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Overcoming immune-mediated resistance to PD-1 blockade remains a major clinical challenge. Enhanced efficacy has been demonstrated in melanoma patients with combined nivolumab (anti-PD-1) and relatlimab (anti-LAG-3) treatment, the first in its class to be FDA approved. However, how these two inhibitory receptors synergize to hinder anti-tumor immunity remains unknown. Here, we show that CD8+ T cells deficient in both PD-1 and LAG-3, in contrast to CD8+ T cells lacking either receptor, mediate enhanced tumor clearance and long-term survival in mouse models of melanoma. PD-1- and LAG-3-deficient CD8+ T cells were transcriptionally distinct, with broad TCR clonality and enrichment of effector-like and interferon-responsive genes, resulting in enhanced IFN-γ release indicative of functionality. LAG-3 and PD-1 combined to drive T cell exhaustion, playing a dominant role in modulating TOX expression. Mechanistically, autocrine, cell-intrinsic IFN-γ signaling was required for PD-1- and LAG-3-deficient CD8+ T cells to enhance anti-tumor immunity, providing insight into how combinatorial targeting of LAG-3 and PD-1 enhances efficacy.
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Antígenos CD , Linfocitos T CD8-positivos , Interferón gamma , Proteína del Gen 3 de Activación de Linfocitos , Ratones Endogámicos C57BL , Receptor de Muerte Celular Programada 1 , Receptor de Muerte Celular Programada 1/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Animales , Interferón gamma/metabolismo , Ratones , Antígenos CD/metabolismo , Comunicación Autocrina , Humanos , Melanoma/inmunología , Melanoma/tratamiento farmacológico , Femenino , Línea Celular Tumoral , Melanoma Experimental/inmunología , Agotamiento de Células TRESUMEN
Exhausted CD8 T (Tex) cells in chronic viral infection and cancer have sustained co-expression of inhibitory receptors (IRs). Tex cells can be reinvigorated by blocking IRs, such as PD-1, but synergistic reinvigoration and enhanced disease control can be achieved by co-targeting multiple IRs including PD-1 and LAG-3. To dissect the molecular changes intrinsic when these IR pathways are disrupted, we investigated the impact of loss of PD-1 and/or LAG-3 on Tex cells during chronic infection. These analyses revealed distinct roles of PD-1 and LAG-3 in regulating Tex cell proliferation and effector functions, respectively. Moreover, these studies identified an essential role for LAG-3 in sustaining TOX and Tex cell durability as well as a LAG-3-dependent circuit that generated a CD94/NKG2+ subset of Tex cells with enhanced cytotoxicity mediated by recognition of the stress ligand Qa-1b, with similar observations in humans. These analyses disentangle the non-redundant mechanisms of PD-1 and LAG-3 and their synergy in regulating Tex cells.
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Antígenos CD , Linfocitos T CD8-positivos , Antígenos de Histocompatibilidad Clase I , Proteína del Gen 3 de Activación de Linfocitos , Subfamília D de Receptores Similares a Lectina de las Células NK , Receptor de Muerte Celular Programada 1 , Animales , Antígenos CD/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Ratones , Receptor de Muerte Celular Programada 1/metabolismo , Subfamília D de Receptores Similares a Lectina de las Células NK/metabolismo , Antígenos de Histocompatibilidad Clase I/metabolismo , Humanos , Subfamília C de Receptores Similares a Lectina de Células NK/metabolismo , Ratones Endogámicos C57BL , Proteínas del Grupo de Alta Movilidad/metabolismo , Proteínas del Grupo de Alta Movilidad/genética , Citotoxicidad Inmunológica , Proliferación Celular , Células Asesinas Naturales/metabolismo , Células Asesinas Naturales/inmunologíaRESUMEN
Virtual urban green environment images and audio stimuli had been proven to have restorative effects on subjects' physical and mental health. In this area, researchers predominantly focused on visual, auditory and olfactory aspects, while tactile and gustatory senses have been minimally explored. However, the optimal combination of sensory stimuli for promoting physical and mental recovery remains unclear. Therefore, a simulated sensory stimulation approach involving 240 participants was employed, with 30 individuals included in each of the eight experimental groups: the visual-auditory (VA), visual-auditory-olfactory (VAO), visual-auditory-tactile (VAT), visual-auditory-gustatory(VAG), visual-auditory-olfactory-tactile (VAOT), visual-auditory-olfactory-gustatory (VAOG), visual-auditory-tactile-gustatory (VATG), and visual-auditory-olfactory-tactile-gustatory (VAOTG) groups. This study aimed to explore the differences in participants' physiological and psychological health recovery after exposure to different combinations of simulated sensory stimuli in virtual UGSs. The results indicated that the following: (1) In terms of physiological recovery, the blood pressure of the 8 experimental groups decreased significantly after the experiment, indicating that the virtual urban green space environment has a certain recovery effect on physiological state. The combination of VAOTG stimuli in the multisensory group resulted in the best blood pressure recovery (p < 0.05). Tactile is an important sense to enhance the physiological recovery effect. Olfactory-tactile or tactile-gustatory stimuli interactions significantly enhance physiological recovery, emphasizing the importance of tactile stimulation in improving physiological recovery. (2) In terms of psychological recovery, the common trigger of olfactory-gustatory is the most key element to enhance psychological recovery through multi-sensory stimulation of virtual urban green space environment. VAOG stimulation had the best effect on psychological recovery (p < 0.05), followed by VAOTG stimulation (p < 0.05). Gustatory is an important sense to enhance the psychological recovery effect, and both the tactile-gustatory interaction and the olfactory-gustatory interaction significantly enhance the recovery effect. At the same time, the psychological recovery effect obtained by four or more sensory combinations was higher than that obtained by two or three sensory stimulation groups. This study confirms more possibilities for ways to restore physical and mental health through virtual natural environments. It expands the research on the benefits of virtual nature experience and provides theoretical support for the application of this method.
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Accumulating evidence highlights p38 as a crucial factor highly activated during the process of acute kidney injury (AKI), but the application of p38 inhibitor in AKI is quite limited due to the low efficiency and poor kidney-targeting ability. Herein, a novel self-assembling peptide nanoparticle with specific p38-inhibiting activity is constructed, which linked mitogen-activated protein kinase kinase 3b (MKK3b), the functional domain of p38, with the cell-penetrating TAT sequence, ultimately self-assembling into TAT-MKK3b nanoparticles (TMNPs) through tyrosinase oxidation. Subsequent in vitro and in vivo studies demonstrated that TMNPs preferably accumulated in the renal tubular epithelial cells (RTECs) through forming protein coronas by binding to albumin, and strongly improved the reduced renal function of ischemia-reperfusion injury (IRI)-induced AKI and its transition to chronic kidney disease (CKD). Mechanically, TMNPs inhibited ferroptosis via its solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) axis-inducing capacity and synergistic potent antioxidant property in AKI. The findings indicated that the multifunctional TMNPs exhibited renal targeting, ROS-scavenging, and ferroptosis-mitigating capabilities, which may serve as a promising therapeutic agent for the treatment of AKI and its progression to CKD.
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BACKGROUND: We aimed to compare the cardiovascular events and mortality in patients who underwent either physician-oriented or patient-oriented kidney replacement therapy (KRT) conversion due to discontinuation of peritoneal dialysis (PD). METHODS: Patients with end-stage kidney disease who were receiving PD and required a switch to an alternative KRT were included. They were divided into physician-oriented group or patient-oriented group based on the decision-making process. Logistic regression analysis was used to explore the influencing factors related to KRT conversion in PD patients. The association of physician-oriented or patient-oriented KRT conversion with outcomes after the conversion was assessed by using Cox proportional hazards models. RESULTS: A total of 257 PD patients were included in the study. The median age at catheterization was 35 years. 69.6% of the participants were male. The median duration of PD was 20 months. 162 participants had patient-oriented KRT conversion, while 95 had physician-oriented KRT conversion. Younger patients, those with higher education levels, higher income, and no diabetes were more likely to have patient-oriented KRT conversion. Over a median follow-up of 39 months, 40 patients experienced cardiovascular events and 16 patients died. Physician-oriented KRT conversion increased nearly 3.8-fold and 4.0-fold risk of cardiovascular events and death, respectively. After adjusting for confounders, physician-oriented KRT conversion remained about a 3-fold risk of cardiovascular events. CONCLUSION: Compared to patient-oriented KRT conversion, PD patients who underwent physician-oriented conversion had higher risks of cardiovascular events and all-cause mortality. Factors included age at catheterization, education level, annual household income, and history of diabetes mellitus.
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Enfermedades Cardiovasculares , Fallo Renal Crónico , Diálisis Peritoneal , Humanos , Masculino , Adulto , Femenino , Terapia de Reemplazo Renal/efectos adversos , Diálisis Peritoneal/efectos adversos , Factores de Riesgo , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/terapia , Enfermedades Cardiovasculares/complicaciones , Diálisis Renal/efectos adversosRESUMEN
Introduction: The triglyceride glucose (TyG) index is a reliable alternative biomarker of insulin resistance, but the association between the TyG index and acute kidney injury (AKI) in critically ill patients remains unclear. Methods: The data for the study were extracted from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Cox regression and restricted cubic spline (RCS) analysis were performed to analyze the association between the TyG index and all-cause mortality. Besides, Cox regression was carried out in subgroups of age, gender, BMI, diabetes history, and dialysis status. Results: A total of 7,508 critically ill participants with AKI from the MIMIC-IV database were included in this study, with 3,688 (49.12%) participants failed to survive. In Cox regression, after confounder adjustment, patients with a higher TyG index had a higher risk of all-cause mortality (HR = 1.845, 95% CI = 1.49-2.285, p < 0.001). In RCS, after confounder adjustment, the risk of death was positively correlated with the increased value of the TyG index when TyG index surpassed 10.014. This relationship was validated in age, gender, BMI, diabetes subgroups but not in the dialysis subgroup. Interestingly, RCS analysis demonstrated that, in patients undertaking dialysis, there is a "U"-shaped curve for the value of TyG index and risk of all-cause mortality. When TyG index is less than 10.460, the risk of all-cause mortality would decrease with the increased value of TyG index, while when TyG index is higher than 11.180, the risk of all-cause mortality would increase firmly with the increased value of TyG index. Conclusion: Overall, a higher TyG index is associated with a higher risk of all-cause mortality in critically ill AKI. Interestingly, the relationship in the dialysis subgroup follows a "U"-shaped curve, indicating the importance of proper clinical blood glucose and lipid management in this particular population.
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Background: Sarcoma is a rare and aggressive malignancy with poor prognosis, in which oncogene activation and tumor suppressor inactivation are involved. Accumulated studies suggested basic leucine zipper transcription factor ATF-like 2 (BATF2) as a candidate tumor suppressor, but its specific role and mechanism in sarcoma remain unclear. Methods: The expression levels of BATF2 and miR-939-3p were evaluated by using human sarcoma samples, cell lines and xenograft mouse models. Bioinformatics analysis, qPCR, Western blot, cell proliferation assay, overexpression plasmid construction, point mutation and dual luciferase reporter assay were utilized to investigate the role and mechanism of miR-939-3p in sarcoma. Results: In this study, we demonstrated that the expression of BATF2 was downregulated in human sarcoma tissues and cell lines. The downregulation of BATF2 was negatively associated with the prognosis of sarcoma patients. Subsequent bioinformatic prediction and experimental validations showed that BATF2 expression was reduced by microRNA (miR)-939-3p mimic and increased by miR-939-3p inhibitor. Additionally, miR-939-3p was upregulated in sarcoma tissues and cells, correlating with a poor prognosis of sarcoma patients. Moreover, miR-939-3p overexpression suppressed sarcoma cell proliferation, which was significantly attenuated by the restoration of BATF2, while siRNA-mediated knockdown of BATF2 aggravated the miR-939-3p-induced promotion of sarcoma cell proliferation. Further computational algorithms and dual-luciferase reporter assays demonstrated that miR-939-3p repressed BATF2 expression via directly binding to its 3' untranslated region (3' UTR). Conclusion: Collectively, these findings identified miR-939-3p as a novel regulator of BATF2, as well as a prognostic biomarker in sarcoma, and revealed that suppressing miR-939-3p or inducing BATF2 expression may serve as a promising therapeutic strategy against sarcoma.
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Treatment effectiveness and biosafety are critical for disease therapy. Bio-membrane modification facilitates the homologous targeting of drugs in vivo by exploiting unique antibodies or antigens, thereby enhancing therapeutic efficacy while ensuring biosafety. To further enhance the precision of disease treatment, future research should shift focus from targeted cellular delivery to targeted subcellular delivery. As the cellular powerhouses, mitochondria play an indispensable role in cell growth and regulation and are closely involved in many diseases (e.g., cancer, cardiovascular, and neurodegenerative diseases). The double-layer membrane wrapped on the surface of mitochondria not only maintains the stability of their internal environment but also plays a crucial role in fundamental biological processes, such as energy generation, metabolite transport, and information communication. A growing body of evidence suggests that various diseases are tightly related to mitochondrial imbalance. Moreover, mitochondria-targeted strategies hold great potential to decrease therapeutic threshold dosage, minimize side effects, and promote the development of precision medicine. Herein, we introduce the structure and function of mitochondrial membranes, summarize and discuss the important role of mitochondrial membrane-targeting materials in disease diagnosis/treatment, and expound the advantages of mitochondrial membrane-assisted drug delivery for disease diagnosis, treatment, and biosafety. This review helps readers understand mitochondria-targeted therapies and promotes the application of mitochondrial membranes in drug delivery. STATEMENT OF SIGNIFICANCE: Bio-membrane modification facilitates the homologous targeting of drugs in vivo by exploiting unique antibodies or antigens, thereby enhancing therapeutic efficacy while ensuring biosafety. Compared to cell-targeted treatment, targeting of mitochondria for drug delivery offers higher efficiency and improved biosafety and will promote the development of precision medicine. As a natural material, the mitochondrial membrane exhibits excellent biocompatibility and can serve as a carrier for mitochondria-targeted delivery. This review provides an overview of the structure and function of mitochondrial membranes and explores the potential benefits of utilizing mitochondrial membrane-assisted drug delivery for disease treatment and biosafety. The aim of this review is to enhance readers' comprehension of mitochondrial targeted therapy and to advance the utilization of mitochondrial membrane in drug delivery.
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Sistemas de Liberación de Medicamentos , Neoplasias , Humanos , Membranas Mitocondriales/metabolismo , Mitocondrias/metabolismo , Neoplasias/metabolismoRESUMEN
Nitrogen has a critical influence on the yield and quality of proso millet. However, the exact impact of nitrogen on the cooking quality of proso millet is not clear. In this study, the cooking quality and starch properties of two proso millet varieties (waxy-Shaanxi millet [wSM] variety and non-waxy-Shaanxi millet [nSM] variety) were compared and analyzed under nitrogen fertilizer treatment (N150, 150 kg/hm2) and a control group without nitrogen application (N0, 0 kg/hm2). Compared with the N0 group, the N150 treatment significantly increased protein content, amylose levels, and total yield. Employing rapid visco analyser and differential scanning calorimetry analyses, we observed that under the N150 treatment, the peak viscosity and breakdown viscosity of proso millet powder were diminished, while the setback viscosity and enthalpy values (ΔH) increased. In addition, nitrogen treatment increased the solids content in the obtained rice soup and significantly hardened the texture of the rice. At the same time, we noticed that the absorption capacity of starch in water and oil was enhanced. These results showed that nitrogen fertilizer had significant effects on the cooking quality and starch properties of proso millet.
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Rewiring exhausted CD8+ T (Tex) cells toward functional states remains a therapeutic challenge. Tex cells are epigenetically programmed by the transcription factor Tox. However, epigenetic remodeling occurs as Tex cells transition from progenitor (Texprog) to intermediate (Texint) and terminal (Texterm) subsets, suggesting development flexibility. We examined epigenetic transitions between Tex cell subsets and revealed a reciprocally antagonistic circuit between Stat5a and Tox. Stat5 directed Texint cell formation and re-instigated partial effector biology during this Texprog-to-Texint cell transition. Constitutive Stat5a activity antagonized Tox and rewired CD8+ T cells from exhaustion to a durable effector and/or natural killer (NK)-like state with superior anti-tumor potential. Temporal induction of Stat5 activity in Tex cells using an orthogonal IL-2:IL2Rß-pair fostered Texint cell accumulation, particularly upon PD-L1 blockade. Re-engaging Stat5 also partially reprogrammed the epigenetic landscape of exhaustion and restored polyfunctionality. These data highlight therapeutic opportunities of manipulating the IL-2-Stat5 axis to rewire Tex cells toward more durably protective states.
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Linfocitos T CD8-positivos , Factores de Transcripción , Factores de Transcripción/genética , Interleucina-2 , Regulación de la Expresión Génica , Receptor de Muerte Celular Programada 1/metabolismoRESUMEN
Organ regeneration necessitates precise coordination of accelerators and brakes to restore organ function. However, the mechanisms underlying this intricate molecular crosstalk remain elusive. In this study, the level of proenkephalin-A (PENK-A), expressed by renal proximal tubular epithelial cells, decreases significantly with the loss of renal proximal tubules and increased at the termination phase of zebrafish kidney regeneration. Notably, this change contrasts with the role of hydrogen peroxide (H2O2), which acts as an accelerator in kidney regeneration. Through experiments with penka mutants and pharmaceutical treatments, we demonstrate that PENK-A inhibits H2O2 production in a dose-dependent manner, suggesting its involvement in regulating the rate and termination of regeneration. Furthermore, H2O2 influences the expression of tcf21, a vital factor in the formation of renal progenitor cell aggregates, by remodeling H3K4me3 in renal cells. Overall, our findings highlight the regulatory role of PENK-A as a brake in kidney regeneration.
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Peróxido de Hidrógeno , Riñón , Animales , Riñón/metabolismo , Peróxido de Hidrógeno/metabolismo , Pez Cebra , Regeneración , Túbulos Renales/metabolismoRESUMEN
After acute kidney injury (AKI), renal tubular epithelial cells (RTECs) are pathologically characterized by intracellular lipid droplet (LD) accumulation, which are involved in RTEC injury and kidney fibrosis. However, its pathogenesis remains incompletely understood. The protein, αKlotho, primarily expressed in RTECs, is well known as an anti-aging hormone wielding versatile functions, and its membrane form predominantly acts as a co-receptor for fibroblast growth factor 23. Here, we discovered a connection between membrane αKlotho and intracellular LDs in RTECs. Fluorescent fatty acid (FA) pulse-chase assays showed that membrane αKlotho deficiency in RTECs, as seen in αKlotho homozygous mutated (kl/kl) mice or in mice with ischemia-reperfusion injury (IRI)-induced AKI, inhibited FA mobilization from LDs by impairing adipose triglyceride lipase (ATGL)-mediated lipolysis and lipophagy. This resulted in LD accumulation and FA underutilization. IRI-induced alterations were more striking in αKlotho deficiency. Mechanistically, membrane αKlotho deficiency promoted E3 ligase peroxin2 binding to ubiquitin-conjugating enzyme E2 D2, resulting in ubiquitin-mediated degradation of ATGL which is a common molecular basis for lipolysis and lipophagy. Overexpression of αKlotho rescued FA mobilization by preventing ATGL ubiquitination, thereby lessening LD accumulation and fibrosis after AKI. This suggests that membrane αKlotho is indispensable for the maintenance of lipid homeostasis in RTECs. Thus, our study identified αKlotho as a critical regulator of lipid turnover and homeostasis in AKI, providing a viable strategy for preventing tubular injury and the AKI-to-chronic kidney disease transition.
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Rice straw incorporation is globally recognized as a viable alternative to incineration. However, it might lead to arsenic (As) methylation in soils, resulting in increased accumulation of methylated As in rice plants, potentially contributing to the emergence of rice straighthead disease. To evaluate the effect of straw incorporation on the As transformation in the paddy field system, we conducted a pot experiment for rice cultivation in two paddy soils with different As background levels and also characterized the response of the soil microbial community to straw incorporation. The results showed that straw incorporation elevated the total and methylated As concentration within the soil solution and rice plants, which in turn reduced rice seed setting rate and yield, and caused straighthead disorder in rice cultivated in soils with high As levels. 16S rRNA-based sequencing demonstrated reduced abundance and diversity of microorganisms upon adding straw. Notably, the dominant phylum, Bacteroidetes, exhibited a significant increase in abundance due to straw integration, while the abundance of Proteobacteria and Acidobacteria decreased. At the family level, the prevalence of Rikenellaceae increased only in soils contaminated with As following straw incorporation. Redundancy analysis showed positive associations between Rikenellaceae and levels of methylated As present in both soil porewater and rice husks, suggesting a potentially pivotal role of Rikenellaceae in the As methylation process after straw integration. These findings collectively emphasize that including straw can reshape the soil's microbial community and amplify As methylation in the soil, thereby promoting the uptake and accumulation of methylated As in rice and inducing straighthead disease in As-contaminated soil.
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Arsénico , Oryza , Contaminantes del Suelo , Arsénico/análisis , Oryza/metabolismo , ARN Ribosómico 16S , Contaminantes del Suelo/análisis , Suelo , BacteroidetesRESUMEN
Identifying molecular mechanisms of exhausted CD8 T cells (Tex) is a key goal of improving immunotherapy of cancer and other diseases. However, high-throughput interrogation of in vivo Tex can be costly and inefficient. In vitro models of Tex are easily customizable and quickly generate high cellular yield, enabling CRISPR screening and other high-throughput assays. We established an in vitro model of chronic stimulation and benchmarked key phenotypic, functional, transcriptional, and epigenetic features against bona fide in vivo Tex. We leveraged this model of in vitro chronic stimulation in combination with CRISPR screening to identify transcriptional regulators of T cell exhaustion. This approach identified several transcription factors, including BHLHE40. In vitro and in vivo validation defined a role for BHLHE40 in regulating a key differentiation checkpoint between progenitor and intermediate Tex subsets. By developing and benchmarking an in vitro model of Tex, then applying high-throughput CRISPR screening, we demonstrate the utility of mechanistically annotated in vitro models of Tex.
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Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Agotamiento de Células T , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas/genética , Linfocitos T CD8-positivos , Diferenciación Celular , EpigenómicaRESUMEN
The excessive formation of peroxynitrite (ONOO-) in mitochondria has been implicated in various pathophysiological processes and diseases. However, owing to short emission wavelengths and small Stokes shifts, previously reported fluorescent probes pose significant challenges for mitochondrial ONOO- imaging in biological systems. In this study, a near-infrared (NIR) fluorescent probe, denoted as DCO-POT, is designed for the visual monitoring of mitochondrial ONOO-, displaying a remarkable Stokes shift of 170 nm. The NIR fluorophore of DCO-CHO is released by DCO-POT upon the addition of ONOO-, resulting in off-on NIR fluorescence at 670 nm. This phenomenon facilitates the high-resolution confocal laser scanning imaging of ONOO- generated in biological systems. The practical applications of DCO-POT as an efficient fluorescence imaging tool are verified in this study. DCO-POT enables the fluorometric visualization of ONOO- in organelles, cells, and organisms. In particular, ONOO- generation is analyzed during cellular and organism-level (zebrafish) inflammation during ferroptosis and in an Alzheimer's disease mouse model. The excellent visual monitoring performance of DCO-POT in vivo makes it a promising tool for exploring the pathophysiological effects of ONOO-.
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Enfermedad de Alzheimer , Ferroptosis , Ratones , Animales , Colorantes Fluorescentes/toxicidad , Ácido Peroxinitroso , Pez Cebra , Enfermedad de Alzheimer/diagnóstico por imagen , Mitocondrias , Inflamación , Imagen Óptica/métodosRESUMEN
Extracting the profiles of images is critical because it can bring simplified description and draw special attention to particular areas in the images. In our work, we designed two filters via the exponential and hypotenuse functions for profile extraction. Their ability to extract the profiles from the images obtained from weak-light conditions, fluorescence microscopes, transmission electron microscopes, and near-infrared cameras is proven. Moreover, they can be used to extract the nesting structures in the images. Furthermore, their performance in extracting images degraded by Gaussian noise is evaluated. We used Gaussian white noise with a mean value of 0.9 to create very noisy images. These filters are effective for extracting the edge morphology in the noisy images. For the purpose of a comparative study, we used several well-known filters to process these noisy images, including the filter based on Gabor wavelet, the filter based on the watershed algorithm, and the matched filter, the performances of which in profile extraction are either comparable or not effective when dealing with extensively noisy images. Our filters have shown the potential for use in the field of pattern recognition and object tracking.
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Algoritmos , Ruido , Microscopía Fluorescente , Microscopía Electrónica de TransmisiónRESUMEN
OBJECTIVES: Malnutrition is associated with adverse outcomes in acute or chronic diseases. However, the prediction value of the Geriatric Nutritional Risk Index (GNRI) in critically ill patients with acute kidney injury (AKI) has not been well studied. METHODS: Data was extracted from the Medical Information Mart for Intensive Care III (MIMIC-III) and the electronic intensive care unit database. We used two nutritional indicators, the GNRI and the modified Nutrition Risk in Critically ill (NUTRIC) score, to evaluate the relationship between the nutritional status of patients with AKI and prognosis. The outcome is in-hospital mortality and 90-day mortality. The prediction accuracy of GNRI was compared with the NUTRIC score. RESULTS: A total of 4,575 participants with AKI were enrolled in this study. The median age of 68 (interquartile range, 56-79) years, and 1,142 (25.0%) patients experienced in-hospital mortality, and 1,238 (27.1%) patients experienced 90-day mortality. Kaplan-Meier survival analysis indicated that lower GNRI levels and high NUTRIC score are associated with lower in-hospital and 90-day survival of patients with AKI (P < .001 by log-rank test). After multivariate adjustment, Cox regression analysis demonstrated a 2-fold increased risk of in-hospital (hazard ratio = 2.019, 95% confidence interval: 1.699-2.400, P < .001) and 90-day (hazard ratio = 2.023, 95% confidence interval: 1.715-2.387, P < .001) mortality in the low GNRI group. Moreover, the multivariate-adjusted Cox model containing GNRI had higher prediction accuracy for the prognosis of patients with AKI than that with NUTRIC score (AUCGNRI model vs. AUCNUTRIC model for in-hospital mortality = 0.738 vs. 0.726, AUCGNRI model vs. AUCNUTRIC model for 90-day mortality = 0.748 vs. 0.726). In addition, the prediction value of GNRI was validated by the electronic intensive care unit database (7,881 patients with AKI) with satisfying performance (AUCGNRI model = 0.680). CONCLUSIONS: Our results demonstrated that GNRI is strongly associated with survival in patients in the intensive care unit coexisting with AKI, and the GNRI has a superior predictive value than the NUTRIC score.
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Lesión Renal Aguda , Desnutrición , Humanos , Anciano , Lactante , Evaluación Nutricional , Enfermedad Crítica , Estado Nutricional , Desnutrición/complicaciones , Factores de Riesgo , Estudios de Cohortes , Lesión Renal Aguda/complicaciones , Evaluación Geriátrica/métodos , Estudios RetrospectivosRESUMEN
Ischemic-reperfusion injury (IRI) is a major pathogenic factor in acute kidney injury (AKI), which directly leads to the hypoxic injury of renal tubular epithelial cells (RTECs). Although emerging studies suggest repressor element 1-silencing transcription factor (REST) as a master regulator of gene repression under hypoxia, its role in AKI remains elusive. Here, we found that REST was upregulated in AKI patients, mice, and RTECs, which was positively associated with the degree of kidney injury, while renal tubule-specific knockout of Rest significantly alleviated AKI and its progression to chronic kidney disease (CKD). Subsequent mechanistic studies indicated that suppression of ferroptosis was responsible for REST-knockdown-induced amelioration of hypoxia-reoxygenation injury, during which process Cre-expressing adenovirus-mediated REST downregulation attenuated ferroptosis through upregulating glutamate-cysteine ligase modifier subunit (GCLM) in primary RTECs. Further, REST transcriptionally repressed GCLM expression via directly binding to its promoter region. In conclusion, our findings revealed the involvement of REST, a hypoxia regulatory factor, in AKI-to-CKD transition and identified the ferroptosis-inducing effect of REST, which may serve as a promising therapeutic target for ameliorating AKI and its progression to CKD.
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Lesión Renal Aguda , Ferroptosis , Insuficiencia Renal Crónica , Factores de Transcripción , Animales , Ratones , Lesión Renal Aguda/patología , Células Epiteliales/metabolismo , Hipoxia/complicaciones , Insuficiencia Renal Crónica/metabolismo , HumanosRESUMEN
BACKGROUND: During the tumourigenesis and development of colorectal cancer (CRC), the inactivation of tumour suppressor genes is closely involved, although detailed molecular mechanisms remain elusive. Accumulating studies, including ours, have demonstrated that basic leucine zipper transcription factor ATF (activating transcription factor)-like 2 (BATF2) is a capable tumour suppressor that localises in the nucleus. However, its different subcellular localisation, potential functions and underlying mechanisms are unclear. METHODS: The translocation of BATF2 and its clinical relevance were detected using CRC samples, cell lines and xenograft nude mice. Candidate BATF2-binding proteins were screened using co-immunoprecipitation, quantitative label-free liquid chromatography-tandem mass spectrometry proteomic analysis, Western blotting and immunofluorescence. Recombinant plasmids, point mutations and siRNAs were applied to clarify the binding sites between BATF2 and chromosome region maintenance 1 (CRM1). RESULTS: The present study found that BATF2 was mainly localised in the cytoplasm, rather than nucleus, of CRC cells in vitro and in vivo, while cytoplasmic BATF2 expression was inversely correlated with the prognosis of CRC patients. Furthermore, we identified the nuclear export and subsequent ubiquitin-mediated degradation of BATF2 in CRC cells. Mechanistically, a functional nuclear export sequence (any amino acid) was characterised in BATF2 protein, through which BATF2 bound to CRM1 and translocated out of nucleus, ultimately enhancing CRC growth via inducing activator protein 1 (AP-1)/cyclin D1/phosphorylated retinoblastoma protein (pRb) signalling pathway. Additionally, nuclear export of BATF2 can be retarded by the mutation of NES in BATF2 or the knockdown of CRM1, whereas CRM1 expression was negatively associated with nuclear BATF2 expression and the prognosis of CRC patients. CONCLUSION: These findings revealed the biological effects and underlying mechanisms of cytoplasmic localisation of BATF2. Furthermore, suppressing nuclear export of BATF2 via mutating its NES region or inhibiting CRM1 expression may serve as a promising therapeutic strategy against CRC.
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Neoplasias Colorrectales , Carioferinas , Animales , Humanos , Ratones , Transporte Activo de Núcleo Celular/genética , Proliferación Celular/genética , Neoplasias Colorrectales/patología , Carioferinas/genética , Carioferinas/química , Carioferinas/metabolismo , Ratones Desnudos , Proteómica , Proteína Exportina 1RESUMEN
Identifying novel molecular mechanisms of exhausted CD8 T cells (T ex ) is a key goal of improving immunotherapy of cancer and other diseases. However, high-throughput interrogation of in vivo T ex can be costly and inefficient. In vitro models of T ex are easily customizable and quickly generate high cellular yield, offering an opportunity to perform CRISPR screening and other high-throughput assays. We established an in vitro model of chronic stimulation and benchmarked key phenotypic, functional, transcriptional, and epigenetic features against bona fide in vivo T ex . We leveraged this model of in vitro chronic stimulation in combination with pooled CRISPR screening to uncover transcriptional regulators of T cell exhaustion. This approach identified several transcription factors, including BHLHE40. In vitro and in vivo validation defined a role for BHLHE40 in regulating a key differentiation checkpoint between progenitor and intermediate subsets of T ex . By developing and benchmarking an in vitro model of T ex , we demonstrate the utility of mechanistically annotated in vitro models of T ex , in combination with high-throughput approaches, as a discovery pipeline to uncover novel T ex biology.