RESUMEN

Background: Klebsiella pneumoniae is a major cause of hospital-acquired infections (HAIs), primarily spread through environmental contamination in hospitals. The effectiveness of current chemical disinfectants is waning due to emerging resistance, which poses environmental hazards and fosters new resistance in pathogens. Developing environmentally friendly and effective disinfectants against multidrug-resistant organisms is increasingly important. Methods: This study developed a bacteriophage cocktail targeting two common carbapenem-resistant Klebsiella pneumoniae (CRKP) strains, ST11 KL47 and ST11 KL64. The cocktail was used as an adjunctive disinfectant in a hospital's respiratory intensive care unit (RICU) via ultrasonic nebulization. Digital PCR was used to quantify CRKP levels post-intervention. The microbial community composition was analyzed via 16S rRNA sequencing to assess the intervention's impact on overall diversity. Results: The phage cocktail significantly reduced CRKP levels within the first 24 hours post-treatment. While a slight increase in pathogen levels was observed after 24 hours, they remained significantly lower than those treated with conventional disinfectants. 16S rRNA sequencing showed a decrease in the target pathogens' relative abundance, while overall species diversity remained stable, confirming that phages selectively target CRKP without disrupting ecological balance. Discussion: The findings highlight the efficacy and safety of phage-based biocleaners as a sustainable alternative to conventional disinfectants. Phages selectively reduce multidrug-resistant pathogens while preserving microbial diversity, making them a promising tool for infection control.

Asunto(s)

Bacteriófagos , Descontaminación , Unidades de Cuidados Intensivos , Klebsiella pneumoniae , ARN Ribosómico 16S , ARN Ribosómico 16S/genética , Klebsiella pneumoniae/virología , Klebsiella pneumoniae/genética , Descontaminación/métodos , Bacteriófagos/genética , Humanos , Reacción en Cadena de la Polimerasa/métodos , Infección Hospitalaria/prevención & control , Infección Hospitalaria/microbiología , Desinfectantes/farmacología , Infecciones por Klebsiella/prevención & control , Infecciones por Klebsiella/microbiología , Análisis de Secuencia de ADN

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Ultrasound, a high-frequency mechanical wave with excellent tissue penetration, has been widely applied in medical diagnostic imaging. Furthermore, it has been reported that ultrasound has broad prospects for extensive applications in the field of disease treatment in recent years due to its non-invasiveness and high efficiency. Ultrasound-responsive nanomaterials have the unique advantages of a small size and a high reactivity. Such materials have the capability for precision control of drug release under ultrasound stimulation, which provides a new approach to enhancing the efficiency of drug therapy. Therefore, these materials have attracted the attention of a wide range of scholars. Inflammation is a defensive response produced by organisms to deal with injuries. However, excessive inflammatory response may lead to various tissue damages in organisms and even endanger patients' lives. Many studies have demonstrated that limiting the inflammatory response using ultrasound-responsive nanomaterials is a viable way of treating diseases. Currently, there are still challenges in the application of ultrasound-responsive nanomaterials in anti-inflammatory therapy. The design and synthesis process of nanomaterials is complicated, and further verification of the biocompatibility and safety of these materials is needed. Therefore, in this review, we summarized and classified common ultrasound-responsive nanomaterials in the field of anti-inflammation and systematically introduced the properties of different nanomaterials. In addition, the anti-inflammatory applications of ultrasound-responsive nanomaterials in various diseases, such as bone diseases, skin and muscle diseases, autoimmune diseases, and respiratory diseases, are also described in detail. It is expected that this review will provide insights for further research and clinical applications in the realms of precision treatment, targeted drug delivery, and clinical trial validation of ultrasound-responsive nanomaterials used in anti-inflammatory therapies.

Asunto(s)

Antiinflamatorios , Inflamación , Nanoestructuras , Nanoestructuras/uso terapéutico , Humanos , Antiinflamatorios/uso terapéutico , Inflamación/diagnóstico por imagen , Sistemas de Liberación de Medicamentos , Ondas Ultrasónicas , Terapia por Ultrasonido/métodos , Animales

RESUMEN

Problem: Chest radiography is a crucial tool for diagnosing thoracic disorders, but interpretation errors and a lack of qualified practitioners can cause delays in treatment. Aim: This study aimed to develop a reliable multi-classification artificial intelligence (AI) tool to improve the accuracy and efficiency of chest radiograph diagnosis. Methods: We developed a convolutional neural network (CNN) capable of distinguishing among 26 thoracic diagnoses. The model was trained and externally validated using 795,055 chest radiographs from 13 datasets across 4 countries. Results: The CNN model achieved an average area under the curve (AUC) of 0.961 across all 26 diagnoses in the testing set. COVID-19 detection achieved perfect accuracy (AUC 1.000, [95% confidence interval {CI}, 1.000 to 1.000]), while effusion or pleural effusion detection showed the lowest accuracy (AUC 0.8453, [95% CI, 0.8417 to 0.8489]). In external validation, the model demonstrated strong reproducibility and generalizability within the local dataset, achieving an AUC of 0.9634 for lung opacity detection (95% CI, 0.9423 to 0.9702). The CNN outperformed both radiologists and nonradiological physicians, particularly in trans-device image recognition. Even for diseases not specifically trained on, such as aortic dissection, the AI model showed considerable scalability and enhanced diagnostic accuracy for physicians of varying experience levels (all P < 0.05). Additionally, our model exhibited no gender bias (P > 0.05). Conclusion: The developed AI algorithm, now available as professional web-based software, substantively improves chest radiograph interpretation. This research advances medical imaging and offers substantial diagnostic support in clinical settings.

RESUMEN

BACKGROUND: Dysfunction or deficiency of corneal epithelium results in vision impairment or blindness in severe cases. The rapid and effective regeneration of corneal epithelial cells relies on the limbal stem cells (LSCs). However, the molecular and functional responses of LSCs and their niche cells to injury remain elusive. METHODS: Single-cell RNA sequencing was performed on corneal tissues from normal mice and corneal epithelium defect models. Bioinformatics analysis was performed to confirm the distinct characteristics and cell fates of LSCs. Knockdown of Creb5 and OSM treatment experiment were performed to determine their roles of in corneal epithelial wound healing. RESULTS: Our data defined the molecular signatures of LSCs and reconstructed the pseudotime trajectory of corneal epithelial cells. Gene network analyses characterized transcriptional landmarks that potentially regulate LSC dynamics, and identified a transcription factor Creb5, that was expressed in LSCs and significantly upregulated after injury. Loss-of-function experiments revealed that silencing Creb5 delayed the corneal epithelial healing and LSC mobilization. Through cell-cell communication analysis, we identified 609 candidate regeneration-associated ligand-receptor interaction pairs between LSCs and distinct niche cells, and discovered a unique subset of Arg1+ macrophages infiltrated after injury, which were present as the source of Oncostatin M (OSM), an IL-6 family cytokine, that were demonstrated to effectively accelerate the corneal epithelial wound healing. CONCLUSIONS: This research provides a valuable single-cell resource and reference for the discovery of mechanisms and potential clinical interventions aimed at ocular surface reconstruction.

Asunto(s)

Plasticidad de la Célula , Células Madre Limbares , Limbo de la Córnea , Cicatrización de Heridas , Animales , Ratones , Epitelio Corneal/metabolismo , Epitelio Corneal/patología , Epitelio Corneal/lesiones , Células Madre Limbares/citología , Células Madre Limbares/metabolismo , Limbo de la Córnea/metabolismo , Limbo de la Córnea/citología , Limbo de la Córnea/patología , Ratones Endogámicos C57BL , Nicho de Células Madre , Cicatrización de Heridas/genética

RESUMEN

Mammalian lung is the important organ for ventilation and exchange of air and blood. Fresh air and venous blood are constantly delivered through the airway and vascular tree to the alveolus. Based on this, the airways and alveolis are persistently exposed to the external environment and are easily suffered from toxins, irritants and pathogens. For example, acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a common cause of respiratory failure in critical patients, whose typical pathological characters are diffuse epithelial and endothelial damage resulting in excessive accumulation of inflammatory fluid in the alveolar cavity. The supportive treatment is the main current treatment for ALI/ARDS with the lack of targeted effective treatment strategies. However, ALI/ARDS needs more targeted treatment measures. Therefore, it is extremely urgent to understand the cellular and molecular mechanisms that maintain alveolar epithelial barrier and airway integrity. Previous researches have shown that the lung epithelial cells with tissue stem cell function have the ability to repair and regenerate after injury. Also, it is able to regulate the phenotype and function of innate immune cells involving in regeneration of tissue repair. Meanwhile, we emphasize that interaction between the lung epithelial cells and innate immune cells is more supportive to repair and regenerate in the lung epithelium following acute lung injury. We reviewed the recent advances in injury and repair of lung epithelial stem cells and innate immune cells in ALI/ARDS, concentrating on alveolar type 2 cells and alveolar macrophages and their contribution to post-injury repair behavior of ALI/ARDS through the latest potential molecular communication mechanisms. This will help to develop new research strategies and therapeutic targets for ALI/ARDS.

Asunto(s)

Lesión Pulmonar Aguda , Inmunidad Innata , Pulmón , Regeneración , Síndrome de Dificultad Respiratoria , Células Madre , Humanos , Síndrome de Dificultad Respiratoria/inmunología , Síndrome de Dificultad Respiratoria/terapia , Lesión Pulmonar Aguda/inmunología , Lesión Pulmonar Aguda/patología , Lesión Pulmonar Aguda/terapia , Pulmón/inmunología , Pulmón/patología , Animales , Células Epiteliales

RESUMEN

The removal of dissolved organic matter (DOM) from seawater before the reverse osmosis (RO) processes is crucial for alleviating organic fouling of RO membranes. However, research is still insufficiently developed in the comparison of the effectiveness of integrating coagulation with ultrafiltration (UF) or sand filtration (SF) in the pretreatment stage of seawater reverse osmosis (SWRO) for the removal of DOM. In this study, we investigated the effect of pretreatment technologies on RO fouling caused by DOM in seawater, including the integration of coagulation and sand filtration (C-S pretreatment) and the integration of coagulation and ultrafiltration (C-U pretreatment). Both integrated pretreatments achieved comparable DOM removal rates (70.2% for C-U and 69.6% for C-S), and C-S exhibited enhanced removal of UV-absorbing compounds. Although C-U was more proficient in reducing the silt density index (below 2) compared to C-S (above 3) and improved the elimination of humic acid-like organics, it left a higher proportion of tyrosine-protein-like organics, soluble microbial by-product-like organics, and finer organics in the effluent, leading to the formation of a dense cake layer on RO membrane and a higher flux decline. Therefore, suitable technologies should be selected according to specific water conditions to efficiently mitigate RO membrane fouling.

RESUMEN

The separation of a toluene/methanol/water ternary mixture is a difficult task due to the toluene/water and toluene/methanol azeotropes. In this article, low-energy pervaporation is proposed for the separation of the ternary azeotrope toluene-methanol-water. This work investigates the effects of feed temperature, feed flow rate, and vacuum on pervaporation and compares the energy consumption of pervaporation with that of distillation. The results showed that at the optimized flow rate of 50 L/h and a permeate side vacuum of 60 kPa at 50 °C, the water and methanol content in the permeate was about 63.2 wt.% and 36.8 wt.%, respectively, the water/ methanol separation factor was 24.04, the permeate flux was 510.7 g/m2·h, the water content in the feed out was reduced from 2.5 wt.% to less than 0.66 wt.%, and the dehydration of toluene methanol could be realized. Without taking into account the energy consumption of pumps and other power equipment, pervaporation requires an energy consumption of 43.53 kW·h to treat 1 ton of raw material, while the energy consumption of distillation to treat 1 ton of raw material is about 261.5 kW·h. Compared to the existing distillation process, the pervaporation process consumes much less energy (about one-sixth of the energy consumption of distillation). There is almost no effect on the surface morphology and chemical composition of the membrane before and after use. The method provides an effective reference for the dehydration of organic solvents from ternary mixtures containing toluene/methanol/water.

RESUMEN

Microbiological Rapid On-Site Evaluation (M-ROSE) is based on smear staining and microscopic observation, providing critical references for the diagnosis and treatment of pulmonary infectious disease. Automatic identification of pathogens is the key to improving the quality and speed of M-ROSE. Recent advancements in deep learning have yielded numerous identification algorithms and datasets. However, most studies focus on artificially cultured bacteria and lack clinical data and algorithms. Therefore, we collected Gram-stained bacteria images from lower respiratory tract specimens of patients with lung infections in Chinese PLA General Hospital obtained by M-ROSE from 2018 to 2022 and desensitized images to produce 1705 images (4,912 × 3,684 pixels). A total of 4,833 cocci and 6,991 bacilli were manually labelled and differentiated into negative and positive. In addition, we applied the detection and segmentation networks for benchmark testing. Data and benchmark algorithms we provided that may benefit the study of automated bacterial identification in clinical specimens.

Asunto(s)

Aprendizaje Profundo , Humanos , Bacterias/aislamiento & purificación , Bacterias/clasificación , Infecciones del Sistema Respiratorio/microbiología , Infecciones del Sistema Respiratorio/diagnóstico , Algoritmos

RESUMEN

BACKGROUND: Sleep deprivation (SD) is a common public health problem that contributes to various physiological disorders and increases the risk of ocular diseases. However, whether sleep loss can damage corneal endothelial function remains unclear. This study aimed to determine the effect and possible mechanism of SD on the corneal endothelium. METHODS: Male C57BL/6J mice were subjected to establish SD models. After 10 days, quantitative RT-PCR (qRT-PCR) and western blot or immunostaining for the expression levels of zonula occludens-1 (ZO-1), ATPase Na+/K + transporting subunit alpha 1 (Atp1a1), and core clock genes in the corneal endothelium were evaluated. Reactive oxygen species staining and mitochondrial abundance characterized the mitochondrial function. The regulatory role of Bmal1 was confirmed by specifically knocking down or overexpressing basic helix-loop-helix ARNT like 1 protein (Bmal1) in vivo. In vitro, a mitochondrial stress test was conducted on cultured human corneal endothelial cells upon Bmal1 knockdown. RESULTS: SD damaged the barrier and pump functions of mouse corneal endothelium, accompanied by mitochondrial dysfunction. Interestingly, SD dramatically downregulated the core clock gene Bmal1 expression level. Bmal1 knockdown disrupted corneal endothelial function, while overexpression of Bmal1 ameliorated the dysfunction induced by SD. Mitochondrial bioenergetic deficiency mediated by Bmal1 was an underlying mechanism for SD induced corneal endothelial dysfunction. CONCLUSION: The downregulation of Bmal1 expression caused by SD led to corneal endothelial dysfunction via impairing mitochondrial bioenergetics. Our findings offered insight into how SD impairs the physiological function of the corneal endothelium and expanded the understanding of sleep loss leading to ocular diseases.

Asunto(s)

Factores de Transcripción ARNTL , Endotelio Corneal , Privación de Sueño , Animales , Masculino , Ratones , Factores de Transcripción ARNTL/genética , Factores de Transcripción ARNTL/metabolismo , Western Blotting , Células Cultivadas , Modelos Animales de Enfermedad , Regulación hacia Abajo , Endotelio Corneal/metabolismo , Endotelio Corneal/patología , Regulación de la Expresión Génica , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Privación de Sueño/complicaciones , Privación de Sueño/metabolismo , Privación de Sueño/fisiopatología

RESUMEN

BACKGROUND: Many older adult patients receive low-dose teicoplanin with varied regimens, leading to a lack of clarity on its optimal regimens and toxicity profiles in China. This study aimed to clarify these aspects by analyzing teicoplanin treatment concentrations and toxicities. METHODS: We included older adult patients administered teicoplanin at four tertiary hospitals in Beijing from June 2021 to July 2023, targeting a trough concentration (Cmin) ≥ 10 mg/L. Teicoplanin concentrations and toxicities were monitored dynamically. RESULTS: From 204 patients, we obtained 632 teicoplanin concentrations. Most patients (83.3%) received low-dose regimens. Suboptimal concentrations were found in 66.4% of patients within 7 days of treatment and 17.0% after 15 days. Cmin gradually increased with treatment duration and was influenced initially by creatinine and by both body weight and creatinine from days 8 to 14. The target concentration was achieved in 53.1%, 33.9%, 15.6%, and 5.5% of patients at 3, ≤ 7, 8-14, and ≥ 15 days after withdrawal, respectively. Slow elimination was associated with average Cmin and eGFR. Nephrotoxicity, hepatotoxicity, and thrombocytopenia occurred in 12.5%, 4.1%, and 31.5% of patients, respectively, without significant differences between concentrations. CONCLUSIONS: Most older adult patients were underdosed, indicating a need for dose adjustment. Given the varied risk factors for suboptimal concentrations in different treatment stages, a one-size-fits-all regimen was ineffective. We recommend an initial dose of 400 mg at 12-h intervals for the first three days, with subsequent doses from days 4 to 14 adjusted based on creatinine and body weight; after day 14, a maintenance dose of 200 mg daily is advised. TRIAL REGISTRATION: ChiCTR2100046811; 28/05/2021.

Asunto(s)

Antibacterianos , Relación Dosis-Respuesta a Droga , Teicoplanina , Humanos , Masculino , Anciano , Femenino , Estudios Prospectivos , Teicoplanina/administración & dosificación , Teicoplanina/efectos adversos , China/epidemiología , Antibacterianos/administración & dosificación , Antibacterianos/efectos adversos , Anciano de 80 o más Años , Persona de Mediana Edad

RESUMEN

BACKGROUND: The concentrations of linezolid, its optimal regimen and the associated side effects in elderly patients remain unclear. METHODS: In this multicentre, prospective study, elderly patients receiving linezolid at four tertiary hospitals in Beijing between May 2021 and December 2022 were included. Linezolid concentrations and haematological toxicity were monitored dynamically. Risk factors for linezolid overexposure and moderate-to-severe linezolid-induced thrombocytopenia (M/S LIT) were analysed, and a predictive model of M/S LIT was developed. RESULTS: A total of 860 linezolid concentrations were measured in 313 patients. The median trough concentrations of linezolid were 24.4 (15.3, 35.8) mg/L at 36-72 h and 26.1 (17.0, 38.1) mg/L at 5-10 days (P = 0.132). Severe linezolid exposure was independently associated with age, estimated glomerular filtration rate (eGFR) and the worst SOFA score (SOFA1), and we further recommended dose regimens for elderly patients based on these findings. The incidences of linezolid-induced thrombocytopenia(LIT) and M/S LIT were 73.5% and 47.6%, respectively. M/S LIT was independently correlated with treatment duration, average trough concentration (TDMa), baseline platelet count, eGFR and baseline SOFA score (SOFA0). The developed nomogram predicted M/S LIT with an area under the curve of 0.767 (95% CI 0.715-0.820), a sensitivity of 71.1% and a specificity of 73.2%. CONCLUSIONS: Linezolid trough concentrations increased dramatically in the elderly, by about 10 mg/L in patients aged 65-80 years, followed by a further increase of 10 mg/L for every 10 years of age. Therapeutic drug monitoring is recommended in elderly patients receiving linezolid. The developed nomogram may predict M/S LIT and guide dosage adjustments of linezolid. Clinical trial registration number: ChiCTR2100045707.

Asunto(s)

Antibacterianos , Monitoreo de Drogas , Linezolid , Nomogramas , Trombocitopenia , Humanos , Linezolid/efectos adversos , Linezolid/farmacocinética , Linezolid/administración & dosificación , Anciano , Masculino , Femenino , Estudios Prospectivos , Antibacterianos/efectos adversos , Antibacterianos/farmacocinética , Antibacterianos/administración & dosificación , Trombocitopenia/inducido químicamente , Anciano de 80 o más Años , Factores de Riesgo , Persona de Mediana Edad

RESUMEN

Sepsis is a dysregulated host response to severe infections, and immune dysfunction plays a crucial role in its pathogenesis. Elderly patients, a special population influenced by immunosenescence, are more susceptible to sepsis and have a worse prognosis. However, the immunopathogenic mechanisms underlying sepsis in elderly patients remain unclear. Here, we performed single-cell RNA sequencing of peripheral blood samples from young and old subjects and patients with sepsis. By exploring the transcriptional profiles of immune cells, we analyzed immune cell compositions, phenotype shifts, expression heterogeneities, and intercellular communication. In elderly patients with sepsis, innate immune cells (e.g., monocytes and DCs) exhibit decreased antigen presentation, presenting an overactive inflammatory and senescent phenotype. However, the immunophenotype of T cells shifted to characterize effector, memory, and exhaustion. Moreover, we identified strong interferon-γ responses of T cells in both aging and sepsis groups and a deranged inflammaging status in elderly sepsis patients. Tregs in elderly patients with sepsis showed increased abundance and enhanced immunosuppressive effects. In addition, metabolism-associated pathways were upregulated in T cells in elderly patients with sepsis, and the lysine metabolism pathway was enriched in Tregs. Cell-cell interaction analysis showed that the expression profile of ligand-receptor pairs was probably associated with aggravated immune dysfunction in elderly patients with sepsis. A novel HLA-KIR interaction was observed between Tregs and CD8 + T cells. These findings illustrate the immunological hallmarks of sepsis in elderly patients, and highlight that immunosuppressive and metabolic regulatory pathways may undergo important alterations in elderly patients with sepsis.

RESUMEN

Two-stage reverse osmosis (RO) processes with intermediate concentrate demineralization (ICD) provide an efficient strategy to treat brines with high CaSO4 contents and reduce concentrate discharge. In this paper, an SRO concentrate is treated using ICD to remove CaSO4 and then mixed with a PRO concentrate for further desalination in SRO, thereby reducing the discharge of the concentrate. We investigate the selection and degradation of scale inhibitors, as well as seeded precipitation in the two-stage RO process with ICD, to achieve a high water recovery rate. A scale inhibitor is added to restrain CaSO4 crystallization on the membrane surface, and the optimized scale inhibitor, RO-400, is found to inhibit calcium sulfate scaling effectively across a wide range of the saturation index of gypsum (SIg) from 2.3 to 6. Under the optimized parameters of 40 W UV light and 70 mg/L H2O2, UV/H2O2 can degrade RO-400 completely in 15 min to destroy the scale inhibitor in the SRO concentrate. After scale inhibitor degradation, the SRO concentrate is desaturated by seeded precipitation, and the reaction degree of CaSO4 reaches 97.12%, leading to a concentrate with a low SIg (1.07) for cyclic desalination. Three UVD-GSP cycle tests show that the reused gypsum seeds can also ensure the effect of the CaSO4 precipitation process. This paper provides a combined UVD-GSP strategy in two-stage RO processes to improve the water recovery rate for CaSO4-contained concentrate.

RESUMEN

BACKGROUND: Although studies have demonstrated the value of the triglyceride-glucose (TyG) index for cardiovascular disease (CVD) and cardiovascular mortality, however, few studies have shown that the TyG index is associated with all-cause or CVD mortality in young patients with diabetes. This study aimed to investigate the association between the TyG index and all-cause and CVD mortality in young patients with diabetes in the United States. METHODS: Our study recruited 2440 young patients with diabetes from the National Health and Nutrition Examination Survey (NHANES) 2001-2018. Mortality outcomes were determined by linking to National Death Index (NDI) records up to December 31, 2019. Cox regression modeling was used to investigate the association between TyG index and mortality in young patients with diabetes. The nonlinear association between TyG index and mortality was analyzed using restricted cubic splines (RCS), and a two-segment Cox proportional risk model was constructed for both sides of the inflection point. RESULTS: During a median follow-up period of 8.2 years, 332 deaths from all causes and 82 deaths from cardiovascular disease were observed. Based on the RCS, the TyG index was found to have a U-shaped association with all-cause and CVD mortality in young patients with diabetes, with threshold values of 9.18 and 9.16, respectively. When the TyG index was below the threshold value (TyG index < 9.18 in all-cause mortality and < 9.16 in CVD mortality), its association with all-cause and CVD mortality was not significant. When the TyG index was above the threshold (TyG index ≥ 9.18 in all-cause mortality and ≥ 9.16 in CVD mortality), it showed a significant positive association with all-cause mortality and CVD mortality (HR 1.77, 95% CI 1.05-2.96 for all-cause mortality and HR 2.38, 95% CI 1.05-5.38 for CVD mortality). CONCLUSION: Our results suggest a U-shaped association between TyG index and all-cause and CVD mortality among young patients with diabetes in the United States, with threshold values of 9.18 and 9.16 for CVD and all-cause mortality, respectively.

Asunto(s)

Biomarcadores , Glucemia , Enfermedades Cardiovasculares , Causas de Muerte , Diabetes Mellitus , Encuestas Nutricionales , Triglicéridos , Humanos , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/diagnóstico , Masculino , Femenino , Glucemia/metabolismo , Triglicéridos/sangre , Medición de Riesgo , Estados Unidos/epidemiología , Diabetes Mellitus/sangre , Diabetes Mellitus/mortalidad , Diabetes Mellitus/diagnóstico , Adulto , Biomarcadores/sangre , Factores de Tiempo , Pronóstico , Adulto Joven , Factores de Edad , Valor Predictivo de las Pruebas , Factores de Riesgo

Asunto(s)

Glucemia , Retinopatía Diabética , Humanos , Retinopatía Diabética/terapia , Retinopatía Diabética/diagnóstico , Glucemia/metabolismo , Glucemia/análisis , Medicina de Precisión/métodos , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/sangre , Control Glucémico , Hemoglobina Glucada/análisis , Hemoglobina Glucada/metabolismo

RESUMEN

Purpose: The lacrimal gland (LG) is the main organ responsible for tear secretion and an important pathogenic site for dry eye disease (DED). This study aimed to comprehensively characterize LG cellular heterogeneity under normal and DED conditions using single-nucleus RNA sequencing (snRNA-seq). Methods: Single LG nuclei isolated from mice with or without DED induced by scopolamine (SCOP)/desiccating stress (DS) were subjected to snRNA-seq using the 10x Genomics platform. These cells were clustered and annotated using the t-distributed stochastic neighbor embedding (t-SNE) method and unbiased computational informatic analysis. Cluster identification and functional analysis were performed based on marker gene expression and bioinformatic data mining. Results: The snRNA-seq analysis of 30,351 nuclei identified eight major cell types, with acinar cells (∼72.6%) being the most abundant cell type in the LG. Subclustering analysis revealed that the LG mainly contained two acinar cell subtypes, two ductal cell subclusters, three myoepithelial cell (MECs) subtypes, and four immunocyte subclusters. In the SCOP-induced DED model, three major LG parenchymal cell types were significantly altered, characterized by a reduced proportion of acinar cells with a lowered secretion potential and an augmented proportion of ductal cells and MECs. LG immunocytes in DED scenarios showed an intensified inflammatory response and dysregulated intercellular communication with three major LG parenchymal cells. Conclusions: Overall, this study offers a systemic single-nucleus transcriptomic profile of LGs in both normal and DED conditions and an atlas of the complicated interactions of immunocytes with major LG parenchymal cells. The findings also facilitate understanding the pathogenesis of DED.

Asunto(s)

Modelos Animales de Enfermedad , Síndromes de Ojo Seco , Aparato Lagrimal , Escopolamina , Animales , Síndromes de Ojo Seco/inducido químicamente , Síndromes de Ojo Seco/metabolismo , Síndromes de Ojo Seco/genética , Ratones , Escopolamina/toxicidad , Aparato Lagrimal/patología , Aparato Lagrimal/metabolismo , Ratones Endogámicos C57BL , Femenino , Núcleo Celular/metabolismo , Lágrimas/metabolismo , Células Epiteliales/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/patología

RESUMEN

Alveoli are complex microenvironments composed of various cell types, including epithelial, fibroblast, endothelial, and immune cells, which work together to maintain a delicate balance in the lung environment, ensuring proper growth, development, and an effective response to lung injuries. However, prolonged inflammation or aging can disrupt normal interactions among these cells, leading to impaired repair processes and a substantial decline in lung function. Therefore, it is essential to understand the key mechanisms underlying the interactions among the major cell types within the alveolar microenvironment. We explored the key mechanisms underlying the interactions among the major cell types within the alveolar microenvironment. These interactions occur through the secretion of signaling factors and play crucial roles in the response to injury, repair mechanisms, and the development of fibrosis in the lungs. Specifically, we focused on the regulation of alveolar type 2 cells by fibroblasts, endothelial cells, and macrophages. In addition, we explored the diverse phenotypes of fibroblasts at different stages of life and in response to lung injury, highlighting their impact on matrix production and immune functions. Furthermore, we summarize the various phenotypes of macrophages in lung injury and fibrosis as well as their intricate interplay with other cell types. This interplay can either contribute to the restoration of immune homeostasis in the alveoli or impede the repair process. Through a comprehensive exploration of these cell interactions, we aim to reveal new insights into the molecular mechanisms that drive lung injury toward fibrosis and identify potential targets for therapeutic intervention.

Asunto(s)

Comunicación Celular , Microambiente Celular , Fibroblastos , Lesión Pulmonar , Alveolos Pulmonares , Humanos , Animales , Lesión Pulmonar/patología , Lesión Pulmonar/metabolismo , Alveolos Pulmonares/patología , Alveolos Pulmonares/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patología , Fibrosis Pulmonar/patología , Fibrosis Pulmonar/metabolismo , Células Epiteliales Alveolares/metabolismo , Células Epiteliales Alveolares/patología , Células Endoteliales/metabolismo , Células Endoteliales/patología , Fibrosis , Macrófagos/metabolismo , Macrófagos/patología