RESUMO

Epithelial-mesenchymal transition (EMT) plays an irreplaceable role in the development of silicosis. However, molecular mechanisms of EMT induced by silica exposure still remain to be addressed. Herein, metabolic profiles of human alveolar type II epithelial cells (A549 cells) exposed directly to silica were characterized using non-targeted metabolomic approaches. A total of 84 differential metabolites (DMs) were identified in silica-treated A549 cells undergoing EMT, which were mainly enriched in metabolisms of amino acids (e.g., glutamate, alanine, aspartate), purine metabolism, glycolysis, etc. The number of DMs identified in the A549 cells obviously increased with the elevated exposure concentration of silica. Remarkably, glutamine catabolism was significantly promoted in the silica-treated A549 cells, and the levels of related metabolites (e.g., succinate) and enzymes (e.g., α-ketoglutarate (α-KG) dehydrogenase) were substantially up-regulated, with a preference to α-KG pathway. Supplementation of glutamine into the cell culture could substantially enhance the expression levels of both EMT-related markers and Snail (zinc finger transcription factor). Our results suggest that the EMT of human alveolar epithelial cells directly induced by silica can be essential to the development of silicosis.

Assuntos

RESUMO

Background: We explore the association between leucocyte telomere length (LTL) and all-cause and cardiovascular disease (CVD)-specific death in CVD patients. Methods: We acquired 1599 CVD patients from a nationally representative US population survey for this study. We applied Kaplan-Meier curves, adjusted weighted Cox regression models, and restricted cubic spline to investigate the association between LTL and all-cause death. Additionally, we employed competing risk regression to assess the impact of LTL on cardiovascular-specific death, setting non-cardiovascular death as a competing event. Results: The overall mortality rate was 31.0% after a median follow-up of 13.9 years. Patients with shorter LTL exhibited a higher risk of all-cause death, with an adjusted hazard ratio (HR) of 1.25 (95% confidence interval (CI): 1.05-1.48). Restricted cubic spline illustrated a linear dose-response relationship. In gender-specific analyses, female patients with shorter LTL showed a higher risk of death (weighted HR, 1.79; 95% CI, 1.29-2.48), whereas this association was not observed in males (weighted HR, 0.90; 95% CI, 0.61-1.32). The Fine-Gray competing risk model revealed no significant relationship between LTL and cardiovascular-specific mortality but a significant association with non-cardiovascular death (adjusted HR, 1.24; 95% CI, 1.02-1.51). Conclusions: LTL is inversely associated with all-cause death in female CVD patients. The significant correlation between reduced LTL and increased all-cause mortality emphasizes LTL as a potential marker for tertiary prevention against cardiovascular disease.

RESUMO

The proven efficacy of immunotherapy in fighting tumors has been firmly established, heralding a new era in harnessing both the innate and adaptive immune systems for cancer treatment. Despite its promise, challenges such as inefficient delivery, insufficient tumor penetration, and considerable potential toxicity of immunomodulatory agents have impeded the advancement of immunotherapies. Recent endeavors in the realm of tumor prophylaxis and management have highlighted the use of living biological entities, including bacteria, oncolytic viruses, and immune cells, as a vanguard for an innovative class of live biotherapeutic products (LBPs). These LBPs are gaining recognition for their inherent ability to target tumors. However, these LBPs must contend with significant barriers, including robust immune clearance mechanisms, cytotoxicity and other in vivo adverse effects. Priority must be placed on enhancing their safety and therapeutic indices. This review consolidates the latest preclinical research and clinical progress pertaining to the exploitation of engineered biologics, spanning bacteria, oncolytic viruses, immune cells, and summarizes their integration with combination therapies aimed at circumventing current clinical impasses. Additionally, the prospective utilities and inherent challenges of the biotherapeutics are deliberated, with the objective of accelerating their clinical application in the foreseeable future.

RESUMO

Rabbit meat is an excellent source of high-quality proteins, essential fatty acids, vitamins, and minerals, which can be further improved through various management, preslaughter, and post-slaughter interventions. Rabbit meat consumption is popular in certain regions of the world. The multidimensional role of rabbits as pet, pest, and laboratory animals, lack of proper knowledge among consumers towards the nutritive value of rabbit meat, animal welfare, and ethical issues, sustainable potential, undeveloped marketing, and processing chain, and price parity with available cheap meat and non-meat alternatives, are some constraints in the rabbit meat production. Increasing awareness of the nutritive value, positive health effects of rabbit meat consumption and production chain, development of processed meat products, and proper animal welfare compliance in rabbit production could improve consumer acceptance. The present manuscript reviewed various factors that affect the meat quality and consumer acceptance of rabbit meat for a more sustainable and viable source for global meat supply.

RESUMO

In this study, the effects of Cl2 radicals on dry development of spin-coated metal oxide resist (MOR) and changes in its surface binding states were investigated to verify the mechanism of dry development. Dry development characteristics of tin hydroxide (Tin OH), which is one of the MOR candidates for next generation lithography, were investigated as functions of process time and temperature using a Cl2 radicals source. Non-UV-exposed Tin OH film showed a linear etch rate (1.77 nm/min) from the initial thickness of ∼50 nm, while the UV-exposed film showed slower etch behavior (1.46 nm/min) in addition to the increase of film thickness for up to 3 min during the Cl2 radical dry development. UV-exposed photoresist (PR) contained more oxygen (Sn-O bonding) in the film due to the removal of butyl compounds from the clusters during the UV exposure process. Therefore, due to the lower reaction of chlorine radicals with Sn-O in the UV-exposed Tin OH than the other bindings, the non-UV-exposed PR was preferentially removed compared to the UV-exposed PR. As the temperature decreases, the overall etch rate decreases, but the difference in etch rate between exposed and unexposed Tin OH becomes larger. Finally, at a substrate temperature of -20 °C, the non-UV-exposed Tin OH with a thickness of 50 nm was completely removed, while ∼30 nm thick PR remained for UV-exposed Tin OH. Eventually, a negative tone development was possible with Cl2 radical plasma due to the difference in activation energy between the UV-exposed and non-UV-exposed films. It is believed that dry development using Cl2 radicals will be one of the most important process techniques for next-generation patterning to remove problems such as pattern leaning, line edge roughness, residue, etc., caused by wet development.

RESUMO

Purpose: The development of "Internet + nursing services" can effectively solve the problem of population aging, and grassroots nurses are the primary providers of such services in rural areas. This study aimed to analyze the factors affecting grassroots nurses' risk perception of "Internet + nursing services" and construct a predictive model. Patients and Methods: A multicenter cross-sectional study of 2220 nurses from 27 secondary hospitals and 36 community health centers in Hubei Province was conducted from August to December 2023 using a multi-stage cluster sampling method. Information was collected through a structured anonymous questionnaire. A Chi-square test, a Welch t-test, and binary logistic regression analyses were employed to determine independent risk factors for grassroots nurses' risk perception of "Internet + nursing services", and a nomogram was constructed. Receiver operating characteristic curves, calibration curves, and decision curves were plotted to evaluate the discrimination, calibration, and clinical effectiveness of the nomogram. Results: A total of 2050 valid questionnaires were collected, demonstrating that 51.95% of grassroots nurses thought that "Internet + nursing services" was a medium-high risk. Age, other sources of income, knowledge about "Internet + nursing services", personal safety, physical function, occupational exposure, social psychosocial, and time risk (P<0.05) were independent risk factors for grassroots nurses' risk perception. The area under the receiver operating characteristic curve of the nomogram was 0.939. The calibration and decision curve analyses demonstrated good calibration ability and clinical application values. Conclusion: The prediction model constructed in this study has good prediction ability. Most grassroots nurses believe that "Internet + nursing services" are risky and influenced by several factors. It is suggested that the government and hospitals should formulate a unified charging standard, improve the safety guarantee, and gradually eliminate the concerns of grassroots nurses.

RESUMO

Histamine is a biogenic amine that is critical in various physiological and pathophysiological processes, including but not limited to allergic reactions, wakefulness, gastric acid secretion and neurotransmission. Here, we determine 9 cryo-electron microscopy (cryo-EM) structures of the 4 histamine receptors in complex with four different G protein subtypes, with endogenous or synthetic agonists bound. Inside the ligand pocket, we identify key motifs for the recognition of histamine, the distinct binding orientations of histamine and three subpockets that facilitate the design of specific ligands. In addition, we also identify key residues responsible for the selectivity of immethridine. Moreover, we reveal distinct structural features as determinants of Gq vs. Gs or Gs vs. Gi coupling differences among the histamine receptors. Our study provides a structural framework for understanding the ligand recognition and G protein coupling of all 4 histamine receptors, which may facilitate the rational design of ligands targeting these receptors.

Assuntos

RESUMO

OBJECTIVE: In this study, we aim to explore the genetic imprint of Bronze Age globalization in East Asia from a phylogeographic perspective by examining the Y-chromosome haplogroup Q1a1a-M120, and to identify key demographic processes involved in the formation of early China and the ancient Huaxia people. METHODS: Over the past few decades, we have collected the sequences of 347 Y chromosomes from the haplogroup Q1a1a-M120. These sequences were utilized to analyze and reconstruct a highly revised phylogenetic tree with age estimates. And we analyzed the geographical distribution and spatial autocorrelation of nine major sub-branches of Q1a1a-M120. Finally, we observed the expansion of Q1a1a-M120 from the beginning of the Bronze Age in East Asia, along with the continuous dissemination of its sub-lineages among East Asian populations. RESULTS: We suggest that certain sub-lineages played a significant role in the formation of states and early civilizations in China, as well as in the development of the ancient Huaxia people, who are the direct ancestors of the Han population. Overall, we propose that haplogroup Q-M120 played a role in the introduction of Bronze Age culture to the central region of East Asia. Therefore, it is haplogroup Q-M120, rather than the Western Eurasian paternal lineage, that expanded and contributed to the gene pool of the East Asian population. CONCLUSION: In summary, the globalization of the Bronze Age led to large-scale population replacement and admixture across various regions of Eurasia; our findings highlight the unique demographic processes that occurred in East Asia during this period.

RESUMO

KEY MESSAGE: Two major QTLs for cold tolerance in pumpkin were localised, and CmoERF017 was identified as a key candidate gene within these QTLs via RNA-seq. Functional analysis revealed that CmoERF017 was a positive regulator of pumpkin in response to low-temperature stress. Low temperature is a key environmental factor that affects the protected cultivation of cucumber (Cucumis sativus L.) in winter, and the cold tolerance of cucumber/pumpkin-grafted seedlings depends on the rootstock. Pumpkin (Cucurbita spp.) has a well-developed root system, high resistance and wide adaptation, commonly used as rootstock for cucumber to improve the cold tolerance of grafted seedlings. This study used two high-generation inbred lines of Cucurbita moschata with significant differences in cold tolerance. We identified key candidate genes within the major cold tolerance QTL of rootstocks using QTL-seq and RNA-seq and investigated the function and molecular mechanisms of these genes in response to low-temperature stress. Results showed that QTL-seq located two cold tolerance QTLs, qCII-1 and qCII-2, while RNA-seq located 28 differentially expressed genes within these QTLs. CmoERF017 was finally identified as a key candidate gene. Functional validation results indicated that CmoERF017 is a positive regulator of pumpkin in response to low-temperature stress and affected root ABA synthesis and signalling by directly regulating the expression of SDR7 and ABI5. This study identified a key gene for low-temperature stress tolerance in rootstock pumpkin and clarified its role in the molecular mechanism of hormone-mediated plant cold tolerance. The study findings enrich the theoretical understanding of low-temperature stress tolerance in pumpkin and are valuable for the selection and breeding of cold-tolerant varieties of pumpkin used for rootstocks.

Assuntos

RESUMO

Gastric and esophageal cancers, the predominant forms of upper gastrointestinal malignancies, contribute significantly to global cancer mortality. Routine detection methods, including medical imaging, endoscopic examination, and pathological biopsy, often suffer from drawbacks such as low sensitivity and laborious and complex procedures. Raman spectroscopy is a non-invasive and label-free optical technique that provides highly sensitive biomolecular information to facilitate effective tumor identification. In this work, we report the use of fiber-optic Raman spectroscopy for the accurate and rapid diagnosis of gastric and esophageal cancers. Using a database of 14,000 spectra from 140 ex vivo tissue pieces of both tumor and normal tissue samples, we compare the random forest (RF) and our established Euclidean distance Raman spectroscopy (EDRS) model. The RF analysis achieves a sensitivity of 85.23% and an accuracy of 83.05% in diagnosing gastric tumors. The EDRS algorithm with improved diagnostic transparency further increases the sensitivity to 92.86% and accuracy to 89.29%. When these diagnostic protocols are extended to esophageal tumors, the RF and EDRS models achieve accuracies of 71.27% and 93.18%, respectively. Finally, we demonstrate that fewer than 20 spectra are sufficient to achieve good Raman diagnostic accuracy for both tumor tissues. This optimizes the balance between acquisition time and diagnostic performance. Our work, although conducted on ex vivo tissue models, offers valuable insights for in vivo in situ endoscopic Raman diagnosis of gastric and esophageal cancer lesions in the future. Our study provides a robust, rapid, and convenient method as a new paradigm in in vivo endoscopic medical diagnostics that integrates spectroscopic techniques and a Raman probe for detecting upper gastrointestinal malignancies.

RESUMO

Type 2 diabetes mellitus (T2DM) involves insulin resistance and elevated blood sugar levels, causing complications. Red ginseng extract powder (RGEP) from Panax ginseng Meyer shows promise for diabetes treatment. However, its efficacy in managing T2DM remains unclear. Therefore, this study aims to evaluate the effectiveness of RGEP in a mouse model of T2DM. The efficacy of RGEP in treating T2DM was assessed in db/db mice. Mice were divided into seven groups: control, db/db, metformin, and RGEP at 50, 100, 200, and 400 mg/kg. Administered orally for 9 weeks, RGEP effects on glucose regulation and insulin sensitivity were assessed through various metabolic parameters. In addition, mRNA expression levels of genes associated with hepatic gluconeogenesis and insulin sensitivity were examined. Fasting blood sugar showed a significant decrease in all RGEP concentration groups, but OGTT and insulin tolerance test showed a significant decrease at the RGEP concentration of 400 mg/kg, indicating enhanced glycemic control. Moreover, RGEP dose-dependently decreased serum glucose, HbA1c levels, and homeostatic model assessment of insulin resistance values, suggesting its effectiveness in reducing insulin resistance in db/db mice. Furthermore, RGEP downregulated mRNA expression of key components in the gluconeogenesis pathway (G6Pase, FOXO1, GLUT4, and PEPCK), insulin sensitivity (leptin, insulin1, PTP1B, GLP-1, and DPP-4), and mitochondria energy metabolism (PGC1) in either the liver or pancreas, while simultaneously upregulating GLP-1 expression. In conclusion, these findings highlight the potential of RGEP as a complementary therapy for T2DM, indicating therapeutic efficacy in managing diabetic complications through improved metabolic parameters.

RESUMO

OBJECTIVES: To investigate the incidence and risk factors for acute kidney injury (AKI) in children with primary nephrotic syndrome (PNS), as well as the role of neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) in the early identification of AKI in these children. METHODS: A prospective collection of clinical data from children hospitalized with PNS at the Children's Hospital of the Capital Institute of Pediatrics from January 2021 to October 2022 was conducted. The children were divided into two groups based on the presence of AKI: the AKI group (47 cases) and the non-AKI group (169 cases). The risk factors for AKI in children with PNS were identified by multivariate logistic regression analysis. Urinary KIM-1 and NGAL levels were compared between the AKI and non-AKI groups, as well as among the different stages of AKI. RESULTS: The incidence of AKI in children with PNS was 21.8%. Multivariate logistic regression analysis revealed that steroid-resistant nephrotic syndrome, gastrointestinal infections, and heavy proteinuria were independent risk factors for AKI in these children with PNS (P<0.05). Urinary KIM-1 and NGAL levels were higher in the AKI group compared to the non-AKI group (P<0.05), and the urinary NGAL and KIM-1 levels in the AKI stage 2 and stage 3 subgroups were higher than those in the AKI stage 1 subgroup (P<0.017). CONCLUSIONS: KIM-1 and NGAL can serve as biomarkers for the early diagnosis of AKI in children with PNS. Identifying high-risk populations for AKI in children with PNS and strengthening the monitoring of related risk factors is of significant importance.

Assuntos

RESUMO

This study examines the effects of vehicle size on driver impressions and behavioral intentions. Study 1 tested whether vehicle size (large vs. small) affects perceived physical size (height, body shape) through socioeconomic status (SES). We found that large (vs. small) vehicle drivers were perceived as tall (vs. short), and this perception was mediated by the drivers' estimated SES (but not by body shape). Study 2 focused on aggressive behavioral intentions (e.g. honking) toward other drivers, examining whether the relationship between vehicle size and intention was serially mediated by estimated physical size and traits (aggression, power). Here, large (vs. small) vehicle driver were perceived as tall (heavy) and possessing high power (high aggression), which is related to less (more) aggressive behavioral intention toward the driver. Our study suggests that individuals perceive other drivers' physical sizes differently, and this perception is associated with differences in behavioral responses toward other drivers.

RESUMO

In the prodrug-based self-assembled nanoassemblies, prodrugs usually consist of drug modules, response modules, and modification modules. Modification modules play a critical role in regulating the nano-assembly ability of the prodrugs. Herein, we carried out a "fatty alcoholization" strategy and chose various lengths of aliphatic alcohol chains (AC) as modification modules to construct disulfide bond bridged paclitaxel (PTX) prodrug nanoassemblies. The PTX-AC prodrugs would self-assemble into nanoassemblies (PTX-AC PNs) with higher drug loading, stability, and tumor selectivity than commercial preparations. After comprehensive exploration, we found the chain length (AC12, AC16, AC20, AC24) of modification modules affected the assembly of PTX-AC PNs, further leading to disparate in vivo fate and antitumor efficacy. With the increase of the chain length of the modification modules (from AC12 to AC20), the assembly ability of the nanoassemblies was improved, attributed to the appropriate enhancement of hydrophobic force. When the chain length was further increased to AC24, the excessive hydrophobic force will lead to the aggregation of prodrugs and weaken the assembly ability. Therefore, PTX-AC20 PNs with proper chain length may solve the paradox of efficacy and tolerance in 4 T1 breast tumor owing to their optimal nano-assembly stability and modest redox-sensitivity. In short, this work highlighted the importance of screening optimal modification modules in developing prodrug nanoassemblies.

RESUMO

Cadmium (Cd) is a heavy metal that pollutes the environment and threatens human and animal health via the food chain. The spleen is one of the target organs affected by Cd toxicity. However, the mechanism of Cd toxicity is not fully understood. In this study, 80 chicks were allocated into 4 groups (n = 20) and exposed to different doses of CdCl2 (0 mg/kg, 35 mg/kg, 70 mg/kg and 140 mg/kg) for 90 d. The pathological changes in the spleen, mitochondrial dynamics-related factors, cytochrome P450 (CYP450) enzyme system contents, activities, transcription levels, nuclear receptors (NRs) response molecule levels, and mitochondrial unfolded protein-related factors were detected. The findings indicate that exposure to Cd significantly leads to spleen injury. In Cd groups, the total contents of CYP450 and cytochrome b5 (Cyt b5) increased, and the activities of the CYP450 enzyme system (APND, ERND, AH, and NCR) changed. The NRs response was induced, and the gene levels of AHR/CAR and corresponding CYP450 isoforms (CYP1B1, CYP1A5, CYP1A1, CYP2C18, CYP2D6 and CYP3A4) were found altered. The study found that Cd exposure altered the mRNA expression levels of mitochondrial dynamics-related factors, such as OPA1, Fis1, MFF, Mfn1, and Mfn2, breaking mitochondrial fusion and cleavage and ultimately leading to mitochondrial dysfunction. Changes were detected in the gene levels of several mitochondrial unfolded protein response (mtUPR)-related factors, namely (SIRT1, PGC-1α, NRF1, TFAM, SOD2, and HtrA2). Cd also altered the gene levels of mitochondrial function-related factors (VDAC1, Cyt-C, COA6, PRDX3, RAF and SIRT3). It is showed that Cd can initiate the NRs response, influence the homeostasis of the CPY450 enzyme system, trigger the mtUPR, impair mitochondrial function, and ultimately lead to Cd toxicity in the spleen of chickens.

Assuntos

RESUMO

The potent CRISPR-Cas9 technology can correct genes in human mutated cells to achieve the treatment of multiple diseases, but it lacks safe and effective delivery systems. Herein, we proposed an oral microto-nano genome-editing system aiming at the enteric excessive level of TNF-α for specific gene therapy of inflammatory bowel disease (IBD). This editing system facilitated the assembly of Cas9/sgRNA ribonucleoprotein (RNP) into nanoclusters (NCs) through the bridging of disulfide bonds. RNP-NCs were subsequently encapsulated within inflammatory cell-targeted lipopolysaccharide-deleted outer membrane vesicles (dOMVs) sourced from Escherichia coli Nissle 1917, which were further shielded by an outer layer of calcium alginate microspheres (CAMs). By leveraging the protection effect of CAMs, the oral administration system withstood gastric acid degradation upon entry into the stomach, achieving targeted delivery to the intestines with high efficiency. As the pH gradually rose, the microscale CAMs swelled and disintegrated, releasing nanoscale RNP-NCs encapsulated in dOMVs into the intestines. These RNP-NCs@dOMVs could traverse the mucosal barrier and target inflammatory macrophages where conditionally activated Cas9/sgRNA RNPs effectively perform genomic editing of TNF-α within the nucleus. Such oral microto-nano genome-editing systems represent a promising translational platform for the treatment of IBD.

Assuntos

RESUMO

Deep-sea mining (DSM) activities are expected to release potentially toxic metal mixtures through the generation of sediment plumes to the marine environment. This may disrupt the normal functioning of biological mechanisms, adversely affecting deep-sea invertebrate organisms. It is thus essential to understand the ecotoxicological effects from these toxic elements in deep-sea organisms and the omics approaches applied to ecotoxicology are seen as promising tools. Here, we provide an overview of the principal biological modifications identified in deep-sea invertebrates when exposed to metals and critically evaluate the current knowledge and discuss which potential biomarkers may be useful after metal exposure. Most of the 50 omics studies on deep-sea invertebrates revised are comparative transcriptomes (n = 41). Forty-three potential biomarker candidates are highlighted from immune system, 46 from cellular metabolism and 29 from oxidative stress. The processes mostly affected by metal toxicity in deep-sea invertebrates are related to innate immune defense; sulfur, chitin, and catabolic metabolism; antioxidation; and detoxification. We acknowledge the current limitations and future perspectives for their uses and emphasize the need to invest in further ecotoxicological studies using the omics approaches.

Assuntos

RESUMO

BACKGROUND: Doxorubicin and cisplatin are both first-line chemotherapeutics for osteosarcoma (OS) treatment. However, the efficacy of doxorubicin/cisplatin chemotherapy varies considerably. Thus, identifying an efficient diagnostic biomarker to distinguish patients with good and poor responses to doxorubicin/cisplatin chemotherapy is of paramount importance. METHODS: To predict the efficacy of doxorubicin/cisplatin chemotherapy, we analyzed the differentially expressed proteins in 37 resected OS samples, which were categorized into the primary group (PG), the recurrent group (RG) and the metastatic group (MG). The characteristics of the enriched differentially expressed proteins were assessed via GO and KEGG analyses. Protein‒protein interactions were identified to determine the relationships among the differentially expressed proteins. Receiver operating characteristic (ROC) curve analyses were performed to explore the clinical significance of the differentially expressed proteins. Parallel reaction monitoring (PRM) was used to validate the candidate proteins. Immunohistochemical (IHC) staining was performed to confirm the expression of cathepsin (CTSG) in patients with good and poor response to doxorubicin/cisplatin. RESULTS: A total of 9458 proteins were identified and quantified, among which 143 and 208 exhibited significant changes (|log2FC|>1, p < 0.05) in the RG and MG compared with the PG, respectively. GO and KEGG enrichment led to the identification of neutrophil extracellular traps (NETs). ROC curve analyses revealed 74 and 86 proteins with areas under the curve greater than 0.7 in the RG and MG, respectively. PRM validation revealed the statistical significance of CTSG, which is involved in NET formation, at the protein level in both the RG and MG. IHC staining of another cohort revealed that CTSG was prominently upregulated in the poor response group after treatment with doxorubicin/cisplatin. CONCLUSION: CTSG and its associated NETs are potential biomarkers with which the efficacy of doxorubicin/cisplatin chemotherapy could be predicted in OS patients.