The Importance of Hypoxia-Related to Hemoglobin Concentration in Breast Cancer.

The importance of hemoglobin (Hgb) as a novel prognostic biomarker in predicting clinical features of cancers has been the subject of intense interest. Anemia is common in various types of cancer including breast cancer (BC) and is considered to be attributed to tumoral hypoxia. Cancer microenvironments are hypoxic compared with normal tissues, and this hypoxia is associated with Hgb concentration. Recent preclinical documents propose a direct or indirect correlation of intratumoral hypoxia, specifically along with acidity, with Hgb concentration and anemia. Analysis of the prognostic value of Hgb in BC patients has demonstrated increased hypoxia in the intratumoral environment. A great number of studies demonstrated that lower concentrations of Hgb before or during common cancer treatments, such as radiation and chemotherapy, is an essential risk factor for poor prognostic and survival, as well as low quality of life in BC patients. This data suggests a potential correlation between anemia and hypoxia in BC. While low Hgb levels are detrimental to BC invasion and survival, identification of a distinct and exact threshold for low Hgb concentration is challenging and inaccurate. The optimal thresholds for Hgb and partial pressure of oxygen (pO2) vary based on different factors including age, gender, therapeutic approaches, and tumor types. While necessitating further investigations, understanding the correlation of Hgb levels with tumoral hypoxia and oxygenation could improve exploring strategies to overcome radio-chemotherapy related anemia in BC patients. This review highlights the collective association of Hgb concentration and hypoxia condition in BC progression.

Association between Peripheral Arterial Lactate Levels and Malignant Brain Edema Following Endovascular Treatment for Ischemic Stroke.

AIMS: To investigate the factors of postoperative malignant brain edema (MBE) in patients with acute ischemic stroke (AIS) treated with endovascular treatment (EVT). BACKGROUND: MBE is a severe complication following EVT for AIS, and it is essential to identify risk factors early. Peripheral arterial lactate (PAL) levels may serve as a potential predictive marker for MBE. OBJECTIVE: To determine whether immediate postoperative PAL levels and the highest PAL level within 24 hours of EVT are independently associated with MBE development in AIS patients. METHODS: We retrospectively analyzed patients with AIS who underwent EVT from October 2019 to October 2022. Arterial blood was collected every 8 h after EVT to measure PAL, and record the immediate postoperative PAL and the highest PAL level within 24 h. Brain edema was evaluated using brain computed tomography scans within 7 days of EVT. RESULTS: The study included 227 patients with a median age of 71 years, of whom 59.5% were male and MBE developed in 25.6% of patients (58/227). Multivariate logistic regression analysis showed that the immediate postoperative PAL (odds ratio, 1.809 [95% confidence interval (CI), 1.215-2.693]; p = 0.004) and the highest PAL level within 24 h of EVT (odds ratio, 2.259 [95% CI, 1.407-3.629]; p = 0.001) were independently associated with MBE. The area under the curve for predicting MBE based on the highest PAL level within 24 hours of EVT was 0.780 (95% CI, 0.711-0.849). CONCLUSION: Early increase in PAL levels is an independent predictor of MBE after EVT in AIS patients.

Nintedanib Mitigates Radiation-Induced Pulmonary Fibrosis by Suppressing Epithelial Cell Inflammatory Response and Inhibiting Fibroblast-to-Myofibroblast Transition.

Radiation-induced pulmonary fibrosis (RIPF) represents a serious complication observed in individuals undergoing thoracic radiation therapy. Currently, effective interventions for RIPF are unavailable. Prior research has demonstrated that nintedanib, a Food and Drug Administration (FDA)-approved anti-fibrotic agent for idiopathic pulmonary fibrosis, exerts therapeutic effects on chronic fibrosing interstitial lung disease. This research aimed to investigate the anti-fibrotic influences of nintedanib on RIPF and reveal the fundamental mechanisms. To assess its therapeutic impact, a mouse model of RIPF was established. The process involved nintedanib administration at various time points, both prior to and following thoracic radiation. In the RIPF mouse model, an assessment was conducted on survival rates, body weight, computed tomography features, histological parameters, and changes in gene expression. In vitro experiments were performed to discover the mechanism underlying the therapeutic impact of nintedanib on RIPF. Treatment with nintedanib, administered either two days prior or four weeks after thoracic radiation, significantly alleviated lung pathological changes, suppressed collagen deposition, and improved the overall health status of the mice. Additionally, nintedanib demonstrated significant mitigation of radiation-induced inflammatory responses in epithelial cells by inhibiting the PI3K/AKT and MAPK signaling pathways. Furthermore, nintedanib substantially inhibited fibroblast-to-myofibroblast transition by suppressing the TGF-ß/Smad and PI3K/AKT/mTOR signaling pathways. These findings suggest that nintedanib exerts preventive and therapeutic effects on RIPF by modulating multiple targets instead of a single anti-fibrotic pathway and encourage the further clinical trials to determine the efficacy of nintedanib in patients with RIPF.

The impact of tertiary lymphoid structures on tumor prognosis and the immune microenvironment in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is a common malignancy whose prognosis and treatment outcome are influenced by many factors. Some studies have found that tertiary lymphoid structures (TLSs) in cancer may contribute to prognosis and the prediction of immunotherapy efficacy However, the combined role of TLSs in NSCLC remains unclear. We accessed The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases to obtain mRNA sequencing data and clinical information as the TCGA cohort, and used our own sample of 53 advanced NSCLC as a study cohort. The samples were divided into TLS+ and TLS- groups by pathological tissue sections. Patients of the TLS+ group had a better OS (p = 0.022), PFS (p = 0.042), and DSS (p = 0.004) in the TCGA cohort, and the results were confirmed by the study cohort (PFS, p = 0.012). Furthermore, our result showed that the count and size of TLSs are closely associated with the efficacy of immunotherapy. In addition, the TLS+ group was associated with better immune status and lower tumor mutation load. In the tumor microenvironment (TME), the expression levels of CD4+ T cells and CD8+ T cells of different phenotypes were associated with TLSs. Overall, TLSs are a strong predictor of survival and immunotherapeutic efficacy in advanced NSCLC, and T cell-rich TLSs suggest a more ordered and active immune response site, which aids in the decision-making and application of immunotherapy in the clinic.

Design and Application of pH-Responsive Liposomes for Site-Specific Delivery of Cytotoxin from Cobra Venom.

Background: Current immunotherapies with unexpected severe side effects and treatment resistance have not resulted in the desired outcomes for patients with melanoma, and there is a need to discover more effective medications. Cytotoxin (CTX) from Cobra Venom has been established to have favorable cytolytic activity and antitumor efficacy and is regarded as a promising novel anticancer agent. However, amphiphilic CTX with excellent anionic phosphatidylserine lipid-binding ability may also damage normal cells. Methods: We developed pH-responsive liposomes with a high CTX load (CTX@PSL) for targeted acidic-stimuli release of drugs in the tumor microenvironment. The morphology, size, zeta potential, drug-release kinetics, and preservation stability were characterized. Cell uptake, apoptosis-promoting effects, and cytotoxicity were assessed using MTT assay and flow cytometry. Finally, the tissue distribution and antitumor effects of CTX@PSL were systematically assessed using an in vivo imaging system. Results: CTX@PSL exhibited high drug entrapment efficiency, drug loading, stability, and a rapid release profile under acidic conditions. These nanoparticles, irregularly spherical in shape and small in size, can effectively accumulate at tumor sites (six times higher than free CTX) and are rapidly internalized into cancer cells (2.5-fold higher cell uptake efficiency). CTX@PSL displayed significantly stronger cytotoxicity (IC50 0.25 µg/mL) and increased apoptosis in than the other formulations (apoptosis rate 71.78±1.70%). CTX@PSL showed considerably better tumor inhibition efficacy than free CTX or conventional liposomes (tumor inhibition rate 79.78±5.93%). Conclusion: Our results suggest that CTX@PSL improves tumor-site accumulation and intracellular uptake for sustained and targeted CTX release. By combining the advantages of CTX and stimuli-responsive nanotechnology, the novel CTX@PSL nanoformulation is a promising therapeutic candidate for cancer treatment.

Advancements in osteosarcoma management: integrating immune microenvironment insights with immunotherapeutic strategies.

Osteosarcoma, a malignant bone tumor predominantly affecting children and adolescents, presents significant therapeutic challenges, particularly in metastatic or recurrent cases. Conventional surgical and chemotherapeutic approaches have achieved partial therapeutic efficacy; however, the prognosis for long-term survival remains bleak. Recent studies have highlighted the imperative for a comprehensive exploration of the osteosarcoma immune microenvironment, focusing on the integration of diverse immunotherapeutic strategies-including immune checkpoint inhibitors, tumor microenvironment modulators, cytokine therapies, tumor antigen-specific interventions, cancer vaccines, cellular therapies, and antibody-based treatments-that are directly pertinent to modulating this intricate microenvironment. By targeting tumor cells, modulating the tumor microenvironment, and activating host immune responses, these innovative approaches have demonstrated substantial potential in enhancing the effectiveness of osteosarcoma treatments. Although most of these novel strategies are still in research or clinical trial phases, they have already demonstrated significant potential for individuals with osteosarcoma, suggesting the possibility of developing new, more personalized and effective treatment options. This review aims to provide a comprehensive overview of the current advancements in osteosarcoma immunotherapy, emphasizing the significance of integrating various immunotherapeutic methods to optimize therapeutic outcomes. Additionally, it underscores the imperative for subsequent research to further investigate the intricate interactions between the tumor microenvironment and the immune system, aiming to devise more effective treatment strategies. The present review comprehensively addresses the landscape of osteosarcoma immunotherapy, delineating crucial scientific concerns and clinical challenges, thereby outlining potential research directions.

Muscle-bone cross-talk through the FNIP1-TFEB-IGF2 axis is associated with bone metabolism in human and mouse.

Clinical evidence indicates a close association between muscle dysfunction and bone loss; however, the underlying mechanisms remain unclear. Here, we report that muscle dysfunction-related bone loss in humans with limb-girdle muscular dystrophy is associated with decreased expression of folliculin-interacting protein 1 (FNIP1) in muscle tissue. Supporting this finding, murine gain- and loss-of-function genetic models demonstrated that muscle-specific ablation of FNIP1 caused decreased bone mass, increased osteoclastic activity, and mechanical impairment that could be rescued by myofiber-specific expression of FNIP1. Myofiber-specific FNIP1 deficiency stimulated expression of nuclear translocation of transcription factor EB, thereby activating transcription of insulin-like growth factor 2 (Igf2) at a conserved promoter-binding site and subsequent IGF2 secretion. Muscle-derived IGF2 stimulated osteoclastogenesis through IGF2 receptor signaling. AAV9-mediated overexpression of IGF2 was sufficient to decrease bone volume and impair bone mechanical properties in mice. Further, we found that serum IGF2 concentration was negatively correlated with bone health in humans in the context of osteoporosis. Our findings elucidate a muscle-bone cross-talk mechanism bridging the gap between muscle dysfunction and bone loss. This cross-talk represents a potential target to treat musculoskeletal diseases and osteoporosis.

Construction of semiconductor nanocomposites for room-temperature gas sensors.

Gas sensors are essential for ensuring public safety and improving quality of life. Room-temperature gas sensors are notable for their potential economic benefits and low energy consumption, and their expected integration with wearable electronics, making them a focal point of contemporary research. Advances in nanomaterials and low-dimensional semiconductors have significantly contributed to the enhancement of room-temperature gas sensors. These advancements have focused on improving sensitivity, selectivity, and response/recovery times, with nanocomposites offering distinct advantages. The discussion here focuses on the use of semiconductor nanocomposites for gas sensing at room temperature, and provides a review of the latest synthesis techniques for these materials. This involves the precise adjustment of chemical compositions, microstructures, and morphologies. In addition, the design principles and potential functional mechanisms are examined. This is crucial for deepening the understanding and enhancing the operational capabilities of sensors. We also highlight the challenges faced in scaling up the production of nanocomposite materials. Looking ahead, semiconductor nanocomposites are expected to drive innovation in gas sensor technology due to their carefully crafted design and construction, paving the way for their extensive use in various sectors.

Cytoplasmic TP53INP2 acts as an apoptosis partner in TRAIL treatment: the synergistic effect of TRAIL with venetoclax in TP53INP2-positive acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) is a hematopoietic malignancy with poor outcomes, especially in older AML patients. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is considered a promising anticancer drug because it selectively induces the extrinsic apoptosis of tumor cells without affecting normal cells. However, clinical trials have shown that the responses of patients to TRAIL are significantly heterogeneous. It is necessary to explore predictable biomarkers for the preselection of AML patients with better responsiveness to TRAIL. Here, we investigated the critical role of tumor protein p53 inducible nuclear protein 2 (TP53INP2) in the AML cell response to TRAIL treatment. METHODS: First, the relationship between TP53INP2 and the sensitivity of AML cells to TRAIL was determined by bioinformatics analysis of Cancer Cell Line Encyclopedia datasets, Cell Counting Kit-8 assays, flow cytometry (FCM) and cell line-derived xenograft (CDX) mouse models. Second, the mechanisms by which TP53INP2 participates in the response to TRAIL were analyzed by Western blot, ubiquitination, coimmunoprecipitation and immunofluorescence assays. Finally, the effect of TRAIL alone or in combination with the BCL-2 inhibitor venetoclax (VEN) on cell survival was explored using colony formation and FCM assays, and the effect on leukemogenesis was further investigated in a patient-derived xenograft (PDX) mouse model. RESULTS: AML cells with high TP53INP2 expression were more sensitive to TRAIL in vitro and in vivo. Gain- and loss-of-function studies demonstrated that TP53INP2 significantly enhanced TRAIL-induced apoptosis, especially in AML cells with nucleophosmin 1 (NPM1) mutations. Mechanistically, cytoplasmic TP53INP2 maintained by mutant NPM1 functions as a scaffold bridging the ubiquitin ligase TRAF6 to caspase-8 (CASP 8), thereby promoting the ubiquitination and activation of the CASP 8 pathway. More importantly, simultaneously stimulating extrinsic and intrinsic apoptosis signaling pathways with TRAIL and VEN showed strong synergistic antileukemic activity in AML cells with high levels of TP53INP2. CONCLUSION: Our findings revealed that TP53INP2 is a predictor of responsiveness to TRAIL treatment and supported a potentially individualized therapeutic strategy for TP53INP2-positive AML patients.

Polydopamine bridging encapsulated laccase on MOF-based mixed-matrix membrane for selective dye/salt separation.

Mixed-matrix membranes (MMMs) exhibit significant potential for dye/salt separation. However, overcoming the "trade-off" between permeability and selectivity, as well as membrane fouling, remains a formidable task. In this work, a biocatalytic membrane was prepared using polydopamine (PDA) as a "bridge" connecting the metal-organic framework (MOF)-based MMM and immobilized laccase. The MOF-based MMM featured an interconnected MOF anchoring on the polyvinylidene fluoride (PVDF) skeleton structure, effectively mitigating the "trade-off" phenomenon and enabling efficient separation of dyes and salts. Enzyme-MOF was in situ grown on the MOF-based MMM via coordination reactions between PDA and metal ion, effectively degrading the adhesion of organic pollutants and fouling, ensuring the long-term stable operation of the membrane. The Lac-MOF@PDA MMM exhibited excellent water permeability of 142.4 L·m-2·h-1, 100 % rejection for dye, and less than 10 % rejection for NaCl. Furthermore, the separation mechanism of Lac-MOF@PDA MMM was systematically investigated, and the results suggested a synergistic combination of rejection, adsorption and catalysis processes. This biocatalytic membrane with multiple sieving and biological catalysis is expected to pave a promising way for efficient wastewater treatment applications.

EGCG Alleviates the Aging Toxicity Induced by 3-MCPD via IIS Pathway in Caenorhabditis elegans with Abnormal Reproduction and Heat Shock Protein.

This study aimed to investigate the mitigation effect of epigallocatechin gallate (EGCG) on aging induced by 3-monochloropropane-1,2-diol (3-MCPD) in Caenorhabditis elegans, evaluate health indicators during the process, and reveal the underlying mechanism through transcriptomics and identification of mutants. The results showed that EGCG alleviated the declined fertility, shortened lifespan, reduced body size, weakened movement, increased reactive oxygen species and lipofuscin, and damaged antioxidative stress response and excessive heat shock proteins caused by 3-MCPD. Transcriptomics study indicated that treatment with 3-MCPD and EGCG altered gene expression, and gene mutants confirmed the involvement of insulin/IGF-1 signaling pathway in mediating the process that EGCG alleviated the aging toxicity induced by 3-MCPD. The study showed that EGCG alleviated the aging toxicity induced by 3-MCPD.

Mendelian randomization unraveled: gender-specific insights into obesity-related phenotypes and colorectal cancer susceptibility.

Objective: Evidence has been increasingly pointing towards a potential link between phenotypes related to obesity and the incidence of colorectal cancer. However, confirming this as a direct causal connection remains elusive. This investigation aims to elucidate the causative links between obesity-associated phenotypes and the incidence of colorectal cancer. Methods: Employing the Two Sample Mendelian Randomization (TwoSampleMR) R package, analyses were conducted using Mendelian randomization (MR) to discern potential causative links between obesity categories sourced from both the Institute for Education and University (IEU) Open GWAS Project and Zenodo, and colorectal tumors (data obtained from IEU Open GWAS and FinnGen). For primary evaluations, the study utilized the Wald ratio and the Inverse Variance Weighting (IVW) methods, while the MR-Egger approach was integrated for sensitivity assessment. Bidirectional Mendelian Randomization (Bidirectional MR), as well as Linkage Disequilibrium (LD) Score Regression with well-imputed HapMap3 single nucleotide polymorphisms (SNPs), were additionally executed. Sensitivity assessments entailed IVW, MR-Egger methodologies to assess heterogeneity and pleiotropy, along with a leave-one-out strategy. Instrumental variables were chosen judiciously based on predetermined P-value thresholds and F-statistics. Results: Results from MR evaluations did not identify a clear causative link between BMI and colorectal malignancy. Conversely, both measures of obesity, the Waist-Hip Ratio (WHR) and its adjusted form for BMI (WHRadjBMI), displayed a connection to increased risk of colorectal cancer, especially prominent among female subjects. Reverse MR analyses dismissed potential reverse causality between colorectal malignancies and obesity. A significant genetic interplay was observed between WHR, WHRadjBMI, and colorectal cancer instances. Ensuing MR probes spotlighted inflammatory bowel ailment as a protective factor, while salad intake was indicated as a potential risk concerning colorectal malignancies. Sensitivity reviews, which included tests for both pleiotropy and heterogeneity, validated the robustness of the MR findings. Conclusion: Findings from this research indicate that specific obesity-related parameters, notably WHR and WHRadjBMI, carry a causal relationship with an elevated colorectal cancer risk. The impact is distinctly more evident among females. Such insights might be pivotal for public health deliberations, hinting that individuals boasting a high WHR might necessitate intensified colorectal cancer screenings.

A Quantity-Dependent Nonlinear Model of Sodium Cromoglycate Suppression on Beta-Conglycinin Transport.

Understanding the transport mechanism is crucial for developing inhibitors that block allergen absorption and transport and prevent allergic reactions. However, the process of how beta-conglycinin, the primary allergen in soybeans, crosses the intestinal mucosal barrier remains unclear. The present study indicated that the transport of beta-conglycinin hydrolysates by IPEC-J2 monolayers occurred in a time- and quantity-dependent manner. The beta-conglycinin hydrolysates were absorbed into the cytoplasm of IPEC-J2 monolayers, while none were detected in the intercellular spaces. Furthermore, inhibitors such as methyl-beta-cyclodextrin (MßCD) and chlorpromazine (CPZ) significantly suppressed the absorption and transport of beta-conglycinin hydrolysates. Of particular interest, sodium cromoglycate (SCG) exhibited a quantity-dependent nonlinear suppression model on the absorption and transport of beta-conglycinin hydrolysates. In conclusion, beta-conglycinin crossed the IPEC-J2 monolayers through a transcellular pathway, involving both clathrin-mediated and caveolae-dependent endocytosis mechanisms. SCG suppressed the absorption and transport of beta-conglycinin hydrolysates by the IPEC-J2 monolayers by a quantity-dependent nonlinear model via clathrin-mediated and caveolae-dependent endocytosis. These findings provide promising targets for both the prevention and treatment of soybean allergies.

Emerging evidence of context-dependent synapse elimination by phagocytes in the CNS.

Precise synapse elimination is essential for the establishment of a fully developed neural circuit during brain development and higher function in adult brain. Beyond immune and nutrition support, recent groundbreaking studies have revealed that phagocytic microglia and astrocytes can actively and selectively eliminate synapses in normal and diseased brains, thereby mediating synapse loss and maintaining circuit homeostasis. Multiple lines of evidence indicate that the mechanisms of synapse elimination by phagocytic glia are not universal but rather depend on specific contexts and detailed neuron-glia interactions. The mechanism of synapse elimination by phagocytic glia is dependent on neuron-intrinsic factors, many innate immune and local apoptosis related molecules. During development, microglial synapse engulfment in the visual thalamus is primarily influenced by the classic complement pathway, whereas in the barrel cortex, the fractalkine pathway is dominant. In Alzheimer's disease, microglia employ complement-dependent mechanisms for synapse engulfment in tauopathy and early ß-amyloid pathology. But microglia are not involved in synapse loss at late ß-amyloid stages. Phagocytic microglia also engulfment synapses in complement dependent way in schizophrenia, anxiety and stress. Besides, phagocytic astrocytes engulf synapses in a MEGF10 dependent way during visual development, memory and stroke. Furthermore, the mechanism of a phenomenon that phagocytes selectively eliminating excitatory and inhibitory synapses is also emphasized in this review. We hypothesize that elucidating context-dependent synapse elimination by phagocytic microglia and astrocytes may reveal the molecular basis of synapse loss in neural disorders and provide a rationale for developing novel candidate therapies that target synapse loss and circuit homeostasis.

Study on the Wettability and Methane Desorption Characteristics of Coal under High Pressure with Different Surfactants.

In the process of coalbed methane extraction, due to the strong hydrophilicity of coal, the surface interaction force between water and the coal matrix is strong. The hydrophobic effect of the coal seam during drainage and pressure reduction is not significant, and adsorbed methane is difficult to desorb. In order to reduce the surface interaction force promoting methane desorption between water and coal, the surfactants NH766, G526, and D001 with a concentration of 0.1% were selected. A pressure of 12 MPa, which is close to that used for the on-site mining of coalbed methane in Baode, was selected as the experimental condition to simulate hydraulic fracturing of high fat coal, and the influence of different surfactants on methane desorption characteristics was analyzed. Combining contact angle experiments and infrared spectroscopy experiments, we explored the changes in wettability of the coal samples. We compared the changes in wettability and methane desorption characteristics and explored the similarities between these changes. The experimental results showed that after NH766 treatment, the content of oxygen-containing functional groups in coal rock decreased by 30%, and the contact angle of the coal matrix surface increased by 10°. Furthermore, its hydrophobicity was enhanced, and the desorption amount increased by 24%. In contrast, the oxygen-containing functional groups in coal rock after G526 and D001 treatments increased by 5% and 16%, respectively, and the contact angle of the coal matrix surface became smaller. Furthermore, its hydrophilicity was enhanced, and the desorption amount was reduced by 12.5% and 20%, respectively. NH766 reduces wettability and promotes methane desorption, and it can be applied to improve CBM extraction efficiency. G526 and D001 enhance wettability and inhibit methane desorption, which make them suitable for dust prevention and gas control in coal mines.

Unlocking Predictive Capability and Enhancing Sensing Performances of Plasmonic Hydrogen Sensors via Phase Space Reconstruction and Convolutional Neural Networks.

This study innovates plasmonic hydrogen sensors (PHSs) by applying phase space reconstruction (PSR) and convolutional neural networks (CNNs), overcoming previous predictive and sensing limitations. Utilizing a low-cost and efficient colloidal lithography technique, palladium nanocap arrays are created and their spectral signals are transformed into images using PSR and then trained using CNNs for predicting the hydrogen level. The model achieves accurate predictions with average accuracies of 0.95 for pure hydrogen and 0.97 for mixed gases. Performance improvements observed are a reduction in response time by up to 3.7 times (average 2.1 times) across pressures, SNR increased by up to 9.3 times (average 3.9 times) across pressures, and LOD decreased from 16 Pa to an extrapolated 3 Pa, a 5.3-fold improvement. A practical application of remote hydrogen sensing without electronics in hydrogen environments is actualized and achieves a 0.98 average test accuracy. This methodology reimagines PHS capabilities, facilitating advancements in hydrogen monitoring technologies and intelligent spectrum-based sensing.

Molecular Characterization of Resistance and Virulence Factors of Trueperella pyogenes Isolated from Clinical Bovine Mastitis Cases in China.

Purpose: The present study was designed to investigate the resistance determinants and virulence factors of 45 Trueperella pyogenes isolates from clinical bovine mastitis in Hexi Corridor of Gansu, China. Methods: Minimum inhibitory concentrations (MICs) was tested by E-test method. Gene of antimicrobial resistance, virulence integrase and integron gene cassettes were determined by PCR and DNA sequencing. Results: The T. pyogenes isolates exhibited high resistance to streptomycin (88.9%) and tetracycline (64.4%), followed by erythromycin (15.6%) and gentamicin (13.3%). Resistance to streptomycin was most commonly encoded by aadA9 (88.9%); and to tetracycline, by tetW (64.4%). Importantly, all streptomycin-resistant isolates carried aadA9 alone or in combination with aadA1, aadA11 and strA-strB. Similarly, all tetracycline-resistant isolates harbored tetW alone or in combination with tetA33. Meanwhile, ermX was detected in 13.3% isolates, only one erythromycin-resistant isolate was not identified for this gene. Moreover, all T. pyogenes isolates carried class 1 integrons, and 17.8% of them contained gene cassettes, including arrays aadA1-aadB (4.4%), aad A24-dfrA1-ORF1 (2.2%) and aadA1 (2.2%). Furthermore, all tested isolates harbored virulent genes plo and fimA, followed by fimC (88.9%), fimE (86.6%) nanP (75.6%), nanH (40.0%), cbpA (35.6%) and fimG (6.7%). Conclusion: To our knowledge, this is the first report of integron gene cassettes of T. pyogenes isolates from bovine mastitis cases in China. These findings are useful for developing the prevention and the virulence factors of T. pyogenes could be promising candidates for vaccine antigens for bovine mastitis caused by T. pyogenes in China.

Targeting metabolism to enhance immunotherapy within tumor microenvironment.

Cancer metabolic reprogramming has been considered an emerging hallmark in tumorigenesis and the antitumor immune response. Like cancer cells, immune cells within the tumor microenvironment or premetastatic niche also undergo extensive metabolic reprogramming, which profoundly impacts anti-tumor immune responses. Numerous evidence has illuminated that immunosuppressive TME and the metabolites released by tumor cells, including lactic acid, Prostaglandin E2 (PGE2), fatty acids (FAs), cholesterol, D-2-Hydroxyglutaric acid (2-HG), adenosine (ADO), and kynurenine (KYN) can contribute to CD8+ T cell dysfunction. Dynamic alterations of these metabolites between tumor cells and immune cells can similarly initiate metabolic competition in the TME, leading to nutrient deprivation and subsequent microenvironmental acidosis, which impedes immune response. This review summarizes the new landscape beyond the classical metabolic pathways in tumor cells, highlighting the pivotal role of metabolic disturbance in the immunosuppressive microenvironment, especially how nutrient deprivation in TME leads to metabolic reprogramming of CD8+ T cells. Likewise, it emphasizes the current therapeutic targets or strategies related to tumor metabolism and immune response, providing therapeutic benefits for tumor immunotherapy and drug development in the future. Cancer metabolic reprogramming has been considered an emerging hallmark in tumorigenesis and the antitumor immune response. Dynamic alterations of metabolites between tumor cells and immune cells initiate metabolic competition in the TME, leading to nutrient deprivation and subsequent microenvironmental acidosis, which impedes immune response.

Regulatory microRNAs and phasiRNAs of paclitaxel biosynthesis in Taxus chinensis.

Paclitaxel (trade name Taxol) is a rare diterpenoid with anticancer activity isolated from Taxus. At present, paclitaxel is mainly produced by the semi-synthetic method using extract of Taxus tissues as raw materials. The studies of regulatory mechanisms in paclitaxel biosynthesis would promote the production of paclitaxel through tissue/cell culture approaches. Here, we systematically identified 990 transcription factors (TFs), 460 microRNAs (miRNAs), and 160 phased small interfering RNAs (phasiRNAs) in Taxus chinensis to explore their interactions and potential roles in regulation of paclitaxel synthesis. The expression levels of enzyme genes in cone and root were higher than those in leaf and bark. Nearly all enzyme genes in the paclitaxel synthesis pathway were significantly up-regulated after jasmonate treatment, except for GGPPS and CoA Ligase. The expression level of enzyme genes located in the latter steps of the synthesis pathway was significantly higher in female barks than in male. Regulatory TFs were inferred through co-expression network analysis, resulting in the identification of TFs from diverse families including MYB and AP2. Genes with ADP binding and copper ion binding functions were overrepresented in targets of miRNA genes. The miRNA targets were mainly enriched with genes in plant hormone signal transduction, mRNA surveillance pathway, cell cycle and DNA replication. Genes in oxidoreductase activity, protein-disulfide reductase activity were enriched in targets of phasiRNAs. Regulatory networks were further constructed including components of enzyme genes, TFs, miRNAs, and phasiRNAs. The hierarchical regulation of paclitaxel production by miRNAs and phasiRNAs indicates a robust regulation at post-transcriptional level. Our study on transcriptional and posttranscriptional regulation of paclitaxel synthesis provides clues for enhancing paclitaxel production using synthetic biology technology.