colonization by Malassezia globosa accelerates tumor growth.

Malassezia globosa is a lipophilic basidiomycetous yeast that occurs abundantly in breast tumors and that may contribute to a shortened overall survival of breast cancer (BRAC) patients, suggesting that the yeast may participate in the carcinogenesis of BRAC. However, the mechanisms involved in the M. globosa-based acceleration of BRAC are unknown. Here, we show that M. globosa can colonize mammary tissue in 7,12-dimethylbenz[a] anthracene-induced mice. The abundance of M. globosa shortened the overall survival and increased the tumor incidence. Transcriptome data illustrated that IL-17A plays a key role in tumor growth due to M. globosa colonization, and tumor-associated macrophage infiltration was elevated during M. globosa colonization which triggers M2 polarization of macrophages via toll-like receptors 4/nuclear factor kappa-B (Nf-κB) signaling. Our results show that the expression of sphingosine kinase 1 (Sphk1) is increased in breast tumors after inoculation with M. globosa. Moreover, we discovered that Sphk1-specific small interfering RNA blocked the formation of lipid droplets, which can effectively alleviate the expression of the signal transducer and activator of the transcription 3 (STAT3)/Nf-κB pathway. Taken together, our results demonstrate that M. globosa could be a possible factor for the progression of BRAC. The mechanisms by which M. globosa promotes BRAC development involve the IL-17A/macrophage axis. Meanwhile, Sphk1 overexpression was induced by M. globosa infection, which also promoted the proliferation of MCF-7 cells.IMPORTANCELiterature has suggested that Malassezia globosa is associated with breast tumors; however, this association has not been confirmed. Here, we found that M. globosa colonizes in breast fat pads leading to tumor growth. As a lipophilic yeast, the expression of sphingosine kinase 1 (Sphk1) was upregulated to promote tumor growth after M. globosa colonization. Moreover, the IL-17A/macrophages axis plays a key role in mechanisms involved in the M. globosa-induced breast cancer acceleration from the tumor immune microenvironment perspective.

α-(N-Alkyl-N-heteroarenium)-α-diazoacetates: synthesis and reactivity of a novel class of 'onium' diazo compounds.

Treatment of alkyl α-(N-heteroaryl)-α-diazoacetates with alkylating reagents affords diazoacetate N-heteroarenium salts. These novel 'onium' diazo compounds are mostly yellow solids, displaying increased thermal and acid stability. Their tetrafluoroborates undergo rhodium catalyzed [2 + 1] and Doyle-Kirmse reactions under mild conditions, suggesting the N-quaternization an effective means of elimination of N-coordination caused catalyst toxicity.

Effect of optimizing cerebral oxygen saturation on postoperative delirium in older patients undergoing one-lung ventilation for thoracoscopic surgery.

OBJECTIVES: This randomized controlled trial investigated whether the regional cerebral oxygenation saturation (rScO2)-guided lung-protective ventilation strategy could improve brain oxygen and reduce the incidence of postoperative delirium (POD) in patients older than 65 years. METHODS: This randomized controlled trial enrolled 120 patients undergoing thoracic surgery who received one-lung ventilation (OLV). Patients were randomly assigned to the lung-protective ventilation group (PV group) or rScO2-oriented lung-protective ventilation group (TPV group). rScO2 was recorded during the surgery, and the occurrence of POD was assessed. RESULTS: The incidence of POD 3 days after surgery-the primary outcome-was significantly lower in the TPV group (23.3% versus 8.5%). Meanwhile, the levels of POD-related biological indicators (S100ß, neuron-specific enolase, tumor necrosis factor-α) were lower in the TPV group. Considering the secondary outcomes, both groups exhibited a lower oxygenation index after OLV, whereas partial pressure of carbon dioxide and mean arterial pressure were significantly increased in the TPV group. In addition, minimum rScO2 during surgery and mean rScO2 were higher in the TPV group than in the PV group. CONCLUSION: Continuous intraoperative monitoring of brain tissue oxygenation and active intervention measures guided by cerebral oxygen saturation are critical for improving brain metabolism and reducing the risk of POD.

Association between psychological resilience and all-cause mortality in the Health and Retirement Study.

BACKGROUND: Psychological resilience refers to an individual's ability to cope with and adapt to challenging life circumstances and events. OBJECTIVE: This study aims to explore the association between psychological resilience and all-cause mortality in a national cohort of US older adults by a cross-sectional study. METHODS: The Health and Retirement Study (2006-2008) included 10 569 participants aged ≥50. Mortality outcomes were determined using records up to May 2021. Multivariable Cox proportional hazards models were used to analyse the associations between psychological resilience and all-cause mortality. Restricted cubic splines were applied to examine the association between psychological resilience and mortality risk. FINDINGS: During the follow-up period, 3489 all-cause deaths were recorded. The analysis revealed an almost linear association between psychological resilience and mortality risk. Higher levels of psychological resilience were associated with a reduced risk of all-cause mortality in models adjusting for attained age, sex, race and body mass index (HR=0.750 per 1 SD increase in psychological resilience; 95% CI 0.726, 0.775). This association remained statistically significant after further adjustment for self-reported diabetes, heart disease, stroke, cancer and hypertension (HR=0.786; 95% CI 0.760, 0.813). The relationship persisted even after accounting for smoking and other health-related behaviours (HR=0.813; 95% CI 0.802, 0.860). CONCLUSIONS: This cohort study highlights the association between psychological resilience and all-cause mortality in older adults in the USA. CLINICAL IMPLICATIONS: Psychological resilience emerges as a protective factor against mortality, emphasising its importance in maintaining health and well-being.

Dynamic changes in postmortem quality of grass carp (Ctenopharyngodon idella) muscle: From the perspectives of muscle degradation and flavor evolution.

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Decoding Long-Chain Fatty Acid Ethyl Esters during the Distillation of Strong Aroma-Type Baijiu and Exploring the Adsorption Mechanism with Magnetic Nanoparticles.

Simultaneous detection of the dynamic distribution of long-chain fatty acid ethyl esters (LCFAEEs) during Baijiu distillation is crucial for optimizing its flavor and health attributes. In this study, we synthesized a simple, cost-effective Fe3O4@NH2 adsorbent to simultaneously extract eight LCFAEEs from Baijiu. Through density functional theory and adsorption experiments, we elucidated 1,6-hexanediamine as a surface modifier, with the -NH2 groups providing adsorption sites for the LCFAEEs via hydrogen-bonding interactions and van der Waals forces. Additionally, we established the magnetic solid-phase extraction-GC-MS extraction technique combined with stable isotope dilution analysis to analyze LCFAEEs. This method revealed the dynamic distribution patterns of LCFAEEs during strong aroma-type Baijiu (SAB) distillation. We observed that the concentrations of the eight LCFAEEs gradually decreased with prolonged distillation and were significantly correlated with ethanol concentration. To ensure optimal flavor and clarity in SAB, it is recommended to select the heart-stage base Baijiu with an alcohol content of 58%-63%.

PLGA-Astragalus Polysaccharide Nanovaccines Exert Therapeutic Effect in Colorectal Cancer.

Background: Tumor vaccines have achieved remarkable progress in treating patients with various tumors in clinical studies. Nevertheless, extensive research has also revealed that tumor vaccines are not up to expectations for the treatment of solid tumors due to their low immunogenicity. Therefore, there is an urgent need to design a tumor vaccine that can stimulate a broad anti-tumor immune response. Methods: In this work, we developed a nanovaccine (NP-TCL@APS), which includes nanoparticles loaded with colorectal cancer tumor cell lysates (TCL) and Astragalus polysaccharides (APS) into poly (lactic-co-glycolic acid) to induce a robust innate immune response. The NP-TCL@APS was identified by transmission electron microscopy and Malvern laser particle size analyzer. The killing and immune activation effects of NP-TCL@APS were evaluated in vitro. Finally, safety and anti-tumor efficacy were evaluated in the colorectal cancer tumor-bearing mouse model. Results: We found that NP-TCL@APS was preferentially uptaken by DC and further promoted the activation of DC in vitro. Additionally, nanoparticles codelivery of TCL and APS enhanced the antigen-specific CD8+ T cell response and suppressed the growth of tumors in mouse models with good biocompatibility. Conclusion: We successfully prepared a nanovaccine termed NP-TCL@APS, which can promote the maturation of DC and induce strong responses by T lymphocytes to exert anti-tumor effects. The strategy proposed here is promising for generating a tumor vaccine and can be extended to various types of cancers.

Causal role of gut microbiota, serum metabolites, immunophenotypes in myocarditis: a mendelian randomization study.

Background: The intricate relationship among gut microbiota, serum metabolites, and immunophenotypes may significantly impact myocarditis. However, direct causal links between these domains and myocarditis are not well understood. Methods: The study performed Mendelian randomization (MR) analysis using genetic data from public sources. Exposure data included 211 gut microbiota, 486 serum metabolites, and 731 immunophenotypes from Mibiogen, the Metabolomics GWAS server, and GWAS catalog databases. Single nucleotide polymorphisms (SNPs) were selected as instrumental variables based on established criteria. Myocarditis data from GWAS (427,911 participants, 24, 180, 570 SNPs) were used as the outcome variable. MR analysis was conducted using Inverse Variance Weighting (IVW), with Cochran's Q test for heterogeneity and Egger's intercept to assess horizontal pleiotropy. Results: 9 gut microbiota, 10 serum metabolites, and 2 immunophenotypes were negatively associated with myocarditis risk. In contrast, 5 gut microbiota, 12 serum metabolites, and 7 immunophenotypes were positively associated with myocarditis risk (all, P < 0.05). Sensitivity analyses confirmed the stability of these results. Conclusion: This MR study suggests that gut microbiota, serum metabolites, and immunophenotypes may causally influence myocarditis risk. These findings provide genetic evidence for myocarditis etiology and could inform future precision prevention and treatment strategies.

Fecal microbiota transplantation derived from mild cognitive impairment individuals impairs cerebral glucose uptake and cognitive function in wild-type mice: Bacteroidetes and TXNIP-GLUT signaling pathway.

Gut microbiome dysbiosis has been widely implicated in cognitive impairment, but the identity of the specific bacterial taxa and mechanisms are not fully elucidated. Brain glucose hypometabolism coincides with the cognitive decline. This study explored the link among cognition, gut microbiota and glucose uptake based on the fecal microbiota transplantation from mild cognitive impairment individuals (MCI-FMT) and investigated whether similar mechanisms were involved in 27-hydroxycholesterol (27-OHC)-induced cognitive decline. Our results showed that the MCI-FMT mice exhibited learning and memory decline and morphological lesions in the brain and colon tissues. There were reduced 18F-fluorodeoxyglucose uptake, downregulated expression of glucose transporters (GLUT1,3,4) and upregulated negative regulator of glucose uptake (TXNIP) in the brain. MCI-FMT altered the bacterial composition and diversity of the recipient mice, and the microbial signatures highlighted by the increased abundance of Bacteroides recapitulated the negative effects of MCI bacterial colonization. However, inhibiting Bacteroidetes or TXNIP increased the expression of GLUT1 and GLUT4, significantly improving brain glucose uptake and cognitive performance in 27-OHC-treated mice. Our study verified that cognitive decline and abnormal cerebral glucose uptake were associated with gut microbiota dysbiosis; we also revealed the involvement of Bacteroidetes and molecular mechanisms of TXNIP-related glucose uptake in cognitive deficits caused by 27-OHC.