De novo production of bioactive sesterterpenoid ophiobolins in Saccharomyces cerevisiae cell factories.

BACKGROUND: Sesterterpenoids are rare species among the terpenoids family. Ophiobolins are sesterterpenes with a 5-8-5 tricyclic skeleton. The oxidized ophiobolins exhibit significant cytotoxic activity and potential medicinal value. There is an urgent need for large amounts of ophiobolins supplication for drug development. The synthetic biology approach has been successfully employed in lots of terpene compound production and inspired us to develop a cell factory for ophiobolin biosynthesis. RESULTS: We developed a systematic metabolic engineering strategy to construct an ophiobolin biosynthesis chassis based on Saccharomyces cerevisiae. The whole-cell biotransformation methods were further combined with metabolic engineering to enhance the expression of key ophiobolin biosynthetic genes and improve the supply of precursors and cofactors. A high yield of 5.1 g/L of ophiobolin F was reached using ethanol and fatty acids as substrates. To accumulate oxidized ophiobolins, we optimized the sources and expression conditions for P450-CPR and alleviated the toxicity of bioactive compounds to cells through PDR engineering. We unexpectedly obtained a novel ophiobolin intermediate with potent cytotoxicity, 5-hydroxy-21-formyl-ophiobolin F, and the known bioactive compound ophiobolin U. Finally, we achieved the ophiobolin U titer of 128.9 mg/L. CONCLUSIONS: We established efficient cell factories based on S. cerevisiae, enabling de novo biosynthesis of the ophiobolin skeleton ophiobolin F and oxidized ophiobolins derivatives. This work has filled the gap in the heterologous biosynthesis of sesterterpenoids in S. cerevisiae and provided valuable solutions for new drug development based on sesterterpenoids.

Proteomic change in the upper lobe of the left lung of Beagle dogs at the lung migration stage of Toxocara canis infection.

BACKGROUND: Toxocara canis is considered one of the most neglected parasitic zoonoses and threatens the health of millions of people worldwide with a predilection for pediatric and adolescent populations in impoverished communities. Exploring the invasion and developmental mechanisms associated with T. canis infection in its definitive canine hosts will help to better control zoonotic toxocariasis. METHODS: Proteomic changes in samples from the upper lobe of the left lung of Beagle puppies were systematically analyzed by quantitative proteomic technology of data-independent acquisition (DIA) at 96 h post-infection (hpi) with T. canis. Proteins with P-values < 0.05 and fold change > 1.5 or < 0.67 were considered proteins with differential abundance (PDAs). RESULTS: A total of 28 downregulated PDAs and 407 upregulated PDAs were identified at 96 hpi, including RhoC, TM4SFs and LPCAT1, which could be associated with the maintenance and repair of lung homeostasis. GO annotation and KEGG pathway enrichment analyses of all identified proteins and PDAs revealed that many lung proteins have correlation to signal transduction, lipid metabolism and immune system. CONCLUSIONS: The present study revealed lung proteomic alterations in Beagle dogs at the lung migration stage of T. canis infection and identified many PDAs of Beagle dog lung, which may play important roles in the pathogenesis of toxocariasis, warranting further experimental validation.

The impact of dietary acid load on super-agers with exceptional cognitive abilities: a propensity score analysis of national health and nutrition examination survey (NHANES) 2011-2014.

OBJECTIVES: 'Super-agers,' individuals over 80 with memory abilities comparable to those 20-30 years younger. The relationship between super-agers and dietary acid load (DAL) is an area that warrants further investigation. We aim to examine the link between DAL and super-agers and assess DAL's effects on cognitive functions across different age groups and cognitive domains. DESIGN: Employing a cross-sectional analysis of the 2011-2014 National Health and Nutrition Examination Survey (NHANES) data, we utilized propensity score analysis and multivariate-adjusted regression to mitigate confounding factors. SETTING: Older adults aged 60 and above in the United States. PARTICIPANTS: Our primary analysis encompassed 985 older adults, supplemented by a sensitivity analysis with 2,522 participants. MEASUREMENTS: DAL was assessed through potential renal acid load (PRAL), estimated net acid excretion (NAEes), and net endogenous acid production (NEAP) indices. RESULTS: Super-agers demonstrate a preference for alkaline diets, shown by their lower DAL indices. After inverse probability of treatment weighting (IPTW), multivariate-adjusted logistic regression reveals that each unit reduction in NAEes and PRAL increases the chances of being a super-ager by 3.9% and 3.0%, respectively. The DAL's impact on cognitive function becomes more pronounced with age. Lower PRAL and NAEes scores are significantly linked to higher situational memory and overall cognitive performance scores in those over 70, with these effects being even more pronounced in participants over 80. CONCLUSION: This research pioneers in demonstrating that super-agers prefer an alkaline diet, highlighting the potential role of alkaline diet in countering cognitive decline associated with aging.

Short- and long-term post-nephrectomy outcomes for retroperitoneal liposarcoma from a high-volume sarcoma center: a propensity score matching analysis.

BACKGROUND: Multivisceral en bloc resection with the ipsilateral kidney is commonly performed in patients with retroperitoneal liposarcoma (RLPS). We evaluated the effect of nephrectomy on short- and long-term outcomes in patients with RLPS. METHODS: Data from a prospectively maintained database of the Peking University Cancer Hospital Sarcoma Center between April 2011 and August 2022 were analyzed. We classified the RLPS patients who underwent surgery into nephrectomy group (NP) and non-nephrectomy group (non-NP). Patients were matched using a 1:1 propensity score to eliminate baseline differences between groups. Postoperative renal function outcomes, major morbidity, and mortality were analyzed to compare short-term outcomes after nephrectomy. Differences in local recurrence-free survival (LRFS) and overall survival (OS) were compared by Kaplan-Meier analysis with respect to oncological benefits. RESULTS: In the matched cohort, patients in the NP group had significantly higher postoperative eGFR and CKD stages, but none required dialysis. Patients between NP and non-NP had a comparable major morbidity (p = 0.820) and 60-day mortality (p = 0.475). Patients in the NP group had a higher 5-year LRFS rates than those in the non-NP group (34.5 vs. 17.8%, p = 0.015), and similar 5-year OS rates (52.4 vs. 47.1%, p = 0.401). Nephrectomy was an independent risk factor for LRFS, but not for major morbidity or OS. CONCLUSIONS: RLPS resection with nephrectomy is related to a mild progression of renal impairment; however, dialysis is rare. En bloc nephrectomy for complete resection of RLPS is safe and improves local control.

Effect of Sarcopenia on 10-Year Risk of Atherosclerotic Cardiovascular Disease in Patients with Type 2 Diabetes Mellitus.

Objective: To investigate the impact of sarcopenia on the 10-year risk of atherosclerotic cardiovascular disease (ASCVD) among individuals with type 2 diabetes mellitus (T2DM). Methods: This study included the clinical, laboratory, and body composition data of 1491 patients with T2DM who were admitted to the Department of Endocrinology and Metabolism at Tianjin Union Medical Center from July 2018 to July 2023. The China-PAR model was utilized to evaluate cardiovascular disease risk. Associations between ASCVD risk and various clinical parameters were analyzed, and the relationship between body composition parameters and ASCVD risk was assessed using logistic regression. Results: The analysis revealed that T2DM patients with sarcopenia had a higher 10-year ASCVD risk compared to those without sarcopenia, with reduced muscle mass independently predicting an increased risk of cardiovascular disease. This association was significant among female T2DM patients, while male T2DM patients with sarcopenia showed a marginally higher median ASCVD risk compared to their non-sarcopenic counterparts. ASCVD risk inversely correlated with body muscle parameters and positively correlated with fat content parameters. Specifically, height- and weight-adjusted fat mass (FM, FM%, FMI) were identified as risk factors for ASCVD. Conversely, muscle parameters adjusted for weight and fat (ASM%, SMM%, FFM%, ASM/FM, SMM/FM, FMM/FM) were protective against ASCVD risk. These findings highlight the critical role of sarcopenia in influencing cardiovascular disease risk among Chinese patients with T2DM, as predicted by the China-PAR model. Conclusion: This study highlights the importance of sarcopenia in T2DM patients, not only as an indicator of ASCVD risk, but possibly as an independent risk factor in this demographics.

Configuration Design and Verification of Shear Compliant Border in Space Membrane Structure.

To solve the non-uniformity of stress in space membrane structure and the lack of shear compliant border configuration design method, shear compliant borders are designed, optimized, and verified in terms of configuration. Firstly, an orthotropic model of the borders is built by combining Hill and Christensen-Lo composite material models. Secondly, a finite element form-finding method is put forward by establishing rectangular and cylindrical coordinates in different areas. The configuration of borders is obtained and the influence of the borders on the edge of the membrane is 0.23%, which means that the borders are compatible with the existing tensegrity systems, especially the tensioning components and the cable sleeves. Thirdly, simulation verifies that borders can cut the spread of shear stress and improve the stress uniformity in membrane structure. The maximum stress in the membrane effective area is decreased by 35.6% and the stress uniformity is improved by 30.5%. Finally, a membrane extension experiment is committed to compare the flatness of membrane surface under shear stress with and without shear compliant borders. The borders decrease the increment speed of flatness by 58.1%, which verifies the amelioration of stress uniformity. The shear compliant border configuration design method provides a reference for space membrane structure stress-uniform design.

Risk assessment and molecular mechanism of Sclerotium rolfsii resistance to boscalid.

Boscalid, a widely used SDHI fungicide, has been employed in plant disease control for over two decades. However, there is currently no available information regarding its antifungal activity against Sclerotium rolfsii and the potential risk of resistance development in this pathogen. In this study, we evaluated the sensitivity of 100 S. rolfsii strains collected from five different regions in China during 2018-2019 to boscalid using mycelial growth inhibition method and assessed the risk of resistance development. The EC50 values for boscalid ranged from 0.2994 µg/mL to 1.0766 µg/mL against the tested strains, with an average EC50 value of 0.7052 ± 0.1473 µg/mL. Notably, a single peak sensitivity baseline was curved, indicating the absence of any detected resistant strains. Furtherly, 10 randomly selected strains of S. rolfsii were subjected to chemical taming to evaluate its resistance risk to boscalid, resulting in the successful generation of six stable and inheritable resistant mutants. These mutants exhibited significantly reduced mycelial growth, sclerotia production, and virulence compared to their respective parental strains. Cross-resistance tests revealed a correlation between boscalid and flutolanil, benzovindiflupyr, pydiflumetofen, fluindapyr, and thifluzamide; however, no cross-resistance was observed between boscalid and azoxystrobin. Thus, we conclude that the development risk of resistance in S. rolfsii to boscalid is low. Boscalid can be used as an alternative fungicide for controlling peanut sclerotium blight when combined with other fungicides that have different mechanisms of action. Finally, the target genes SDHB, SDHC, and SDHD in S. rolfsii were initially identified, cloned and sequenced to elucidate the mechanism of S. rolfsii resistance to boscalid. Two mutation genotypes were found in the mutants: SDHD-D111H and SDHD-H121Y. The mutants carrying SDHD-H121Y exhibited moderate resistance, while the mutants with SDHD-D111H showed low resistance. These findings contribute to our comprehensive understanding of molecular mechanisms underlying plant pathogens resistance to SDHI fungicides.

Ultralong-life and high-capacity magnesium/sodium hybrid-ion battery using a ternary CoSe/NiSe2/CuSe2 cathode and dual-ion electrolyte.

An ultrahigh-performance magnesium/sodium hybrid-ion battery (MNHB) is developed using ternary CoSe/NiSe2/CuSe2 (CNCS) "micro-flowers" as cathode materials, working with a coordinative [Mg2Cl2][AlCl4]2 and bis(trifluoroethylsulfonyl)imide anionic sodium salt in triglyme electrolyte. After 2000 cycles at 2.0 A g-1, the MNHB shows a stable capacity of 115.5 mA h g-1 and a high Coulombic efficiency exceeding 99.8%. The battery shows very rapid charging, and good stability in extreme environments, providing new opportunities to develop other hybrid-ion systems.

Unveiling Metal Tolerance Mechanisms in Leersia hexandra Swartz under Cr/Ni Co-Pollution by Studying Endophytes and Plant Metabolites.

Heavy metal pollution poses significant environmental challenges, and understanding how plants and endophytic bacteria interact to mitigate these challenges is of utmost importance. In this study, we investigated the roles of endophytic bacteria, particularly Chryseobacterium and Comamonas, in Leersia hexandra Swartz (L. hexandra) in response to chromium and nickel co-pollution. Our results demonstrated the remarkable tolerance of Chryseobacterium and Comamonas to heavy metals, and their potential to become dominant species in the presence of co-pollution. We observed a close relationship between these endophytic bacteria and the significant differences in metabolites, particularly carbohydrates, flavonoids, and amino acids in L. hexandra. These findings shed light on the potential of endophytic bacteria to promote the production of aspartic acid and other metabolites in plants as a response to abiotic stressors. Furthermore, our study presents a new direction for plant and bioremediation strategies in heavy metal pollution and enhances our understanding of L. hexandra's mechanisms for heavy metal tolerance.

Development and validation of the hospice professional coping scale among Chinese nurses.

BACKGROUND: Hospice care professionals often experience trauma patient deaths and multiple patient deaths in a short period of time (more so than other nurses). This repeated exposure to the death process and the death of patients leads to greater psychological pressure on hospice care professionals. But at present, people pay more attention to the feelings and care burden of the family members of dying patients but pay less attention to medical staff. Thus, this study aimed to develop a scale on the burden of care for hospice care providers and assess the coping capacity of hospice professionals. Raising awareness of the psychological burden of hospice professionals. METHODS: Through a literature review, research group discussion, Delphi method and a pre-survey of professional coping skills among nurses, 200 hospice professionals who had received training in hospice care from pilot institutions engaged in or providing hospice care were selected for investigation. Cronbach's α coefficient and split-half reliability were used to test the internal consistency of the scale, and content validity and explore factor analysis (EFA) were used to test the construct validity of the scale. RESULTS: Two rounds of Delphi methods were carried out, and the effective recovery rate was 100%. The expert authority coefficients of the two rounds were 0.838 and 0.833, respectively. The Kendall's W coefficient of experts in the first round was 0.121 ~ 0.200 (P < 0.05), and the Kendall's W coefficient of the second round was 0.115-0.136 (P < 0.05), indicating a good level of expert coordination. The final survey scale for the care burden of hospice professionals included four dimensions-working environment (9 items), professional roles (8 items), clinical nursing (9 items) and psychological burden (7 items)-with a total of 33 items. The total Cronbach's α coefficient of the scale was 0.963, and the Cronbach's α coefficients of the working environment, professional roles, clinical nursing and psychological burden dimensions were 0.920, 0.889, 0.936 and 0.910, respectively. The total split-half reliability of the scale was 0.927, and the split-half reliability of each dimension was 0.846, 0.817, 0.891, and 0.832. The content validity of the scale items ranged from 0.90 to 1.00. Exploratory factor analysis revealed 5 common factors, with a total cumulative contribution rate of 68.878%. The common degree of each item in the scale was > 0.4, and the factor loading of each item was also > 0.4. CONCLUSION: The scale is an open-access, short, easy-to-administer scale. And which for assessing hospice care burden among hospice professionals developed in this study demonstrated strong reliability and validity. This tool can serve as a dependable instrument for evaluating the burden of hospice care for terminally ill patients by professionals in the hospice setting.

A Comparative Study of Human Pluripotent Stem Cell-Derived Macrophages in Modeling Viral Infections.

Macrophages play multiple roles in innate immunity including phagocytosing pathogens, modulating the inflammatory response, presenting antigens, and recruiting other immune cells. Tissue-resident macrophages (TRMs) adapt to the local microenvironment and can exhibit different immune responses upon encountering distinct pathogens. In this study, we generated induced macrophages (iMACs) derived from human pluripotent stem cells (hPSCs) to investigate the interactions between the macrophages and various human pathogens, including the hepatitis C virus (HCV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and Streptococcus pneumoniae. iMACs can engulf all three pathogens. A comparison of the RNA-seq data of the iMACs encountering these pathogens revealed that the pathogens activated distinct gene networks related to viral response and inflammation in iMACs. Interestingly, in the presence of both HCV and host cells, iMACs upregulated different sets of genes involved in immune cell migration and chemotaxis. Finally, we constructed an image-based high-content analysis system consisting of iMACs, recombinant GFP-HCV, and hepatic cells to evaluate the effect of a chemical inhibitor on HCV infection. In summary, we developed a human cell-based in vitro model to study the macrophage response to human viral and bacterial infections; the results of the transcriptome analysis indicated that the iMACs were a useful resource for modeling pathogen-macrophage-tissue microenvironment interactions.

Correlation between lesion location and dysphagia characteristics in post-stroke patients.

OBJECTIVE: To assess the correlation between lesion location and swallowing function characteristics in post-stroke dysphagia (PSD) patients. MATERIALS AND METHODS: We enrolled 133 PSD. The patients were divided into supratentorial and infratentorial stroke groups. We compared the measurements in the videofluoroscopic swallowing study (VFSS) with 3ml and 5 ml of diluted and thickened barium liquid data between supratentorial and brainstem stroke groups. We further compared the difference of VFSS measurements between patients with left hemispheric or right hemispheric lesions (further divided into unilateral hemispheric cortical and subcortical subgroups) and brianstem leison stroke group.To explore the lesion location's effect on different bolus volume, the VFSS measurements of 3ml and 5ml in each subgroups were compared respectively. The measurements of VFSS included the oral transit time, soft palate elevation duration, hyoid bone movement duration (HMD), UES opening duration, pharyngeal transit duration (PTD), stage of ansition duration, and laryngeal closure duration (LCD), the upper esophageal sphincter opening (UESO), hyoid bone superior horizontal displacement, and hyoid bone anterior horizontal displacement. General swallowing function was assessed using the Penetration Aspiration Scale (PAS) and Functional Oral Intake Scale (FOIS). We performed the paired t-test, Spearman's correlation, and Kruskal-Wallis test analysis to characterize the parameters among the groups. RESULTS: Fifty-eight patients were assessed in the final analysis. The HMD (p = 0.019), PTD (p = 0.048) and LCD (p = 0.013) were significantly different between the supratentorial and brainstem lesion groups in 5ml volume. The HMD was significantly different (p = 0.045) between the left cortical and brainstem lesion groups. Significant differences in the HMD (p = 0.037) and LCD (p = 0.032) between the left subcortical and brainstem lesion groups were found in 5ml volume bolus. There was no group different when taking the 3ml volume bolus. Regarding the relationship between food bolus volume and swallowing functions, only the UESO demonstrated a significant difference in the subcortical lesion of the right hemisphere (p = 0.0032) compared the 3 ml and 5 ml volume bolus. The PTD demonstrated a moderate correlation with the PAS scores (r = 0.38, p = 0.0044). The HMD (r = 0.32, p = 0.018) and LCD (r = 0.29, p = 0.039) demonstrated weak correlations with the PAS scores. We did not identify any correlation between the VFSS parameters and FOIS scores in each subgroup level. CONCLUSION: The PSD with brainstem lesion shows more sever dysfunction in the pharyngeal phases. The left hemisphere was engaged in both the oral and pharyngeal phases. Lesions in the bilateral cortical, subcortical, and brainstem regions may impair sensory input.

Corrigendum: ITGB5 promotes innate radiation resistance in pancreatic adenocarcinoma by promoting DNA damage repair and the MEK/ERK signaling pathway.

[This corrects the article DOI: 10.3389/fonc.2022.887068.].

MicroRNA-7 deficiency ameliorates d-galactose-induced aging in mice by regulating senescence of Kupffer cells.

Aging is intricately linked to immune system dysfunction. Recent studies have highlighted the biological function of microRNA-7 (miR-7) as a novel regulator of immune cell function and related diseases. However, the potential role of miR-7 in aging remains unexplored. Here, we investigated the contribution of miR-7 to d-gal-induced aging in mice, focusing on its regulation of senescent Kupffer cells. Our findings revealed that miR-7 deficiency significantly ameliorated the aging process, characterized by enhanced CD4+ T-cell activation. However, the adoptive transfer of miR-7-deficient CD4+ T cells failed to improve the age-related phenotype. Further analysis showed that miR-7 deficiency significantly reduced IL-1ß production in liver tissue, and inhibiting IL-1ß in vivo slowed down the aging process in mice. Notably, IL-1ß is mainly produced by senescent Kupffer cells in the liver tissue of aging mice, and miR-7 expression was significantly up-regulated in these cells. Mechanistically, KLF4, a target of miR-7, was down-regulated in senescent Kupffer cells in aging mouse model. Furthermore, miR-7 deficiency also modulated the NF-κB activation and IL-1ß production in senescent Kupffer cells through KLF4. In conclusion, our findings unveil the role of miR-7 in d-gal-induced aging in mice, highlighting its regulation of KLF4/NF-κB/IL-1ß pathways in senescent Kupffer cells. This research may enhance our understanding of miRNA-based aging immune cells and offer new avenues for new intervention strategies in aging process.

Expression of ethylene biosynthetic genes during flower senescence and in response to ethephon and silver nitrate treatments in Osmanthus fragrans.

BACKGROUND: Sweet osmanthus (Osmanthus fragrans) is an ornamental evergreen tree species in China, whose flowers are sensitive to ethylene. The synthesis of ethylene is controlled by key enzymes and restriction enzymes, 1-aminocyclopropane-1-carboxylic acid synthase (ACS) and 1-aminocyclopropane-1-carboxylic acid oxidase (ACO), which are encoded by multigene families. However, the key synthase responsible for ethylene regulation in O. fragrans is still unknown. OBJECTIVE: This study aims to screen the key ethylene synthase genes of sweet osmanthus flowers in response to ethylene regulation. METHODS: In this study, we used the ACO and ACS sequences of Arabidopsis thaliana to search for homologous genes in the O. fragrans petal transcriptome database. These genes were also analyzed bioinformatically. Finally, the expression levels of O. fragrans were compared before and after senescence, as well as after ethephon and silver nitrate treatments. RESULTS: The results showed that there are five ACO genes and one ACS gene in O. fragrans transcriptome database, and the phylogenetic tree revealed that the proteins encoded by these genes had high homology to the ACS and ACO proteins in plants. Sequence alignment shows that the OfACO1-5 proteins have the 2OG-Fe(II) oxygenase domain, while OfACS1 contains seven conserved domains, as well as conserved amino acids in transaminases and glutamate residues related to substrate specificity. Expression analysis revealed that the expression levels of OfACS1 and OfACO1-5 were significantly higher at the early senescence stage compared to the full flowering stage. The transcripts of the OfACS1, OfACO2, and OfACO5 genes were upregulated by treatment with ethephon. However, out of these three genes, only OfACO2 was significantly downregulated by treatment with AgNO3. CONCLUSION: Our study found that OfACO2 is an important synthase gene in response to ethylene regulation in sweet osmanthus, which would provide valuable data for further investigation into the mechanisms of ethylene-induced senescence in sweet osmanthus flowers.

The novel TERF2::PDGFRB fusion gene enhances tumorigenesis via PDGFRB/STAT5 signalling pathways and sensitivity to TKI in ph-like ALL.

Patients with Philadelphia chromosome-like acute lymphoblastic leukaemia (Ph-like ALL) often face a grim prognosis, with PDGFRB gene fusions being commonly detected in this subgroup. Our study has unveiled a newfound fusion gene, TERF2::PDGFRB, and we have found that patients carrying this fusion gene exhibit sensitivity to dasatinib. Ba/F3 cells harbouring the TERF2::PDGFRB fusion display IL-3-independent cell proliferation through activation of the p-PDGFRB and p-STAT5 signalling pathways. These cells exhibit reduced apoptosis and demonstrate sensitivity to imatinib in vitro. When transfused into mice, Ba/F3 cells with the TERF2::PDGFRB fusion gene induce tumorigenesis and a shortened lifespan in cell-derived graft models, but this outcome can be improved with imatinib treatment. In summary, we have identified the novel TERF2::PDGFRB fusion gene, which exhibits oncogenic potential both in vitro and in vivo, making it a potential therapeutic target for tyrosine kinase inhibitors (TKIs).

Metabolic-dysfunction associated steatotic liver disease-related diseases, cognition and dementia: A two-sample mendelian randomization study.

BACKGROUND: The results of current studies on metabolic-dysfunction associated steatotic liver disease (MASLD)-related diseases, cognition and dementia are inconsistent. This study aimed to elucidate the effects of MASLD-related diseases on cognition and dementia. METHODS: By using single-nucleotide polymorphisms (SNPs) associated with different traits of NAFLD (chronically elevated serum alanine aminotransferase levels [cALT], imaging-accessed and biopsy-proven NAFLD), metabolic dysfunction-associated steatohepatitis, and liver fibrosis and cirrhosis, we employed three methods of mendelian randomization (MR) analysis (inverse-variance weighted [IVW], weighted median, and MR-Egger) to determine the causal relationships between MASLD-related diseases and cognition and dementia. We used Cochran's Q test to examine the heterogeneity, and MR-PRESSO was used to identify outliers (NbDistribution = 10000). The horizontal pleiotropy was evaluated using the MR-Egger intercept test. A leave-one-out analysis was used to assess the impact of individual SNP on the overall MR results. We also repeated the MR analysis after excluding SNPs associated with confounding factors. RESULTS: The results of MR analysis suggested positive causal associations between MASLD confirmed by liver biopsy (p of IVW = 0.020, OR = 1.660, 95%CI = 1.082-2.546) and liver fibrosis and cirrhosis (p of IVW = 0.009, OR = 1.849, 95%CI = 1.169-2.922) with vascular dementia (VD). However, there was no evidence of a causal link between MASLD-related diseases and cognitive performance and other types of dementia (any dementia, Alzheimer's disease, dementia with lewy bodies, and frontotemporal dementia). Sensitivity tests supported the robustness of the results. CONCLUSIONS: This two-sample MR analysis suggests that genetically predicted MASLD and liver fibrosis and cirrhosis may increase the VD risk. Nonetheless, the causal effects of NAFLD-related diseases on VD need more in-depth research.

Targeting lipid metabolism of macrophages: A new strategy for tumor therapy.

BACKGROUND: Lipid metabolism has been implicated in a variety of normal cellular processes and strongly related to the development of multiple diseases, including tumor. Tumor-associated macrophage (TAM) has emerged as a crucial regulator in tumorigenesis and promising target for tumor treatment. AIM OF REVIEW: A thorough understanding of TAM lipid metabolism and its value in tumorigenesis may provide new ideas for TAM-based anti-tumor therapy. Key scientific concepts of review: TAMs can be divided into two main types, M1-like TAMs and M2-like TAMs, which play anti-tumor and pro-tumor functions in tumor occurrence and development, respectively. Accumulating evidence has shown that lipid metabolic reprogramming, including fatty acid uptake and utilization, cholesterol expulsion, controls the polarization of TAMs and affects the tumorgenesis. These advances in uncovering the intricacies of lipid metabolism and TAMs have yielded new insights on tumor development and treatment. In this review, we aim to provide an update on the current understanding of the lipid metabolic reprogramming made by TAMs to adapt to the harsh tumor microenvironment (TME). In particular, we emphasize that there is complex lipid metabolism connections between TAMs and distinct tumors, which influences TAM to bias from M1 to M2 phenotype in tumor progression, and ultimately promotes tumor occurrence and development. Finally, we discuss the existing issues on therapeutic strategies by reprogramming TAMs based on lipid metabolism regulation (or increasing the ratio of M1/M2-like TAMs) that could be applied in the future to clinical tumor treatment.