Pro-resolving lipid mediator reduces amyloid-ß42-induced gene expression in human monocyte-derived microglia.

JOURNAL/nrgr/04.03/01300535-202503000-00031/figure1/v/2024-06-17T092413Z/r/image-tiff Specialized pro-resolving lipid mediators including maresin 1 mediate resolution but the levels of these are reduced in Alzheimer's disease brain, suggesting that they constitute a novel target for the treatment of Alzheimer's disease to prevent/stop inflammation and combat disease pathology. Therefore, it is important to clarify whether they counteract the expression of genes and proteins induced by amyloid-ß. With this objective, we analyzed the relevance of human monocyte-derived microglia for in vitro modeling of neuroinflammation and its resolution in the context of Alzheimer's disease and investigated the pro-resolving bioactivity of maresin 1 on amyloid-ß42-induced Alzheimer's disease-like inflammation. Analysis of RNA-sequencing data and secreted proteins in supernatants from the monocyte-derived microglia showed that the monocyte-derived microglia resembled Alzheimer's disease-like neuroinflammation in human brain microglia after incubation with amyloid-ß42. Maresin 1 restored homeostasis by down-regulating inflammatory pathway related gene expression induced by amyloid-ß42 in monocyte-derived microglia, protection of maresin 1 against the effects of amyloid-ß42 is mediated by a re-balancing of inflammatory transcriptional networks in which modulation of gene transcription in the nuclear factor-kappa B pathway plays a major part. We pinpointed molecular targets that are associated with both neuroinflammation in Alzheimer's disease and therapeutic targets by maresin 1. In conclusion, monocyte-derived microglia represent a relevant in vitro microglial model for studies on Alzheimer's disease-like inflammation and drug response for individual patients. Maresin 1 ameliorates amyloid-ß42-induced changes in several genes of importance in Alzheimer's disease, highlighting its potential as a therapeutic target for Alzheimer's disease.

A gold nanoparticle-enhanced dCas9-mediated fluorescence resonance energy transfer for nucleic acid detection.

Clustered regularly interspaced short palindromic repeats (CRISPR)-associated Cas proteins coupled with pre-amplification have shown great potential in molecular diagnoses. However, the current CRISPR-based methods require additional reporters and time-consuming process. Herein, a gold nanoparticle (AuNP)-enhanced CRISPR/dCas9-mediated fluorescence resonance energy transfer (FRET) termed Au-CFRET platform was proposed for rapid, sensitive, and specific detection of nucleic acid for the first time. In the Au-CFRET sensing platform, AuNP was functionalized with dCas9 and used as nanoprobe. Target DNA was amplified with FAM-labeled primers and then precisely bound with AuNP-dCas9. The formed complex rendered the distance between AuNP acceptor and FAM donor to be short enough for the occurrence of FRET, thus resulting in fluorescence quenching. Moreover, AuNPs were demonstrated to enhance binding efficiency of dCas9 to target DNA in Au-CFRET system. The key factors regarding the FRET efficiency were analyzed and characterized in detail, including the length of donor/acceptor and the size of AuNPs. Under the optimal conditions, Au-CFRET could determinate CaMV35S promoter of genetically modified rice as low as 21 copies µL-1. Moreover, Au-CFRET sensing system coupled with one-step extraction and recombinase polymerase amplification can identify the genuine plant seeds within 30 min from sampling to results at room/body temperature without expensive equipment or technical expertise, and requires no additional exogenous reporters. Therefore, the proposed sensing platform significantly simplified the system and shortened the assay time for nucleic acid diagnoses.

Behavioural responses to mammalian grazing expose insect herbivores to elevated risk of avian predation.

Large mammalian herbivores (LMH) are important functional components and drivers of biodiversity and ecosystem functioning in grasslands. Yet their role in regulating food-web dynamics and trophic cascades remains poorly understood. In the temperate grasslands of northern China, we explored whether and how grazing domestic cattle (Bos taurus) alter the predator-prey interactions between a dominant grasshopper (Euchorthippus unicolor) and its avian predator the barn swallow (Hirundo rustica). Using two large manipulative field experiments, we found that in the presence of cattle, grasshoppers increased their jumping frequency threefold, swallows increased foraging visits to these fields sixfold, and grasshopper density was reduced by about 50%. By manipulatively controlling the grasshoppers' ability to jump, we showed that jumping enables grasshoppers to avoid being incidentally consumed or trampled by cattle. However, jumping behaviour increased their consumption rates by swallows 37-fold compared with grasshoppers that were unable to jump. Our findings illustrate how LMH can indirectly alter predator-prey interactions by affecting behaviour of avian predators and herbivorous insects. These non-plant-mediated effects of LMH may influence trophic interactions in other grazing ecosystems and shape community structure and dynamics. We highlight that convoluted multispecies interactions may better explain how LMH control food-web dynamics in grasslands.

Expression and Diagnostic Value of miR-3591-5p in Patients with Congenital Heart Disease-Associated Pulmonary Arterial Hypertension.

OBJECTIVES: This study explored the expression and diagnostic value of differentially expressed miR-3591-5p in congenital heart disease-associated pulmonary arterial hypertension (CHD-PAH). METHODS: A total of 110 CHD patients were divided into four groups based on their mean pulmonary artery pressure (PAPm). The plasma miR-3591-5p expression was determined by reverse transcription polymerase chain reaction. The correlation between the miR-3591-5p expression and various clinical indices, as well as its diagnostic value for CHD-PAH patients, were analyzed. RESULTS: The plasma levels of miR-3591-5p were significantly higher in the patients in the no PAH group, mild PAH group, and moderate to severe PAH group than in the control group, and they were significantly higher in the moderate to severe PAH group than in the no PAH group. Correlation analysis revealed that the miR-3591-5p expression level was significantly positively correlated with various clinical indicators, including the PAPm, pulmonary artery systolic pressure, brain natriuretic peptide, pulmonary vascular resistance, red blood cell distribution width, uric acid, Na + , systolic blood pressure, left atrial internal dimension, left ventricular end-diastolic dimension, and left ventricular end-systolic dimension. Univariate and multivariate regression analyses identified the plasma miR-3591-5p level as an independent risk factor for CHD-PAH. Receiver operating characteristic curve analysis demonstrated that the plasma miR-3591-5p level had a moderate diagnostic value for CHD-PAH, which was further improved when combined with a B-type natriuretic peptide. CONCLUSION: This study identified the expression profiles of differentially expressed plasma miRNAs in patients with CHD-PAH, focusing on the upregulation of miR-3591-5p. Bioinformatics analysis suggested that miR-3591-5p is involved in the pathogenesis of CHD-PAH and may serve as a circulating biomarker that may have diagnostic and prognostic value in CHD-PAH.

Novel magnetic adsorbents based on oyster and clam shells for the removal of cadmium in soil.

Magnetic adsorbents can effectively remove heavy metals from soil. However, the magnetization process may reduce availability of adsorption sites, making it challenging to balance magnetic and adsorption properties. In this study, oyster shell (OS) and clam shell (CS) material was magnetized by an improved chemical co-precipitation method. The organic matter in the shells was destroyed by calcination modification to expose new active sites, and calcinated ferro-magnetic adsorbent was produced with either ferrosodium EDTA (giving CEOS and CECS) or with iron citrate (for CCOS and CCCS). All four modified adsorbents reached adsorption equilibrium for Cd2+ in solution within 120 min, with maximum adsorption capacities ranging from 115.5 to 266.5 mg/g, giving high removal efficiencies for Cd2+. Adsorption by precipitation and cation exchange mechanisms was dominant, together contributing >60 % of all adsorption capacity, followed by complexation. When used for remediation of Cd-contaminated soil, CEOS demonstrated the best Cd removal efficiency, achieving removal rates of 46 % and 58 % for total and available Cd, respectively. This was mainly because CEOS had the highest magnetic recovery rate, of 98 %. CEOS maintained removal rates of 34 % for total Cd after regeneration and reuse three cycles, with recovery rates remaining above 90 %. Contaminated soil was treated with the novel adsorbents and in pot experiments with water spinach cultivation it was shown that both CEOS and CECS treatment significantly reduced Cd content (by up to 56 %). The magnetic adsorbents presented here demonstrate excellent performance to remove Cd from water and soil, and have promising application prospects.

High-parametric protein maps reveal the spatial organization in early-developing human lung.

The respiratory system, including the lungs, is essential for terrestrial life. While recent research has advanced our understanding of lung development, much still relies on animal models and transcriptome analyses. In this study conducted within the Human Developmental Cell Atlas (HDCA) initiative, we describe the protein-level spatiotemporal organization of the lung during the first trimester of human gestation. Using high-parametric tissue imaging with a 30-plex antibody panel, we analyzed human lung samples from 6 to 13 post-conception weeks, generating data from over 2 million cells across five developmental timepoints. We present a resource detailing spatially resolved cell type composition of the developing human lung, including proliferative states, immune cell patterns, spatial arrangement traits, and their temporal evolution. This represents an extensive single-cell resolved protein-level examination of the developing human lung and provides a valuable resource for further research into the developmental roots of human respiratory health and disease.

Unveiling the impact of exposed mineral facets on chromium repartitioning in aging lepidocrocite.

As a typical intermediate product of metastable iron oxide phase transformation, lepidocrocite is a critical player in migrating and transforming heavy metals (HMs) in soils and sediments. However, the repartitioning behavior of its associated HMs during the aging of lepidocrocite is not fully understood. We investigated the phase transformation of Cr(VI)-lepidocrocite with different exposed facets at various aging conditions (pH: 7 and 10; temperature: 25 °C and 75 °C). The results indicated that the phase transformation of lepidocrocite is facet-dependent. The rod-like lepidocrocite (R-LEP), characterized by a high ratio of (001)/(010) facets, demonstrated significant structural stability, with only minimal transformation to goethite observed over 9 days. In contrast, the dominant (010) facet in plate-like lepidocrocite (P-LEP) directly underwent the phase transformation from lepidocrocite to hematite. Meanwhile, the coordination of Cr(VI) onto the facets of lepidocrocite notably strengthened the resistance to its phase transformation. Specifically, the interaction between Cr(VI) and the (001) facets was particularly effective in inhibiting the phase transformation of lepidocrocite. In addition, the release behavior of Cr(VI) also showed lepidocrocite facet dependence. For instance, at pH = 7 and 75 °C, the release percentage of Cr(VI) on P-LEP reached up to 81 %, 1.7 times that of the release on R-LEP (46.7 %). Moreover, more non-extractable Cr speciation in P-LEP transformed into aqueous speciation and was partially redistributed on hematite. These findings provide novel insights into the role that the mineral exposed facets play in regulating the environmental behavior of Cr during the iron oxide phase transformation.

Network meta-analysis evaluating the impact of diverse exercise regimens on quality of life in women post-breast cancer surgery.

BACKGROUND: This study used network meta-analysis to compare the effects of various exercise interventions, with the aim of identifying the most effective intervention measures. METHODS: Data were extracted from 8 databases, comprising of PubMed, Web of Science, EBSCO, and Embase. The Cochrane risk of bias assessment tool was used to assess the quality of the research. Network meta-analysis and meta-analysis were performed using STATA15.0 and Review Manager 5.4, respectively. RESULTS: This analysis incorporated 58 research papers that had 4998 participants, of which 2480 were assigned to the test group and 2518 to the control group. As revealed by the data, the following is a descending order of the impact of various exercise regimens on the quality of life (QoL) of women who have undergone breast cancer surgery: For the MOS item short form health survey, the recommended sequence was as follows: aerobic + resistance exercise, football, baduanjin, walking, tai chi, yoga, resistance exercise, slow-moving qigong, aerobic exercise, and usual care; for functional assessment of cancer therapy for breast cancer, the sequence was as follows: aerobic + resistance exercise, resistance exercise, relaxation, baduanjin, square dance, aerobic exercise, tai chi, yoga, Pilates, mixer dance, aquatic sports, cycle ergometer, and usual care; and for European Organization for Research and Treatment of Cancer quality of life questionnaire, the sequence was aerobic + resistance exercise, aerobic + yoga, aerobic exercise, Pilates, yoga, muscle strengthening, resistance exercise, square dance, usual care, walking, and aerobic + edema massage. CONCLUSION: The majority of exercise interventions demonstrated a discernible impact on the QoL in women following breast cancer surgery. The effects of diverse exercise interventions on the 3 QoL outcome indicators in patients with breast cancer exhibited variability. However, irrespective of the QoL measurement technique used, aerobic and resistance exercise continue to be the most favorable choices.

Global, regional, and national temporal trends in mortality and disability-adjusted life years for cardiovascular disease attributable to low temperature during 1990-2019: an age-period-cohort analysis of the global burden of disease 2019 study.

Background: Few studies have focused on the region-specific relationship between cardiovascular disease (CVD) and low temperature worldwide. Objective: We aimed to provide an overview of trends in mortality and disability-adjusted life years (DALYs) for CVD and its subtypes attributable to low temperature over the past 30 years in 204 countries and regions, along with the associations of these trends with age, period, and birth cohorts. Methods: Data on the estimated burden of CVDs (including ischemic heart disease, hypertensive heart disease, and stroke) attributable to low temperature were obtained from the Global Burden of Disease Study 2019. We utilized an age-period-cohort model to estimate overall annual percentage changes in mortality (net drifts), annual percentage changes from 15 ~ 19 to 81 ~ 85 years (local drifts), and period and cohort relative risk (period/cohort effects) between 1990 and 2019. Results: Among noncommunicable diseases, CVDs had the highest mortality rate and DALY loss attributable to low temperature worldwide and has increased from 65.7 to 67.3%, which is mainly attributed to the increase in East Asia and Pacific region. In terms of the level of economic and social development, an inverted U-shape was found in the age-standardized mortality rates (ASMR) due to low-temperature across different sociodemographic indices (SDI) regions. Both high CVD mortality (19.45, 95% CI [14.54, 24.17%]) and a decreasing mortality rate related to low temperature (from 1990 to 2019, net drift, -3.25% [-3.76, 2.73%] per year) was found in high SDI countries or territories, with opposite outcome found in low SDIs regions. The older adults (70+) and men share the highest rate of CVD ASMR and DALY attributed to low temperature across all regions, especially in North America and Europe and Central Asia. Conclusion: Mortality and DALY loss from CVD attributable to low temperature showed an overall decreasing trend globally except for East Asia and Pacific region. SDI, sex, age and geographic location contributed to the diversity of the CVD disease burden associated with low temperature worldwide. More attention should be given to the older adults, men, and low SDI regions.

Genetic Landscape of Patients With Dilated Cardiomyopathy and a Systemic Immune-Mediated Disease.

BACKGROUND: Systemic immune-mediated diseases (SIDs) are a well-known cause of dilated cardiomyopathy (DCM), a cardiac phenotype influenced by genetic predispositions and environmental factors. OBJECTIVES: This study sought to examine if an underlying genetic predisposition is present in patients with DCM and SID. METHODS: Genotyped DCM-SID patients (n = 183) were enrolled at 3 European centers. Genetic variants were compared with healthy control subjects (n = 20,917), DCM patients without SID (n = 560), and individuals with a suspicion of an SID (n = 1,333). Clinical outcomes included all-cause mortality, heart failure hospitalization, and life-threatening arrhythmias. RESULTS: The SID diagnosis preceded the DCM diagnosis by 4.8 months (Q1-Q3: -68.4 to +2.4 months). The prevalence of pathogenic/likely pathogenic (P/LP) variants in DCM patients with an SID from the Maastricht cohort was 17.1%, compared with 1.9% in healthy control subjects (P < 0.001). In the Madrid/Trieste cohort, the prevalence was 20.5% (P < 0.001). Truncating variants showed the strongest enrichment (10.7% [OR: 24.5] (Maastricht) and 16% [OR: 116.6 (Madrid/Trieste); both P < 0.001), with truncating TTN (titin) variant (TTNtv) being the most prevalent. Left ventricular ejection fraction at presentation was reduced in TTNtv-SID patients compared with DCM patients with SID without a P/LP (P = 0.016). The presence of a P/LP variant in DCM-SID had no impact on clinical outcomes over a median follow-up of 8.4 years (Q1-Q3: 4.9-12.1 years). CONCLUSIONS: One in 6 DCM patients with an SID has an underlying P/LP variant in a DCM-associated gene. This highlights the role of genetic testing in those patients with immune-mediated DCM, and supports the concept that autoimmunity may play a role in unveiling a DCM phenotype in genotype-positive individuals.

Exploring the microbe-mediated biological processes of BTEX and toxic metal(loid)s in aging petrochemical landfills.

Aging petrochemical landfills serve as reservoirs of inorganic and organic contaminants, posing potential risks of contamination to the surrounding environment. Identifying the pollution characteristics and elucidating the translocation/ transformation processes of typical contaminants in aging petrochemical landfills are crucial yet challenging endeavors. In this study, we employed a combination of chemical analysis and microbial metagenomic technologies to investigate the pollution characteristics of benzene, toluene, ethylbenzene, and xylene (BTEX) as well as metal(loid)s in a representative aging landfill, surrounding soils, and underlying groundwater. Furthermore, we aimed to explore their transformations driven by microbial activity. Our findings revealed widespread distribution of metal(loid)s, including Cd, Ni, Cu, As, Mn, Pb, and Zn, in these environmental media, surpassing soil background values and posing potential ecological risks. Additionally, microbial processes were observed to contribute significantly to the degradation of BTEX compounds and the transformation of metal(loid)s in landfills and surrounding soils, with identified microbial communities and functions playing key roles. Notably, co-occurrence network analysis unveiled the coexistence of functional genes associated with BTEX degradation and metal(loid) transformation, driven primarily by As, Ni, and Cd. These results shed light on the co-selection of resistance traits against BTEX and metal(loid) contaminants in soil microbial consortia under co-contamination scenarios, supporting microbial adaptive evolution in aging petrochemical landfills. The insights gained from this study enhance our understanding of characteristic pollutants and microbial transformation processes in aging landfills, thereby facilitating improved landfill management and contamination remediation strategies.

Temperature differentially regulates estuarine microbial N2O production along a salinity gradient.

Nitrous oxide (N2O) is atmospheric trace gas that contributes to climate change and affects stratospheric and ground-level ozone concentrations. Ammonia oxidizers and denitrifiers contribute to N2O emissions in estuarine waters. However, as an important climate factor, how temperature regulates microbial N2O production in estuarine water remains unclear. Here, we have employed stable isotope labeling techniques to demonstrate that the N2O production in estuarine waters exhibited differential thermal response patterns between nearshore and offshore regions. The optimal temperatures (Topt) for N2O production rates (N2OR) were higher at nearshore than offshore sites. 15N-labeled nitrite (15NO2-) experiments revealed that at the nearshore sites dominated by ammonia-oxidizing bacteria (AOB), the thermal tolerance of 15N-N2OR increases with increasing salinity, suggesting that N2O production by AOB-driven nitrifier denitrification may be co-regulated by temperature and salinity. Metatranscriptomic and metagenomic analyses of enriched water samples revealed that the denitrification pathway of AOB is the primary source of N2O, while clade II N2O-reducers dominated N2O consumption. Temperature regulated the expression patterns of nitrite reductase (nirK) and nitrous oxide reductase (nosZ) genes from different sources, thereby influencing N2O emissions in the system. Our findings contribute to understanding the sources of N2O in estuarine waters and their response to global warming.

Ultrasmall Prussian Blue Nanozyme Attenuates Osteoarthritis by Scavenging Reactive Oxygen Species and Regulating Macrophage Phenotype.

Osteoarthritis (OA) is a degenerative joint disease characterized by obscure etiology and unsatisfactory therapeutic outcomes, making the development of new efficient therapies urgent. Superfluous reactive oxygen species (ROS) have historically been considered one of the crucial factors inducing the pathological progression of OA. Ultrasmall Prussian blue nanoparticles (USPBNPs), approximately sub-5 nm in size, are developed by regulating the configuration of polyvinylpyrrolidone chains. USPBNPs display an excellent ROS eliminating capacity and catalase-like activity, capable of decomposing hydrogen peroxide (H2O2) into O2. The anti-inflammatory mechanism of USPBNPs can be attributed to repolarizing macrophages from pro-inflammatory M1 to anti-inflammatory M2 phenotype by decreasing the ROS levels accompanied by O2 improvement. Additionally, USPBNPs exhibit an exciting therapeutic efficiency against OA, comparable to that of hydrocortisone in vivo. This study not only develops a new therapeutic agent for OA but also offers an estimable insight into the application of the nanozyme.

TRMT10C-mediated m7G modification of circFAM126A inhibits lung cancer growth by regulating cellular glycolysis.

The N7-methylguanosine (m7G) modification and circular RNAs (circRNAs) have been shown to play important roles in the development of lung cancer. However, the m7G modification of circRNAs has not been fully elucidated. This study revealed the presence of the m7G modification in circFAM126A. We propose the novel hypothesis that the methyltransferase TRMT10C mediates the m7G modification of circFAM126A and that the stability of m7G-modified circFAM126A is reduced. circFAM126A is downregulated in lung cancer and significantly inhibits lung cancer growth both in vitro and in vivo. The expression of circFAM126A correlates with the stage of lung cancer and with the tumour diameter, and circFAM126A can be used as a potential molecular target for lung cancer. The molecular mechanism by which circFAM126A increases HSP90 ubiquitination and suppresses AKT1 expression to regulate cellular glycolysis, ultimately inhibiting the progression of lung cancer, is elucidated. This study not only broadens the knowledge regarding the expression and regulatory mode of circRNAs but also provides new insights into the molecular mechanisms that regulate tumour cell metabolism and affect tumour cell fate from an epigenetic perspective. These findings will facilitate the development of new strategies for lung cancer prevention and treatment.

Study on chemical constituents and antioxidant activities of Dianthus caryophyllus L.

Objective: Carnation is a plant that holds high value in terms of its edibility, medicinal properties, and ornamental appeal. Creating no sense he aim of this study was to evaluate the antioxidant and antitumor properties of extracts derived from various parts of the carnation plant. Metabolomics technology was employed to identify the primary chemical constituents. Methods: Initially, we measured the total phenolic and total flavonoid contents in carnation roots, stems, leaves, and flowers, followed by assessing the antioxidant and anti-tumor capabilities of each component using diverse experimental methods. Subsequently, UPLC-MS/MS was employed to identify metabolites in different parts of carnation and investigate their roles in antioxidant and anti-tumor activities. Results: Mention numerical value- for better underatnding- Results of the study indicated that the methanol extract obtained from carnation flowers and roots exhibited superior antioxidant capacity compared to that from the stems and leaves. This disparity may be attributed to the abundance of polyphenols, flavonoids, and antioxidants present in the flowers, including methyl ferulate and luteolin-4'-O-glucoside. Furthermore, the significant presence of the anthraquinone compound rhein-8-O-glucoside in carnation roots may contribute to their enhanced antioxidant properties. Ten distinct compounds were isolated and recognized in carnation flowers, with Isoorientin 2"-O-rhamnoside and Kurarinone demonstrating notable antioxidant activity and binding affinity to SOD1 and SOD3, as validated through antioxidant screening and molecular docking. Conclusion: Overall, the findings from this study have expanded our knowledge of the phytochemical composition across different anatomical regions of the carnation plant, providing valuable insights for its holistic utilization.

Profiles of differential expression of miRNAs in the late stage of red blood cell preservation and their potential roles.

OBJECTIVE: To detect the differentially expressed regulatory miRNAs in the late stage of red blood cell (RBC) preservation and predict their roles. METHODS: Suspended RBCs with different storage periods of 35 day, 42 day, and 50 day were collected for routine blood tests, RNA extraction, and preparation of small RNA sequencing libraries. The constructed libraries were sequenced and the biological functions of differential miRNAs in RBCs in the late storage were analyzed by bioinformatics. RESULTS: Routine indicators of RBCs in the late stage were not significantly affected by preservation time. The Pearson correlation analysis performing on RBC miRNAs with different storage days revealed that RBC miRNAs changed with the increase of storage days. RBC miRNAs from day 35 (D35), day 42 (D42) and day 50 (D50) showed significant differences (P < 0.05). Compared RBC miRNAs from D42 with these from D35, there were 690 up-regulated miRNAs and 82 down-regulated miRNAs; compared RBC miRNAs from D50 with these from D35, there were 638 up-regulated miRNAs and 123 down-regulated miRNAs; compared RBC miRNAs from D42 with these from D50, there were 271 up-regulated miRNAs and 515 down-regulated miRNAs. GO enrichment analysis of target genes of differential miRNAs were mainly involved in cell metabolism, biosynthesis, protein modification, gene expression and transcriptional regulation of biological processes. KEGG pathway enrichment analysis of miRNA target genes showed that differential miRNA target genes were closely related to pathways in cancer. CONCLUSION: MiRNAs were differentially expressed in the late stage of RBC preservation, and may be involved in various biological processes, especially cancer.

CCKBR+ cancer cells contribute to the intratumor heterogeneity of gastric cancer and confer sensitivity to FOXO inhibition.

The existence of heterogeneity has plunged cancer treatment into a challenging dilemma. We profiled malignant epithelial cells from 5 gastric adenocarcinoma patients through single-cell sequencing (scRNA-seq) analysis, demonstrating the heterogeneity of gastric adenocarcinoma (GA), and identified the CCKBR+ stem cell-like cancer cells associated poorly differentiated and worse prognosis. We further conducted targeted analysis using single-cell transcriptome libraries, including 40 samples, to confirm these screening results. In addition, we revealed that FOXOs are involved in the progression and development of CCKBR+ gastric adenocarcinoma. Inhibited the expression of FOXOs and disrupting cancer cell stemness reduce the CCKBR+ GA organoid formation and impede tumor progression. Mechanically, CUT&Tag sequencing and Lectin pulldown revealed that FOXOs can activate ST3GAL3/4/5 as well as ST6GALNAC6, promoting elevated sialyation levels in CCKBR+ tumor cells. This FOXO-sialyltransferase axis contributes to the maintenance of homeostasis and the growth of CCKBR+ tumor cells. This insight provides novel perspectives for developing targeted therapeutic strategies aimed at the treating CCKBR associated gastric cancer.

Vascular restoration through local delivery of angiogenic factors stimulates bone regeneration in critical size defects.

Critical size bone defects represent a significant challenge worldwide, often leading to persistent pain and physical disability that profoundly impact patients' quality of life and mental well-being. To address the intricate and complex repair processes involved in these defects, we performed single-cell RNA sequencing and revealed notable shifts in cellular populations within regenerative tissue. Specifically, we observed a decrease in progenitor lineage cells and endothelial cells, coupled with an increase in fibrotic lineage cells and pro-inflammatory cells within regenerative tissue. Furthermore, our analysis of differentially expressed genes and associated signaling pathway at the single-cell level highlighted impaired angiogenesis as a central pathway in critical size bone defects, notably influenced by reduction of Spp1 and Cxcl12 expression. This deficiency was particularly pronounced in progenitor lineage cells and myeloid lineage cells, underscoring its significance in the regeneration process. In response to these findings, we developed an innovative approach to enhance bone regeneration in critical size bone defects. Our fabrication process involves the integration of electrospun PCL fibers with electrosprayed PLGA microspheres carrying Spp1 and Cxcl12. This design allows for the gradual release of Spp1 and Cxcl12 in vitro and in vivo. To evaluate the efficacy of our approach, we locally applied PCL scaffolds loaded with Spp1 and Cxcl12 in a murine model of critical size bone defects. Our results demonstrated restored angiogenesis, accelerated bone regeneration, alleviated pain responses and improved mobility in treated mice.

Electrochemical aptasensor based on a dual signal amplification strategy of 1-AP-CNHs and ROP for highly sensitive detection of ERα.

Estrogen receptor alpha (ERα) serves as a crucial biomarker for early breast cancer diagnosis. In this study, we proposed an electrochemical aptasensor with nanomaterial carbon nanohorns/gold nanoparticle composites (1-AP-CNHs/AuNPs) as the substrate, and the primary amine groups on the antibody initiated the ring-opening polymerization (ROP) of monomer amino acid-ferrocene (NCA-Fc) on the electrode surface for ultrasensitive detection of ERα. The composite of 1-AP-CNHs/AuNPs not only possessed more active sites, but also increased the specific surface area of the electrode and allowed a large amount of ferrocene polymer long chains to be grafted onto the electrode surface to achieve signal amplification. Under optimal conditions, the detection limit of the method was 11.995 fg mL-1 with a detection range of 100 fg mL-1-100 ng mL-1. In addition, the biotin-streptavidin system was used to further improve the sensitivity of the sensor. Importantly, this approach could be applied for the practical detection of ERα in real samples.