Taurine Inhibits Lung Metastasis in Triple-Negative Breast Cancer by Modulating Macrophage Polarization Through PTEN-PI3K/Akt/mTOR Pathway.

SUMMARY: Taurine (Tau) has been found to inhibit triple-negative breast cancer (TNBC) invasion and metastasis. However, its effect on tumor-promoting macrophages and tumor suppressor macrophages in breast cancer progression remains unknown. In this study, we investigated the effects of Tau on macrophage polarization and its role in TNBC cell growth, invasion, and metastasis. We induced human THP-1 monocytes to differentiate into M2 macrophages through exogenous addition of interleukin-4. We used the TNBC cell lines MDA-MB-231 and BT-549 cultured in a conditioned medium from M2 macrophages to investigate the effect of Tau on tumor growth and invasion. We analyzed macrophage subset distribution, M1 and M2 macrophage-associated markers, and mRNA expression by quantitative polymerase chain reaction. We also detected the PTEN-PI3K/Akt/mTOR signaling pathway that mediates M1 macrophage to suppress tumor invasion using western blotting. Our results showed that Tau inhibits breast cancer metastasis to the lungs in vivo and cell invasion by altering the polarization of tumor-associated macrophage in vitro. In addition, Tau can up-regulate PTEN expression, suppress the PI3K-Akt signaling pathway, and promote the M1 polarization of macrophages, which ultimately inhibits the metastasis of TNBC cells. Our findings suggest that Tau inhibits the activation of the PI3K-Akt-mTOR signaling pathway by up-regulating PTEN, promotes the proportion of M1 macrophages in tumor-associated macrophage, and suppresses the invasion and metastasis of TNBC. This provides a potential therapeutic approach to influence cancer progression and metastasis.

Semiphysical Design Concept for Developing Miniaturized Microrobots In Vivo.

The miniaturization of biomedical microrobots is crucial for their in vivo applications. However, it is challenging to reduce their size while maintaining their biomedical functions. To resolve this contradiction, we propose a semiphysical design concept for developing miniaturized microrobots, in which invisible components such as light beams are utilized to replace most of the physical parts of a microrobot, thus minimizing its physical size without sacrificing its biomedical functions. According to this design, we have constructed a semiphysical microrobot (SPM) composed of main light beam, light-responsive microparticle, and auxiliary light beam, serving as the actuation system, recognition part, and surgical claws, respectively. Based on the functions of actuation, biosensing, and microsurgery, a SPM has been applied for a series of applications, including thrombus elimination at the branch vessel, stratified removal of multilayer thrombus, and biosensing-guided microsurgery. The proposed semiphysical design concept should bring new insight into the development of miniaturized biomedical microrobots.

Effect of Bi on the Performance of Al-Ga-In Sacrificial Anodes.

Cathodic protection is widely used for metal corrosion protection. To improve their performance, it is necessary and urgent to study the influence of metal oxides on the microstructure and performance of aluminum alloy sacrificial anodes. Taking an Al-Ga-In sacrificial anode as the research object, the dissolution morphology and current efficiency characteristics were studied by means of electrochemical testing and microstructural observation, and the influence of varying Pb and Bi contents on the performance of an aluminum alloy sacrificial anode was investigated. The test results reveal that: (1) The Al-Ga-In sacrificial anode with 4% Pb and 1% Bi contents exhibits the best sacrificial anode performance. (2) The inclusion of an appropriate Bi element content shifts the open-circuit potential in a negative direction and promotes activation dissolution. Conversely, excessive Bi content leads to uneven dissolution, resulting in the shedding of anode grains and greatly reducing the current efficiency. (3) During the activation dissolution of the aluminum alloy, the second phase preferentially dissolves, and the activation point destroys the oxide film, resulting in the dissolution of the exposed aluminum matrix. Consequently, the concentration of dissolved metal ions is reduced and deposited back on the surface of the anode sample, promoting the continuous dissolution of the anode.

Lactobacillus acidophilus suppresses non-alcoholic fatty liver disease-associated hepatocellular carcinoma through producing valeric acid.

BACKGROUND: Gut probiotic depletion is associated with non-alcoholic fatty liver disease-associated hepatocellular carcinoma (NAFLD-HCC). Here, we investigated the prophylactic potential of Lactobacillus acidophilus against NAFLD-HCC. METHODS: NAFLD-HCC conventional and germ-free mice were established by diethylnitrosamine (DEN) injection with feeding of high-fat high-cholesterol (HFHC) or choline-deficient high-fat (CDHF) diet. Orthotopic NAFLD-HCC allografts were established by intrahepatic injection of murine HCC cells with HFHC feeding. Metabolomic profiling was performed using liquid chromatography-mass spectrometry. Biological functions of L. acidophilus conditional medium (L.a CM) and metabolites were determined in NAFLD-HCC human cells and mouse organoids. FINDINGS: L. acidophilus supplementation suppressed NAFLD-HCC formation in HFHC-fed DEN-treated mice. This was confirmed in orthotopic allografts and germ-free tumourigenesis mice. L.a CM inhibited the growth of NAFLD-HCC human cells and mouse organoids. The protective function of L. acidophilus was attributed to its non-protein small molecules. By metabolomic profiling, valeric acid was the top enriched metabolite in L.a CM and its upregulation was verified in liver and portal vein of L. acidophilus-treated mice. The protective function of valeric acid was demonstrated in NAFLD-HCC human cells and mouse organoids. Valeric acid significantly suppressed NAFLD-HCC formation in HFHC-fed DEN-treated mice, accompanied by improved intestinal barrier integrity. This was confirmed in another NAFLD-HCC mouse model induced by CDHF diet and DEN. Mechanistically, valeric acid bound to hepatocytic surface receptor GPR41/43 to inhibit Rho-GTPase pathway, thereby ablating NAFLD-HCC. INTERPRETATION: L. acidophilus exhibits anti-tumourigenic effect in mice by secreting valeric acid. Probiotic supplementation is a potential prophylactic of NAFLD-HCC. FUNDING: Shown in Acknowledgments.

Gut microbiota and clinical response to immune checkpoint inhibitor therapy in patients with advanced cancer.

BACKGROUND: There is currently no well-accepted consensus on the association between gut microbiota and the response to treatment of immune checkpoint inhibitors (ICIs) in patients with advanced cancer. METHODS: Fecal samples were collected before ICI treatment. Gut microbiota was analyzed using 16 S ribosomal RNA sequencing. We investigated the relationship between the α-diversity of fecal microbiota and patients' clinical outcomes. Microbiota profiles from patients and healthy controls were determined. Pre-treatment serum was examined by cytokine array. RESULTS: We analyzed 74 patients, including 42 with melanoma, 8 with kidney cancer, 13 with lung cancer, and 11 with other cancers. Combination therapy of anti-PD1 and anti-CTLA-4 was used in 14 patients, and monotherapy in the rest. Clinical benefit was observed in 35 (47.3 %) cases, including 2 complete responses, 16 partial responses, and 17 stable diseases according to RECIST criteria. No significant difference in α-diversity was found between the benefiter and non-benefiter groups. However, patients with α-diversity within the range of our healthy control had a significantly longer median overall survival (18.9 months), compared to the abnormal group (8.2 months) (p = 0.041, hazard ratio = 0.546) for all patients. The microbiota composition of the benefiters was similar to that of healthy individuals. Furthermore, specific bacteria, such as Prevotella copri and Faecalibacterium prausnitzii, were associated with a favorable outcome. We also observed that serum IL-18 before treatment was significantly lower in the benefiters, compared to non-benefiters. CONCLUSIONS: The α-diversity of gut microbiota is positively correlated with more prolonged overall survival in cancer patients following ICI therapy.

Impact of fast-track rehabilitation nursing on pressure ulcers and postoperative complications in patients with inter-trochanteric fractures: A meta-analysis.

We sought to investigate the effects of fast-track rehabilitation nursing on pressure ulcers, length of hospital stay and postoperative complications in patients with inter-trochanteric fractures (ITF). The PubMed, Web of Science, Embase, Cochrane Library, China National Knowledge Infrastructure and WanFang databases were searched for randomised controlled trials (RCTs) published from inception to September 2023 on the application of fast-track rehabilitative nursing to ITF. Two investigators independently screened the literature and performed data extraction and quality assessments using the Cochrane Risk of Bias Assessment Tool. The meta-analysis was performed using RevMan 5.4. Overall, 22 RCTs involving 1904 patients were included. Meta-analysis revealed that after fast-track rehabilitation nursing intervention in patients with ITF, the occurrence of pressure ulcers (odds ratio [OR]: 0.29; 95% confidence interval [CI]: 0.18-0.47; p < 0.001) and postoperative complications (OR: 0.19; 95% CI: 0.14-0.26; p < 0.001) were significantly reduced and hospital stay was significantly shorter (standardised mean difference: -3.10; 95% CI: -3.82 to -2.38; p < 0.001). Nursing care for patients with ITF based on the concept of fast-track rehabilitation is conducive to reducing the occurrence of pressure ulcers, lowering the occurrence of complications, shortening the length of hospitalisation and promoting postoperative rehabilitation.

Fully Active Delivery of Nanodrugs In Vivo via Remote Optical Manipulation.

The active delivery of nanodrugs has been a bottleneck problem in nanomedicine. While modification of nanodrugs with targeting agents can enhance their retention at the lesion location, the transportation of nanodrugs in the circulation system is still a passive process. The navigation of nanodrugs with external forces such as magnetic field has been shown to be effective for active delivery, but the existing techniques are limited to specific materials like magnetic nanoparticles. In this study, an alternative actuation method is proposed based on optical manipulation for remote navigation of nanodrugs in vivo, which is compatible with most of the common drug carriers and exhibits significantly higher manipulation precision. By the programmable scanning of the laser beam, the motion trajectory and velocity of the nanodrugs can be precisely controlled in real time, making it possible for intelligent drug delivery, such as inverse-flow transportation, selective entry into specific vascular branch, and dynamic circumvention across obstacles. In addition, the controlled mass delivery of nanodrugs can be realized through indirect actuation by the microflow field. The developed optical manipulation method provides a new solution for the active delivery of nanodrugs, with promising potential for the treatment of blood diseases such as leukemia and thrombosis.

High Soluble Fiber Promotes Colorectal Tumorigenesis Through Modulating Gut Microbiota and Metabolites in Mice.

BACKGROUND & AIMS: Dietary fibers are mainly fermented by the gut microbiota, but their roles in colorectal cancer (CRC) are largely unclear. Here, we investigated the associations of different fibers with colorectal tumorigenesis in mice. METHODS: Apcmin/+ mice and C57BL/6 mice with azoxymethane (AOM) injection were used as CRC mouse models. Mice were fed with mixed high-fiber diet (20% soluble fiber and 20% insoluble fiber), high-inulin diet, high-guar gum diet, high-cellulose diet, or diets with different inulin dose. Germ-free mice were used for validation. Fecal microbiota and metabolites were profiled by shotgun metagenomic sequencing and liquid chromatography-mass spectrometry, respectively. RESULTS: Mixed high-fiber diet promoted colorectal tumorigenesis with increased tumor number and tumor load in AOM-treated and Apcmin/+ mice. Antibiotics use abolished the pro-tumorigenic effect of mixed high-fiber diet, while transplanting stools from mice fed with mixed high-fiber diet accelerated tumor growth in AOM-treated germ-free mice. We therefore characterized the contribution of soluble and insoluble fiber in CRC separately. Our results revealed that soluble fiber inulin or guar gum, but not insoluble fiber cellulose, promoted colorectal tumorigenesis in AOM-treated and Apcmin/+ mice. Soluble fiber induced gut dysbiosis with Bacteroides uniformis enrichment and Bifidobacterium pseudolongum depletion, accompanied by increased fecal butyrate and serum bile acids and decreased inosine. We also identified a positive correlation between inulin dosage and colorectal tumorigenesis. Moreover, transplanting stools from mice fed with high-inulin diet increased colonic cell proliferation and oncogene expressions in germ-free mice. CONCLUSION: High-dose soluble but not insoluble fiber potentiates colorectal tumorigenesis in a dose-dependent manner by dysregulating gut microbiota and metabolites in mice.

Ampelopsis grossedentata Represents a New Host of the 16SrI Group of Phytoplasma Associated with Yellow Leaf Symptoms in China.

Ampelopsis grossedentata, commonly known as "Vine Tea" and well-recognized for its rich flavonoid content, is mainly distributed in the southern regions of the Yangtze River basin in China. These regions include Hunan, Hubei, Jiangxi, and Guizhou provinces. Vine Tea is mainly consumed as an herbal tea and has garnered attention for its reported health benefits, including antioxidant, anti-inflammatory, anti-tumor, anti-diabetic, and neuroprotective properties. It has been used to alleviate coughs and sore throats (Zhang et al., 2021; Wang et al., 2017; Gao et al., 2009). In the Zhangjiajie region of Hunan province alone, the Vine Tea planting area reached 7,670.5 hectares and produced commercial goods worth 1.417 billion RMB in 2022. In May 2021, leaf margins and veins fading to yellowing mottling, and crumpling of leaf blades in the shape of a boat symptoms were found in ~16% of Vine Tea plants in the Sanjiakuan Township, Yongding District, Zhangjiajie region (29°15'E, 110°30' N) (Figure 1a, b, c). (Figure 1a, b, c). Phytoplasma-like microbial cells (small oval shaped bacterial cells, around 1000 nm in size) were observed in sieve tube cells in the phloem of diseased leaves using transmission electron microscopy. No such cell was observed in the phloem of healthy leaves (Figure 2a, b). To investigate the potential association between phytoplasma and the observed symptoms of the diseased plants, total DNA was isolated from ten diseasedeaves and compared with ten healthy leaves from the same field using SteadyPure Plant Genomic DNA Extraction Kit. The isolated DNAs were analyzed first in a direct PCR using universal phytoplasma primer pair R16mF2/R16mR1 targeting the 16S rRNA gene (Gundersen and Lee 1996) and specific pair rpF1/rpR1 (Lee et al. 1998) targeting the DNA fragment encoding partial ribosomal proteins (rp) L22 (complete) and S3 and S19 (partial). The initial amplified products were used as templates and further amplified by nested PCR respectively with primer pair R16F2n/R16R2 for the 16S rRNA gene (Lee et al. 1998) and the rpF2/rpR2 primer pair for the rp gene (Martini et al. 2007). No amplification was obtained with DNA from healthy leaf samples using any of the four primer pairs. The amplified fragments from diseased leaves by nested PCR were cloned and sequenced (Qingke Biotech, China). The obtained sequences have been deposited in GenBank with accession numbers OR282806 for the 16S rRNA gene and GenBank OR353012 for the rp gene. BLASTn analysis revealed that the partial 16S rRNA gene sequence in our sample shared 99.4% nucleotide sequence identity with 'Candidatus Phytoplasma sp.' (MW364378) and 'Peony yellows phytoplasma' (KY814723) of the 16SrI group. Similarly, our rp gene sequence shared 99.6% nucleotide identity with the rpI group of phytoplasma such as the 'Balsamine virescence phytoplasma' (JN572890) and 'Paulownia witches'-broom phytoplasma' (HM146079). Phylogenetic analysis of the 16S rRNA and rp sequences using MEGA version 7.0 revealed that the phytoplasma strain associated with A. grossedentata yellow leaf syndrome in our study site belonged to the 16SrI (Candidatus Phytoplasma asteris) group of phytoplasma (Figure 3a, b). Using the interactive online phytoplasma classification tool iPhyClassifier (Zhao et al., 2009), virtual restriction fragment length polymorphism (RFLP) analysis of the 16S rRNA gene sequences showed our strain having a distinct RFLP map but was closest to that of the onion yellow phytoplasma 16SrI-B subgroup (GenBank accession number: AP006628), with a similarity coefficient of 0.94 (Figure 4a, b). To confirm phytoplasma transmission, healthy plants were inoculated with three scions of infected plants of A. grossedentata. After 16 days, the new leaves of the inoculated A. grossedentata showed yellow leaf symptoms (Figure 5a, b, c), akin to the symptoms originally observed in the field, and the outer contour of the leaf margin appeared chlorotic. After 26 days, primer pairs R16mF2/R16R1 and R16F2n/R16R2 were used for nested PCR detection of phytoplasma in symptomatic A. grossedentata leaves. Phytoplasma was detected in the first and second leaves of symptomatic branches and leaves while negative control showed no amplification. Sequencing of the amplified fragments showed 100% nucleotide identity to the strain from the grafting source. Our results indicated that the pathogen and the disease can be transmitted by tissue grafting, consistent with the biological characteristics of phytoplasma, and further confirmed that the phytoplasma was the pathogen of yellow leaf syndrome of A. grossedentata. Toour knowledge, this is the first report of phytoplasma of group 16SrI affecting A. grossedentata.

NIR-activated quercetin-based nanogels embedded with CuS nanoclusters for the treatment of drug-resistant biofilms and accelerated chronic wound healing.

We have developed multifunctional nanogels with antimicrobial, antioxidant, and anti-inflammatory properties, facilitating rapid wound healing. To prepare the multifunctional nanogels, we utilized quercetin (Qu) and a mild carbonization process to form carbonized nanogels (CNGs). These CNGs possess excellent antioxidative and bacterial targeting properties. Subsequently, we utilized the Qu-CNGs as templates to prepare nanogels incorporating copper sulfide (CuS) nanoclusters, further enhancing their functionality. Notably, the CuS/Qu-CNGs nanocomposites demonstrated an exceptional minimum inhibitory concentration against tested bacteria, approximately 125-fold lower than monomeric Qu or Qu-CNGs. This enhanced antimicrobial effect was achieved by leveraging near-infrared II (NIR-II) light irradiation. Additionally, the CuS/Qu-CNGs exhibited efficient penetration into the extracellular biofilm matrix, eradicating methicillin-resistant Staphylococcus aureus-associated biofilms in diabetic mice wounds. Furthermore, the nanocomposites were found to suppress proinflammatory cytokines, such as IL-1ß, at the wound sites while regulating the expression of anti-inflammatory factors, including IL-10 and TGF-ß1, throughout the recovery process. The presence of CuS/Qu-CNGs promoted angiogenesis, epithelialization, and collagen synthesis, thereby accelerating wound healing. Our developed CuS/Qu-CNGs nanocomposites have great potential in addressing the challenges associated with delayed wound healing caused by microbial pathogenesis.

Optically Programmable Living Microrouter in Vivo.

With high reconfigurability and swarming intelligence, programmable medical micromachines (PMMs) represent a revolution in microrobots for executing complex coordinated tasks, especially for dynamic routing of various targets along their respective routes. However, it is difficult to achieve a biocompatible implantation into the body due to their exogenous building blocks. Herein, a living microrouter based on an organic integration of endogenous red blood cells (RBCs), programmable scanning optical tweezers and flexible optofluidic strategy is reported. By harvesting energy from a designed optical force landscape, five RBCs are optically rotated in a controlled velocity and direction, under which, a specific actuation flow is achieved to exert the well-defined hydrodynamic forces on various biological targets, thus enabling a selective routing by integrating three successive functions, i.e., dynamic input, inner processing, and controlled output. Benefited from the optofluidic manipulation, various blood cells, such as the platelets and white blood cells, are transported toward the damaged vessel and cell debris for the dynamic hemostasis and targeted clearance, respectively. Moreover, the microrouter enables a precise transport of nanodrugs for active and targeted delivery in a large quantity. The proposed RBC microrouter might provide a biocompatible medical platform for cell separation, drug delivery, and immunotherapy.

Targeting of SLC25A22 boosts the immunotherapeutic response in KRAS-mutant colorectal cancer.

KRAS is an important tumor intrinsic factor driving immune suppression in colorectal cancer (CRC). In this study, we demonstrate that SLC25A22 underlies mutant KRAS-induced immune suppression in CRC. In immunocompetent male mice and humanized male mice models, SLC25A22 knockout inhibits KRAS-mutant CRC tumor growth with reduced myeloid derived suppressor cells (MDSC) but increased CD8+ T-cells, implying the reversion of mutant KRAS-driven immunosuppression. Mechanistically, we find that SLC25A22 plays a central role in promoting asparagine, which binds and activates SRC phosphorylation. Asparagine-mediated SRC promotes ERK/ETS2 signaling, which drives CXCL1 transcription. Secreted CXCL1 functions as a chemoattractant for MDSC via CXCR2, leading to an immunosuppressive microenvironment. Targeting SLC25A22 or asparagine impairs KRAS-induced MDSC infiltration in CRC. Finally, we demonstrate that the targeting of SLC25A22 in combination with anti-PD1 therapy synergizes to inhibit MDSC and activate CD8+ T cells to suppress KRAS-mutant CRC growth in vivo. We thus identify a metabolic pathway that drives immunosuppression in KRAS-mutant CRC.

Carnobacterium maltaromaticum boosts intestinal vitamin D production to suppress colorectal cancer in female mice.

Carnobacterium maltaromaticum was found to be specifically depleted in female patients with colorectal cancer (CRC). Administration of C. maltaromaticum reduces intestinal tumor formation in two murine CRC models in a female-specific manner. Estrogen increases the attachment and colonization of C. maltaromaticum via increasing the colonic expression of SLC3A2 that binds to DD-CPase of this bacterium. Metabolomic and transcriptomic profiling unveils the increased gut abundance of vitamin D-related metabolites and the mucosal activation of vitamin D receptor (VDR) signaling in C. maltaromaticum-gavaged mice in a gut microbiome- and VDR-dependent manner. In vitro fermentation system confirms the metabolic cross-feeding of C. maltaromaticum with Faecalibacterium prausnitzii to convert C. maltaromaticum-produced 7-dehydrocholesterol into vitamin D for activating the host VDR signaling. Overall, C. maltaromaticum colonizes the gut in an estrogen-dependent manner and acts along with other microbes to augment the intestinal vitamin D production to activate the host VDR for suppressing CRC.

Combining virtual screening with cis-/trans-cleavage enzymatic assays effectively reveals broad-spectrum inhibitors that target the main proteases of SARS-CoV-2 and MERS-CoV.

The main protease (Mpro) of SARS-CoV-2 is essential for viral replication, which suggests that the Mpro is a critical target in the development of small molecules to treat COVID-19. This study used an in-silico prediction approach to investigate the complex structure of SARS-CoV-2 Mpro in compounds from the United States National Cancer Institute (NCI) database, then validate potential inhibitory compounds against the SARS-CoV-2 Mpro in cis- and trans-cleavage proteolytic assays. Virtual screening of ∼280,000 compounds from the NCI database identified 10 compounds with highest site-moiety map scores. Compound NSC89640 (coded C1) showed marked inhibitory activity against the SARS-CoV-2 Mpro in cis-/trans-cleavage assays. C1 strongly inhibited SARS-CoV-2 Mpro enzymatic activity, with a half maximal inhibitory concentration (IC50) of 2.69 µM and a selectivity index (SI) of >74.35. The C1 structure served as a template to identify structural analogs based on AtomPair fingerprints to refine and verify structure-function associations. Mpro-mediated cis-/trans-cleavage assays conducted with the structural analogs revealed that compound NSC89641 (coded D2) exhibited the highest inhibitory potency against SARS-CoV-2 Mpro enzymatic activity, with an IC50 of 3.05 µM and a SI of >65.57. Compounds C1 and D2 also displayed inhibitory activity against MERS-CoV-2 with an IC50 of <3.5 µM. Thus, C1 shows potential as an effective Mpro inhibitor of SARS-CoV-2 and MERS-CoV. Our rigorous study framework efficiently identified lead compounds targeting the SARS-CoV-2 Mpro and MERS-CoV Mpro.

Altered gut microbiota of obesity subjects promotes colorectal carcinogenesis in mice.

BACKGROUND: Obesity is a risk factor for colorectal cancer (CRC). The role of gut microbiota in mediating the cancer-promoting effect of obesity is unknown. METHODS: Azoxymethane (AOM)-treated, ApcMin/+ and germ-free mice were gavaged with feces from obese individuals and control subjects respectively. The colonic tumor load and number were recorded at the endpoint in two carcinogenic models. The gut microbiota composition and colonic transcriptome were assessed by metagenomic sequencing and RNA sequencing, respectively. The anticancer effects of bacteria depleted in fecal samples of obese individuals were validated. FINDINGS: Conventional AOM-treated and ApcMin/+ mice receiving feces from obese individuals showed significantly increased colon tumor formation compared with those receiving feces from control subjects. AOM-treated mice receiving feces from obese individuals showed impaired intestinal barrier function and significant upregulation of pro-inflammatory cytokines and activation of oncogenic Wnt signaling pathway. Consistently, transferring feces from obese individuals to germ-free mice led to increased colonic cell proliferation, intestinal barrier function impairment, and induction of oncogenic and proinflammatory gene expression. Moreover, germ-free mice transplanted with feces from obese human donors had increased abundance of potential pathobiont Alistipes finegoldii, and reduced abundance of commensals Bacteroides vulgatus and Akkermansia muciniphila compared with those receiving feces from human donors with normal body mass index (BMI). Validation experiments showed that B. vulgatus and A. muciniphila demonstrated anti-proliferative effects in CRC, while A. finegoldii promoted CRC tumor growth. INTERPRETATION: Our results supported the role of obesity-associated microbiota in colorectal carcinogenesis and identified putative bacterial candidates that may mediate its mechanisms. Microbiota modulation in obese individuals may provide new approaches to prevent or treat obesity-related cancers including CRC. FUNDING: This work was funded by National Key Research and Development Program of China (2020YFA0509200/2020YFA0509203), National Natural Science Foundation of China (81922082), RGC Theme-based Research Scheme Hong Kong (T21-705/20-N), RGC Research Impact Fund Hong Kong (R4632-21F), RGC-CRF Hong Kong (C4039-19GF and C7065-18GF), RGC-GRF Hong Kong (14110819, 14111621), and NTU Start-Up Grant (021337-00001).

Drivers of the spatiotemporal patterns of the mangrove crab metacommunity in a tropical bay.

Revealing community patterns and driving forces is essential in community ecology and a prerequisite for effective management and conservation efforts. However, the mangrove ecosystem and its important fauna group such as the crabs, still lack multi-processes research under metacommunity framework, resulting in evidence and theorical application gaps. To fill these gaps, we selected China's most representative mangrove bay reserve in tropical zone as a stable experimental system and conducted a seasonal investigation (July 2020, October 2020, January 2021, and April 2021) of mangrove crabs. We performed a multi-approach analysis using both pattern-based and mechanistic method to distinguish the processes driving the mangrove crab metacommunity. Our results showed that the crab metacommunity exhibits a Clementsian pattern in the bay-wide mangrove ecosystem but is influenced by both local environmental heterogeneity and spatial processes, thus representing a combined paradigm of species sorting and mass effect. Moreover, the long-distance spatial constraints are more pronounced compared to the local environmental factors. This is reflected in the greater importance of the broad-scale Moran's Eigenvector Maps, the distance-decay pattern of similarity, and the difference in beta diversity dominated by the turnover component. This pattern changes throughout the year, mainly due to changes in dominant functional groups caused by the stress of changes in water salinity and temperature induced by air temperature and precipitation. This research provides multi-dimension research data and relevant analysis, offering clear evidence for understanding the patterns and related driving forces of crab metacommunity in tropical bay mangroves, and verifies the applicability of some general laws in the system. Future studies can address more diverse spatiotemporal scales, gaining a clearer understanding to serve the conservation of mangrove ecosystems and economically important fishery species.

In Vitro Assessment of the Antioxidant and Anticancer Properties of Flammulina velutipes Stipe Extracts.

BACKGROUND/AIM: Flammulina velutipes (FV), also known as the golden needle mushroom, is an edible and medicinal fungus that contains bioactive substances regulating various physiological functions. While the fruiting bodies of FV are commonly consumed, their stipes are often discarded despite containing polysaccharides. In this study, the biological functions of FV stipes (FV-S) were investigated to reduce waste and pollution while increasing their value. MATERIALS AND METHODS: The antioxidant activity of FV was evaluated using three methods: the DPPH radical-scavenging capacity assay, ferrous ion chelating assay, and reducing power analysis. The anti-cancer potential was assessed through MTT viability and immunoblotting analyses. RESULTS: Results showed that FV-S had higher polysaccharide and total phenolic contents and greater antioxidant abilities, particularly in ethanolic extracts. FV-S also exhibited significant anticancer properties, specifically in hot water extracts with high polysaccharide contents, and suppressed prostate cancer cell viability by inhibiting androgen receptor and PCa-specific antigen mRNA expression while inducing caspase-3/7 activation. CONCLUSION: FV-S is rich in bioactive components, possesses higher antioxidant and anticancer abilities, and has potential as an anticancer agent, which could enhance the value of FV.

Fabrication and Characterization of Carrageenan/ZnO/Chitosan Composite Films.

In this study, a high-performance carrageenan/ZnO/chitosan composite film (FCA/ZnO/CS) was fabricated by the solution/dispersion casting method and layer-by-layer method. The first layer was nano-ZnO dispersed in carrageenan solution, and the second layer was chitosan dissolved in acetic acid. The morphology, chemical structure, surface wettability, barrier properties, mechanical properties, optical properties, and antibacterial activity of FCA/ZnO/CS were evaluated compared with a carrageenan film (FCA) and carrageenan/ZnO composite film (FCA/ZnO). This study revealed that the Zn element in FCA/ZnO/CS existed in the form of Zn2+ in FCA/ZnO/CS. There existed electrostatic interaction and hydrogen bonding between CA and CS. As a result, the mechanical strength and transparency of FCA/ZnO/CS were enhanced and the water vapor transmittance of FCA/ZnO/CS was decreased compared with that of FCA/ZnO. Furthermore, the addition of ZnO and CS greatly enhanced the antibacterial activity of Escherichia coli and also had a certain inhibitory effect on Staphylococcus aureus. FCA/ZnO/CS is expected to be a potential candidate material for food packaging, wound dressings, and various surface antimicrobial coatings.

ALKBH5 Drives Immune Suppression Via Targeting AXIN2 to Promote Colorectal Cancer and Is a Target for Boosting Immunotherapy.

BACKGROUND & AIMS: Immune checkpoint blockade therapy benefits only a small subset of patients with colorectal cancer (CRC), and identification of CRC-intrinsic events modulating immune checkpoint blockade efficacy is an unmet need. We found that AlkB homolog 5 (ALKBH5), an RNA N6-methyladenosine eraser, drives immunosuppression and is a molecular target to boost immune checkpoint blockade therapy in CRC. METHODS: Clinical significance of ALKBH5 was evaluated in human samples (n = 205). Function of ALKBH5 was investigated in allografts, CD34+ humanized mice, and Alkbh5 knockin mice. Immunity change was determined by means of flow cytometry, immunofluorescence, and functional investigation. Methylated RNA immunoprecipitation sequencing and RNA sequencing were used to identify ALKBH5 targets. Vesicle-like nanoparticle-encapsulated ALKBH5-small interfering RNA was constructed for targeting ALKBH5 in vivo. RESULTS: High ALKBH5 expression predicts poor prognosis in CRC. ALKBH5 induced myeloid-derived suppressor cell accumulation but reduced natural killer cells and cytotoxic CD8+ T cells to induce colorectal tumorigenesis in allografts, CD34+ humanized mice, and intestine-specific Alkbh5 knockin mice. Mechanistically, AXIN2, a Wnt suppressor, was identified as a target of ALKBH5. ALKBH5 binds and demethylates AXIN2 messenger RNA, which caused its dissociation from N6-methyladenosine reader IGF2BP1 and degradation, resulting in hyperactivated Wnt/ß-catenin. Subsequently, Wnt/ß-catenin targets, including Dickkopf-related protein 1 (DKK1) were induced by ALKBH5. ALKBH5-induced DKK1 recruited myeloid-derived suppressor cells to drive immunosuppression in CRC, and this effect was abolished by anti-DKK1 in vitro and in vivo. Finally, vesicle-like nanoparticle-encapsulated ALKBH5-small interfering RNA, or anti-DKK1 potentiated anti-PD1 treatment in suppressing CRC growth by enhancing antitumor immunity. CONCLUSIONS: This study identified an ALKBH5-N6-methyladenosine-AXIN2-Wnt-DKK1 axis in CRC, which drives immune suppression to facilitate tumorigenesis. Targeting of ALKBH5 is a promising strategy for sensitizing CRC to immunotherapy.

The Application of Wireless Underground Sensor Networks to Monitor Seepage inside an Earth Dam.

Earth dams or embankments are susceptible to instability due to internal seepage, piping, and erosion, which can lead to catastrophic failure. Therefore, monitoring the seepage water level before the dam collapses is an important task for early warning of dam failure. Currently, there are hardly any monitoring methods that use wireless underground transmission to monitor the water content inside earth dams. Real-time monitoring of changes in the soil moisture content can more directly determine the water level of seepage. Wireless transmission of sensors buried underground requires signal transmission through the soil medium, which is more complex than traditional air transmission. Henceforth, this study establishes a wireless underground transmission sensor that overcomes the distance limitation of underground transmission through a hop network. A series of feasibility tests were conducted on the wireless underground transmission sensor, including peer-to-peer transmission tests, multi-hop underground transmission tests, power management tests, and soil moisture measurement tests. Finally, field seepage tests were conducted to apply wireless underground transmission sensors to monitor the internal seepage water level before an earth dam failure. The findings show that wireless underground transmission sensors can achieve the monitoring of seepage water levels inside earth dams. In addition, the results supersede those of a conventional water level gauge. This could be crucial in early warning systems during the era of climate change, which has caused unprecedented flooding events.