PREX2 contributes to radiation resistance by inhibiting radiotherapy-induced tumor immunogenicity via cGAS/STING/IFNs pathway in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) lacks established biomarkers or molecular targets for predicting or enhancing radiation response. Phosphatidylinositol-3,4,5-triphosphate-dependent Rac exchange factor 2 (PREX2) exhibits intricate implications in tumorigenesis and progression. Nevertheless, the precise role and underlying mechanisms of PREX2 in CRC radioresistance remain unclear. METHODS: RNA-seq was employed to identify differentially expressed genes between radioresistant CRC cell lines and their parental counterparts. PREX2 expression was scrutinized using Western blotting, real-time PCR, and immunohistochemistry. The radioresistant role of PREX2 was assessed through in vitro colony formation assay, apoptosis assay, comet assay, and in vivo xenograft tumor models. The mechanism of PREX2 was elucidated using RNA-seq and Western blotting. Finally, a PREX2 small-molecule inhibitor, designated PREX-in1, was utilized to enhance the efficacy of ionizing radiation (IR) therapy in CRC mouse models. RESULTS: PREX2 emerged as the most significantly upregulated gene in radioresistant CRC cells. It augmented the radioresistant capacity of CRC cells and demonstrated potential as a marker for predicting radioresistance efficacy. Mechanistically, PREX2 facilitated DNA repair by upregulating DNA-PKcs, suppressing radiation-induced immunogenic cell death, and impeding CD8+ T cell infiltration through the cGAS/STING/IFNs pathway. In vivo, the blockade of PREX2 heightened the efficacy of IR therapy. CONCLUSIONS: PREX2 assumes a pivotal role in CRC radiation resistance by inhibiting the cGAS/STING/IFNs pathway, presenting itself as a potential radioresistant biomarker and therapeutic target for effectively overcoming radioresistance in CRC.

The updates on metastatic mechanism and treatment of colorectal cancer.

Colorectal cancer (CRC) is a main cause of cancer death worldwide. Metastasis is a major cause of cancer-related death in CRC. The treatment of metastatic CRC has progressed minimally. However, the potential molecular mechanisms involved in CRC metastasis have remained to be comprehensively clarified. An improved understanding of the CRC mechanistic determinants is needed to better prevent and treat metastatic cancer. In this review, based on evidence from a growing body of research in metastatic cancers, we discuss the cellular and molecular mechanisms involved in CRC metastasis. This review reveals both the molecular mechanisms of metastases and identifies new opportunities for developing more effective strategies to target metastatic relapse and improve CRC patient outcomes.

Cuproptosis-related risk score predicts prognosis and characterizes the tumor microenvironment in colon adenocarcinoma.

Introduction: Cuproptosis is a novel copper-dependent regulatory cell death (RCD), which is closely related to the occurrence and development of multiple cancers. However, the potential role of cuproptosis-related genes (CRGs) in the tumor microenvironment (TME) of colon adenocarcinoma (COAD) remains unclear. Methods: Transcriptome, somatic mutation, somatic copy number alteration and the corresponding clinicopathological data of COAD were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus database (GEO). Difference, survival and correlation analyses were conducted to evaluate the characteristics of CRGs in COAD patients. Consensus unsupervised clustering analysis of CRGs expression profile was used to classify patients into different cuproptosis molecular and gene subtypes. TME characteristics of different molecular subtypes were investigated by using Gene set variation analysis (GSVA) and single sample gene set enrichment analysis (ssGSEA). Next, CRG Risk scoring system was constructed by applying logistic least absolute shrinkage and selection operator (LASSO) cox regression analysis and multivariate cox analysis. Real-time quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC) were used to exam the expression of key Risk scoring genes. Results: Our study indicated that CRGs had relatively common genetic and transcriptional variations in COAD tissues. We identified three cuproptosis molecular subtypes and three gene subtypes based on CRGs expression profile and prognostic differentially expressed genes (DEGs) expression profile, and found that changes in multilayer CRGs were closely related to the clinical characteristics, overall survival (OS), different signaling pathways, and immune cell infiltration of TME. CRG Risk scoring system was constructed according to the expression of 7 key cuproptosis-related risk genes (GLS, NOX1, HOXC6, TNNT1, GLS, HOXC6 and PLA2G12B). RT-qPCR and IHC indicated that the expression of GLS, NOX1, HOXC6, TNNT1 and PLA2G12B were up-regulated in tumor tissues, compared with those in normal tissues, and all of GLS, HOXC6, NOX1 and PLA2G12B were closely related with patient survival. In addition, high CRG risk scores were significantly associated with high microsatellite instability (MSI-H), tumor mutation burden (TMB), cancer stem cell (CSC) indices, stromal and immune scores in TME, drug susceptibility, as well as patient survival. Finally, a highly accurate nomogram was constructed to promote the clinical application of the CRG Risk scoring system. Discussion: Our comprehensive analysis showed that CRGs were greatly associated with TME, clinicopathological characteristics, and prognosis of patient with COAD. These findings may promote our understanding of CRGs in COAD, providing new insights for physicians to predict prognosis and develop more precise and individualized therapy strategies.

Predictive value of serum HIF-1α and VEGF for arrhythmia in acute coronary syndrome patients.

Percutaneous coronary intervention (PCI) has been widely used in the alleviation of myocardial ischemia in patients with acute coronary syndrome (ACS). However, the incidence of reperfusion arrhythmia (RA) after PCI is high, which seriously affects the prognosis of ACS patients. Therefore, this study aimed to study the predictive value of serum HIF-1α and VEGF levels before PCI for RA in ACS patients post PCI. A total of 200 ACS patients who underwent PCI were selected and divided into those with RA after PCI (RA, n = 93) and those without RA after PCI (non-RA, n = 107) according to Lown grade. Spearman correlation analysis was applied for the relationship between serum hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) levels and Lown grade. Patients with RA after PCI tended to have higher levels of creatine kinase muscle and brain isoenzyme (CK-MB), serum HIF-1α and VEGF before surgery. Low left ventricular ejection fraction (LVEF), high CK-MB, high serum VEGF and HIF-1α were risk factors for RA in ACS patients within 24 h after PCI. Receiver operating characteristic (ROC) analysis revealed that serum HIF-1α and VEGF levels could predict RA in ACS patients after PCI, and the combined detection could increase the sensitivity of single HIF-1α detection and the specificity of single VEGF detection. Lown grade was positively correlated with the serum HIF-1α and VEGF concentrations. In conclusion, serum HIF-1α and VEGF levels before PCI are risk factors for the occurrence of RA in ACS patients after PCI, and have certain predictive values for the occurrence of RA in ACS patients after PCI.

A study of clinical and molecular characteristics in bilateral primary breast cancer.

BACKGROUND: Bilateral primary breast cancer (BPBC) is a rare type of breast cancer. Studies on the clinicopathologic and molecular characteristics of BPBC in a metastatic context are very limited. METHODS: A total of 574 unselected metastatic breast cancer patients with clinical information were enrolled in our next-generation sequencing (NGS) database. Patients with BPBC from our NGS database were regarded as the study cohort. In addition, 1467 patients with BPBC and 2874 patients with unilateral breast cancer (UBC) from the Surveillance, Epidemiology, and End Results (SEER) public database were also analyzed to determine the characteristics of BPBC. RESULTS: Among the 574 patients enrolled in our NGS database, 20 (3.5%) patients had bilateral disease, comprising 15 (75%) patients with synchronous bilateral disease and 5 (25%) patients with metachronous bilateral disease. Eight patients had bilateral hormone receptor-positive (HR+)/human epidermal growth factor receptor-negative (HER2-) tumors, and three had unilateral HR+/HER2- tumors. More HR+/HER2- tumors and lobular components were found in BPBC patients than in UBC patients. The molecular subtype of the metastatic lesions in three patients was inconsistent with either side of the primary lesions, which suggested the importance of rebiopsy. Strong correlations in clinicopathologic features between the left and right tumors in BPBC were exhibited in the SEER database. In our NGS database, only one BPBC patient was found with a pathogenic germline mutation in BRCA2. The top mutated somatic genes in BPBC patients were similar to those in UBC patients, including TP53 (58.8% in BPBC and 60.6% in UBC) and PI3KCA (47.1% in BPBC and 35.9% in UBC). CONCLUSIONS: Our study suggested that BPBC may tend to be lobular carcinoma and have the HR+/HER2- subtype. Although our study did not find specific germline and somatic mutations in BPBC, more research is needed for verification.

Analysis of clinical features, genomic landscapes and survival outcomes in HER2-low breast cancer.

BACKGROUND: Novel human epidermal growth factor receptor 2 (HER2)-directed antibody-drug conjugates prompt the identification of the HER2-low subtype. However, the biological significance of HER2-low expression in breast cancer is unclear. METHODS: Clinical and genomic data of 579 metastatic breast cancer patients were reviewed from our next-generation sequencing (NGS) database and genomic analysis of early breast cancer patients from TCGA was also analyzed. FINDINGS: First, the clinicopathological characteristics of HER2-low patients were profoundly influenced by HR status and no difference of prognosis was observed between HER2-low and HER2-zero patients when paired by HR status, but notably HER2-low patients showed similar metastatic patterns to HER2-positive patients in the HR-positive (HR+ ) subgroup, with more brain and initial lung metastases and more cases of de novo stage IV breast cancer than HER2-zero patients. Second, among patients with primary HER2-low or HER2-zero tumors, the discordance of HER2 status between primary and metastatic tumors was significant, with 48.4% of patients with HER2-zero primary tumors exhibiting HER2-low phenotype in metastatic tumors in the HR+ subgroup. Third, within HR+ and HR-negative subtypes, HER2-low and HER2-zero tumors showed no substantial differences in mutation alterations and copy number variations. Forth, germline BRCA2 mutations were observed only in HER2-low patients in our NGS database, especially in HR+ HER2-low tumors. Finally, three molecular subtypes based on genomic alterations in HER2-low breast cancer were identified, which provided novel insights into heterogeneity in HER2-low breast cancer. CONCLUSIONS: After correcting for HR expression, only marginal differences in clinical and molecular phenotypes were determined between HER2-low and HER2-zero breast cancer. Therefore, HER2-low breast cancer is insufficient to be defined as a distinct molecular entity, but rather a heterogenous disease.

Chromatin Remodelling Molecule ARID1A Determines Metastatic Heterogeneity in Triple-Negative Breast Cancer by Competitively Binding to YAP.

Heterogeneity represents a pivotal factor in the therapeutic failure of triple-negative breast cancer (TNBC). In this study, we retrospectively collected and analysed clinical and pathological data from 258 patients diagnosed with TNBC at the Fudan University Cancer Hospital. Our findings show that low ARID1A expression is an independent prognostic indicator for poor overall survival (OS) and recurrence-free survival (RFS) in TNBC patients. Mechanistically, both nuclear and cytoplasmic protein analyses and immunofluorescent localisation assays confirm that ARID1A recruits the Hippo pathway effector YAP into the nucleus in human triple-negative breast cancer cells. Subsequently, we designed a YAP truncator plasmid and confirmed through co-immunoprecipitation that ARID1A can competitively bind to the WW domain of YAP, forming an ARID1A/YAP complex. Moreover, the downregulation of ARID1A promoted migration and invasion in both human triple-negative breast cancer cells and xenograft models through the Hippo/YAP signalling axis. Collectively, these findings demonstrate that ARID1A orchestrates the molecular network of YAP/EMT pathways to affect the heterogeneity in TNBC.

Study on optimization of multi-UAV nucleic acid sample delivery paths in large cities under the influence of epidemic environment.

In the context of global novel coronavirus infection, we studied the distribution problem of nucleic acid samples, which are medical supplies with high urgency. A multi-UAV delivery model of nucleic acid samples with time windows and a UAV (Unmanned Aerial Vehicle) dynamics model for multiple distribution centers is established by considering UAVs' impact cost and trajectory cost. The Golden Eagle optimization algorithm (SGDCV-GEO) based on gradient optimization and Corsi variation is proposed to solve the model by introducing gradient optimization and Corsi variation strategy in the Golden Eagle optimization algorithm. Performance evaluation by optimizing test functions, Friedman and Nemenyi test compared with Golden Jackal Optimization (GJO), Hunter-Prey Optimization (HPO), Pelican Optimization Algorithm (POA), Reptile Search Algorithm (RSA) and Golden Eagle Optimization (GEO), the convergence performance of SGDCV-GEO algorithm was demonstrated. Further, the improved RRT (Rapidly-exploring Random Trees) algorithm is used in the UAV path planning, and the pruning process and logistic chaotic mapping strategy are introduced in the path generation method. Finally, simulation experiments are conducted based on 8 hospitals and 50 randomly selected communities in the Pudong district of Shanghai, southern China. The experimental results show that the developed algorithm can effectively reduce the delivery cost and total delivery time compared with simulated annealing algorithm (SA), crow search algorithm (CSA), particle swarm algorithm (PSO), and taboo search algorithm (TS), and the developed algorithm has good uniformity, robustness, and high convergence accuracy, which can be effectively applied to the multi-UAV nucleic acid sample delivery path optimization in large cities under the influence of an epidemic environment.

Optimization of urban emergency support material distribution under major public health emergencies based on improved sparrow search algorithm.

The outbreak of major public health emergencies such as the coronavirus epidemic has put forward new requirements for urban emergency management procedures. Accuracy and effective distribution model of emergency support materials, as an effective tool to inhibit the deterioration of the public health sector, have gradually become a research hotspot. The distribution of urban emergency support devices, under the secondary supply chain structure of "material transfer center-demand point," which may involve confusing demands, is studied to determine the actual situation of fuzzy requests under the impact of an epidemic outbreak. An optimization model of urban emergency support material distribution, based on Credibility theory, is first constructed. Then an improved sparrow search algorithm, ISSA, was designed by introducing Sobol sequence, Cauchy variation and bird swarm algorithm into the structure of the classical SSA. In addition, numerical validation and standard test set validation were carried out and the experimental results showed that the introduced improved strategy effectively improved the global search capability of the algorithm. Furthermore, simulation experiments are conducted, based on Shanghai, and the comparison with existing cutting-edge algorithms shows that the designed algorithm has stronger superiority and robustness. And the simulation results show that the designed algorithm can reduce vehicle cost by 4.83%, time cost by 13.80%, etc. compared to other algorithms. Finally, the impact of preference value on the distribution of emergency support materials is analyzed to help decision-makers to develop reasonable and effective distribution strategies according to the impact of major public health emergencies. The results of the study provide a practical reference for the solution of urban emergency support materials distribution problems.

Landscape of DNA damage response gene alterations in breast cancer: A comprehensive investigation.

BACKGROUND: DNA damage response (DDR) gene alterations are prevalent in breast cancer (BC) and important for treatment decisions. Intensive studies on DDR alterations in BC are still needed. METHODS: The authors included 438 patients with metastatic breast cancer from their next-generation sequencing database and 1091 patients with early-stage breast cancer from The Cancer Genome Atlas (TCGA) database in the analysis to characterize molecular alterations in the DDR pathway. RESULTS: Germline DDR mutations were more prevalent in younger patients and those with HER2-negative cancers. Tumors with germline DDR mutations more commonly had somatic DDR mutations, especially those with germline Fanconi anemia (FA) pathway mutations. Notably, 66.67% (four of six) of patients with germline PALB2 mutations had tumors that harbored somatic PALB2 mutations. No differences in prognosis were observed in patients with germline or tumor somatic DDR mutations compared to patients and tumors that were wild-type. Compared to early BC, the frequency of somatic DDR mutations in metastatic cancers was significantly higher (24.89% vs. 16.02%, p < .001). Higher tumor mutation burdens were observed in cancers with somatic DDR mutations, but not in cancers with germline DDR mutations. Furthermore, tumors with somatic DDR mutations showed an abundance of anticancer immunological phenotypes. Somatic FA and mismatch repair pathway mutations were associated with increased expression of immune checkpoint molecules. Although most DDR genes were significantly positively associated with expression of proliferation-related genes, PARP3 expression was negatively correlated with MKI67 expression. Lower PARP3 expression was associated with a worse prognosis in TCGA database by multivariate Cox analysis. CONCLUSIONS: Patients with germline FA mutations more frequently have tumors with somatic DDR mutations. Somatic DDR mutations lead to anticancer immunological phenotypes in BC. No differences in prognosis according to germline or somatic DDR mutations were found.

Trx CDSP32-overexpressing tobacco plants improves cadmium tolerance by modulating antioxidant mechanism.

The effects of overexpression of the thioredoxin-like protein CDSP32 (Trx CDSP32) on reactive oxygen species (ROS) metabolism in tobacco leaves exposed to cadmium (Cd) were studied by combining physiological measures and proteomics technology. Thus, the number of differentially expressed proteins (DEPs) in plants overexpressing the Trx CDSP32 gene in tobacco (OE) was observed to be evidently lower than that in wild-type (WT) tobacco under Cd exposure, especially the number of down-regulated DEPs. Cd exposure induced disordered ROS metabolism in tobacco leaves. Although Cd exposure inhibited the activities of superoxide dismutase (SOD), catalase (CAT), and l-ascorbate peroxidase (APX) and the expression of proteins related to the thioredoxin-peroxiredoxin (Trx-Prx) pathway, the increase in the activities of peroxidase (POD), monodehydroascorbate reductase (MDHAR), dehydroascorbate reductase (DHAR), glutathione reductase (GR), glutathione peroxidase (GPX), and glutathione S-transferase (GST) and their protein expression levels played an important role in the physiological response to Cd exposure. Notably, Trx CDSP32 was observed to alleviate the decrease in the expression and activities of SOD and CAT caused by Cd exposure and enhance the function of POD. Trx CDSP32 was observed to increase the H2O2 scavenging capacity of the ascorbic acid-glutathione (AsA-GSH) cycle and Trx-Prx pathway under Cd exposure, and it can especially regulate 2-Cys peroxiredoxin (2-Cys Prx) protein expression and thioredoxin peroxidase (TPX) activity. Thus, overexpression of the Trx CDSP32 gene can alleviate the oxidative damage that occurs in tobacco leaves under Cd exposure by modulating antioxidant defense systems.

Identification of cuproptosis-related subtypes, construction of a prognosis model, and tumor microenvironment landscape in gastric cancer.

Introduction: Cuproptosis is a novel identified regulated cell death (RCD), which is correlated with the development, treatment response and prognosis of cancer. However, the potential role of cuproptosis-related genes (CRGs) in the tumor microenvironment (TME) of gastric cancer (GC) remains unknown. Methods: Transcriptome profiling, somatic mutation, somatic copy number alteration and clinical data of GC samples were downloaded from the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database to describe the alterations of CRGs from genetic and transcriptional fields. Differential, survival and univariate cox regression analyses of CRGs were carried out to investigate the role of CRGs in GC. Cuproptosis molecular subtypes were identified by using consensus unsupervised clustering analysis based on the expression profiles of CRGs, and further analyzed by GO and KEGG gene set variation analyses (GSVA). Genes in distinct molecular subtypes were also analyzed by GO and KEGG gene enrichment analyses (GSEA). Differentially expressed genes (DEGs) were screened out from distinct molecular subtypes and further analyzed by GO enrichment analysis and univariate cox regression analysis. Consensus clustering analysis of prognostic DEGs was performed to identify genomic subtypes. Next, patients were randomly categorized into the training and testing group at a ratio of 1:1. CRG Risk scoring system was constructed through logistic least absolute shrinkage and selection operator (LASSO) cox regression analysis, univariate and multivariate cox analyses in the training group and validated in the testing and combined groups. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to evaluate the expression of key Risk scoring genes. Sensitivity and specificity of Risk scoring system were examined by using receiver operating characteristic (ROC) curves. pRRophetic package in R was used to investigate the therapeutic effects of drugs in high- and low- risk score group. Finally, the nomogram scoring system was developed to predict patients' survival through incorporating the clinicopathological features and CRG Risk score. Results: Most CRGs were up-regulated in tumor tissues and showed a relatively high mutation frequency. Survival and univariate cox regression analysis revealed that LIAS and FDX1 were significantly associated with GC patients' survival. After consensus unsupervised clustering analysis, GC patients were classified into two cuproptosis molecular subtypes, which were significantly associated with clinical features (gender, age, grade and TNM stage), prognosis, metabolic related pathways and immune cell infiltration in TME of GC. GO enrichment analyses of 84 DEGs, obtained from distinct molecular subtypes, revealed that DEGs primarily enriched in the regulation of metabolism and intracellular/extracellular structure in GC. Univariate cox regression analysis of 84 DEGs further screened out 32 prognostic DEGs. According to the expression profiles of 32 prognostic DEGs, patients were re-classified into two gene subtypes, which were significantly associated with patients' age, grade, T and N stage, and survival of patients. Nest, the Risk score system was constructed with moderate sensitivity and specificity. A high CRG Risk score, characterized by decreased microsatellite instability-high (MSI-H), tumor mutation burden (TMB) and cancer stem cell (CSC) index, and high stromal and immune score in TME, indicated poor survival. Four of five key Risk scoring genes expression were dysregulated in tumor compared with normal samples. Moreover, CRG Risk score was greatly related with sensitivity of multiple drugs. Finally, we established a highly accurate nomogram for promoting the clinical applicability of the CRG Risk scoring system. Discussion: Our comprehensive analysis of CRGs in GC demonstrated their potential roles in TME, clinicopathological features, and prognosis. These findings may improve our understanding of CRGs in GC and provide new perceptions for doctors to predict prognosis and develop more effective and personalized therapy strategies.

Modeling and optimization of cascaded lasing in a holmium doped fluoride fiber laser with efficient output at 3.92†µm.

In this paper, we investigate the output performance of a continuous-wave Ho3+-doped fluoride fiber laser operating at 3.92 µm from the 5I5 → 5I6 transition of Ho3+ using numerical simulation. A double-clad Ho3+-doped fluoroindate fiber with a doping concentration of 10.0 mol.% is assumed, with direct pumping at 888 nm. We propose simultaneous lasing on the 5I6 → 5I7 transition to enhance the slope efficiency while reducing the threshold and heat accumulation. Simulation results indicate that a slope efficiency of 17% and a threshold of 2.5 W can be obtained using a 9 cm-long fiber. Moreover, with the heat accumulation reduced by >40%, watt level laser output can be achieved in this cascade system at room temperature without the gain fiber being damaged by heat accumulation. The theoretical maximum output power of 1.27 W is 6 times higher than the highest reported value (197 mW), which is limited by the fiber damage due to excess heat load.

Single-pixel neural network object classification of sub-Nyquist ghost imaging.

A single-pixel neural network object classification scenario in the sub-Nyquist ghost imaging system is proposed. Based on the neural network, objects are classified directly by bucket measurements without reconstructing images. Classification accuracy can still be maintained at 94.23% even with only 16 measurements (less than the Nyquist limit of 1.56%). A parallel computing scheme is applied in data processing to reduce the object acquisition time significantly. Random patterns are used as illumination patterns to illuminate objects. The proposed method performs much better than existing methods for both binary and grayscale images in the sub-Nyquist condition, which is also robust to environment noise turbulence. Benefiting from advantages of ghost imaging, it may find applications for target recognition in the fields of remote sensing, military defense, and so on.

Characterization of the complete chloroplast genome of Hedysarum polybotrys var. alaschanicum (Fabaceae) and its phylogeny.

Hedysarum polybotrys var. alaschanicum is an important medicinal plant and is widely used in traditional Chinese medicine. The complete chloroplast genome of H. polybotrys var. alaschanicum was assembled from Illumina pair-end sequence reads. The whole chloroplast genome is 122,933 bp in length and encodes a total of 110 genes, including 76 protein-coding genes, 30 tRNA genes and 4 rRNA genes. The overall GC content of the cp genome is 35.3%. A maximum likelihood (ML) phylogenetic analysis revealed that H. polybotrys var. alaschanicum was close to Hedysarum semenovii.

Exploring the microbiota-Alzheimer's disease linkage using short-term antibiotic treatment followed by fecal microbiota transplantation.

Gut microbiota is proven to be involved in the development of beta amyloid (Aß) pathology in Alzheimer's disease (AD). Since there are difficulties in translating microbiota findings based on germ-free mice into clinical practice, here, we used short-term antibiotic cocktail treatment to develop a novel model with a near-germ-free status and without impacting Aß pathology. Three months old APPSWE/PS1ΔE9 mice were fed with antibiotic cocktails for two weeks by gavage to obtain a near "germ-free" status, and then received the donor fecal matter from the 16 months old APPSWE/PS1ΔE9 mice for 7 consecutive days. Fecal pellets were collected prior to antibiotics treatment, following antibiotic exposure, prior to and following fecal microbiota transplantation for gut microbiota analysis. Also, Aß pathology, astrocyte and microglia morphology were further explored. Pre-antibiotic-treated mice successfully allowed engraftment of gut microbiota following 7 consecutive days gavage with aged APPSWE/PS1ΔE9 mice microbiota. Microbiota reconstitution by transplantation was largely attributable to the donor source (e.g. g_Coriobacteriaceae and g_Clostridium) and led to a significant increase in Aß plaques. Surprisingly, astrocyte activation around Aß plaques was suppressed rather than microglia, the well-recognized plaque phagocytic cell type in Aß clearance, following microbiota engraftment. Our findings provide a novel framework for understanding the mechanisms of AD through the gut-brain axis and the translation of gut microbiota manipulation from bench to clinical practice.

Bifidobacterium Lactis Probio-M8 regulates gut microbiota to alleviate Alzheimer's disease in the APP/PS1 mouse model.

PURPOSE: Studies have shown that Alzheimer's disease is associated with significant alterations in the gut microbiota. But the effect of probiotics and/or prebiotics on Alzheimer's disease still remains to be explored. The aim of this study was to determine whether Bifidobacterium Lactis Probio-M8 could alleviate Alzheimer's disease pathophysiologies in the APP/PS1 transgenic mouse model. METHODS: 4-month old APP/PS1 mice were randomly put into two groups and fed with either Probio-M8 or saline water for 45 days. Fecal samples of mice were collected at the beginning and the end of the treatment period to determine the composition of the gut microbiota via 16S ribosomal RNA sequencing technology. The number and size of Aß plaques in the brain were quantified. In addition, Y maze, novel object recognition and nest building were employed to access cognitive function in the 8-months old APP/PS1 mice at the end of the treatment period. CONCLUSION: Our results demonstrated that Probio-M8 reduced Aß plaque burden in the whole brain and protected against gut microbiota dysbiosis. Furthermore, Probio-M8 could alleviate cognitive impairment in the APP/PS1 mouse.

Anxiety and depression are risk factors for recurrent pregnancy loss: a nested case-control study.

BACKGROUND: To evaluate the interaction of depression and anxiety with the development of recurrent pregnancy loss (RPL). METHODS: A nested case-control study involving 2558 participants was conducted with data from the prospective Miscarriage Woman Cohort study between 2017 and 2019 in the province of Gansu, China. The questionnaire data, self-rating anxiety scale and self-rating depression scale were collected after each participant's first miscarriage. Information on RPL outcomes was obtained from the medical records within the subsequent 2 years. All patients diagosed RPL were recruited as cases whilst a randomly selected group of women with only one miscarriage in the past were recruited as controls. The logistic regression and the interaction effects between anxiety and depression and RPL were analysed. RESULTS: The prevalence of anxiety (n = 325, 28.7% vs. n = 278, 19.5%) and depression symptoms (n = 550, 48.6% vs. n = 589, 41.3%) for the 1132 RPL cases were higher than 1426 non-RPL controls (P < 0.001). After adjusting for possible confounding variables, the odds ratio (OR) value, reflecting the multiplicative interaction, was 1.91 (95% CI 1.50-2.44, P < 0.001) for cases with both anxiety and depression symptoms compared with the non-RPL group. The relative excess risk of interaction value, reflecting the additive interaction between anxiety and depression to RPL was 1.15 (95% CI 0.32-4.21). Moreover, the adjusted OR for RPL cases with mild anxiety and severe depression was 2.77 (95% CI 1.07-44.14, P < 0.001), for RPL cases with severe anxiety and mild depression was 4.23 (95% CI 1.01-22.21, P < 0.001), for RPL cases with severe anxiety and moderate depression was 4.34 (95% CI 1.03-21.28, P < 0.001) and for RPL cases with severe anxiety and severe depression was 5.95 (95% CI 1.09-45.09, P < 0.05). CONCLUSIONS: Either depression or anxiety alone could increase the risk of subsequent RPL. Anxiety and depression had a synergistic effect after the first miscarriage which increased the development of subsequent RPL disease.

Analysis the alteration of systemic inflammation in old and young APP/PS1 mouse.

The impairment of cognitive function was considered as a major clinic feature in Alzheimer's disease (AD) patients. Thus, a number of researches related to AD were focused on the changes in brain. However, as a neurodegenerative disorder with systemic inflammation, the periphery organs may also play a key role in AD pathology. Here, we pose the hypothesis that histopathology and inflammatory response of periphery organs may alter with aging in APP/PS1 mouse model. Therefore, we performed immunohistochemical staining technology to double label Aß plaques and microglia cells in brain. The H&E staining was performed in periphery tissues and the mRNA expression of inflammatory factors IL-6, IL-10 and TNF-α were also determined. Next, the index of oxidative stress was measured. Consequently, the level of inflammatory factors was significantly increased in 24 months APP/PS1 mice. Furthermore, the enzyme activity of SOD, CAT and GSH were significantly decreased in colon and other organs. Our results demonstrated the increased inflammation response and declined antioxidative capacity of periphery organs in aged APP/PS1 mice, which suggesting that a more comprehensive perspective to study AD were necessary.

Identification of Microbiota within Aß Plaque in APP/PS1 Transgenic Mouse.

Microbes like viruses, bacteria, and fungi have all been reported in the brain of Alzheimer's postmortem patients and/or AD mouse model; however, the relationship between brain microbes and Aß plaque deposition remains to be elucidated. In the present study, we first analyzed bacteria populations in the brain of 4-, 5-, and 6-month-old APP/PS1 mice and then examined the Aß-positive loads of APP/PS1 mouse at 9 months old to identify bacteria in the brain by 16S rDNA sequencing. Finally, blood-brain barrier permeability was measured by injecting dextrans through the tail vein. Surprisingly, the diversity of microbial community gradually decreased in APP/PS1 mouse while wild-type mouse showed no obvious regularity. Moreover, Aß-positive deposits in the brain showed a significantly higher relative abundance of microbiota than Aß-negative tissues and age-matched wild-type mouse brain tissues. In addition, an increase in blood-brain barrier permeability was also observed in APP/PS1 mouse. The present study revealed the exact location of microbes within the Aß plaques in the brain and suggested the potential antimicrobial effect of the Aß peptide. We strongly recommend that future research on microbiota-related AD pathology should focus on the migration route of microbiota into the brain and how the microbiota enhance AD progression.