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We report all-soft vertical organic photodetectors composed of only soft components. Chemically and physically enhanced interfacial adhesion between layers enables robust operation under mechanical deformation. Their excellent light-sensing capability and deformable features, combined with powerless operation, promise significant advancements in optoelectronic applications.
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Hair growth cycles are mainly regulated by human dermal papilla cells (hDPCs) and human outer root sheath cells (hORSCs). Protecting hDPCs from excessive oxidative stress and hORSCs from glycogen phosphorylase (PYGL) is crucial to maintaining the hair growth phase, anagen. In this study, we developed a new PYGL inhibitor, Hydroxytrimethylpyridinyl Methylindolecarboxamide (HTPI) and assessed its potential to prevent hair loss. HTPI reduced oxidative damage, preventing cell death and restored decreased level of anagen marker ALP and its related genes induced by hydrogen peroxide in hDPCs. Moreover, HTPI inhibited glycogen degradation and induced cell survival under glucose starvation in hORSCs. In ex-vivo culture, HTPI significantly enhanced hair growth compared to the control with minoxidil showing comparable results. Overall, these findings suggest that HTPI has significant potential as a therapeutic agent for the prevention and treatment of hair loss.
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This study reports intrinsic multimodal memristivity of a nonconjugated radical polymer with ambient stability. Organic memristive devices represent powerful candidates for biorealistic data storage and processing. However, there exists a substantial knowledge gap in realizing the synthetic biorealistic systems capable of effectively emulating the cooperative and multimodal activation processes in biological systems. In addition, conventional organic memristive materials are centered on conjugated small and macromolecules, making them synthetically challenging or difficult to process. In this work, we first describe the intrinsic resistive switching of the radical polymer that resulted in an exceptional state retention of >105 s and on/off ratio of >106. Next, we demonstrate its bimodal cooperative switching, in response to the proton accumulation as a biological input. Last, we expand our system toward an advanced in-sensor computing system. Our research demonstrates a nonconjugated radical polymer with intrinsic memristivity, which is directly applicable to future electronics including data storage, neuromorphics, and in-sensor computing.
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Self-assembly of CuX2 (X- = BF4-, ClO4-, and CF3SO3-) with a new tridentate 5,5',5â³-(((2,4,6-trimethylbenzene-1,3,5-triyl)tris(methylene))tris(oxy))triisoquinoline (L) gives rise to single-crystal pairs consisting of small and large cages, [X@Cu2X2L4]X and [Cu6X12L8], respectively, via selection of solvents. In particular, the large cage is transformed into a small cage in acetonitrile above 50 °C. A significant difference in heterogeneous catechol oxidation catalysis between the small and large cages is observed. Such notable catechol-oxidation-catalytic effects can be explained by maintenance of the Cu···Cu distance at the catalytic center. This research is a direct systematic example of both cage-size control via solvent selection and the significance of the Cu···Cu distance in catechol oxidation catalysis with copper (Cu).
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Colorectal cancer (CRC) is one of the top five most common and life-threatening malignancies worldwide. Most CRC develops from advanced colorectal adenoma (ACA), a precancerous stage, through the adenoma-carcinoma sequence. However, its underlying mechanisms, including how the tumor microenvironment changes, remain elusive. Therefore, we conducted an integrative analysis comparing RNA-seq data collected from 40 ACA patients who visited Dongguk University Ilsan Hospital with normal adjacent colons and tumor samples from 18 CRC patients collected from a public database. Differential expression analysis identified 21 and 79 sequentially up- or down-regulated genes across the continuum, respectively. The functional centrality of the continuum genes was assessed through network analysis, identifying 11 up- and 13 down-regulated hub-genes. Subsequently, we validated the prognostic effects of hub-genes using the Kaplan-Meier survival analysis. To estimate the immunological transition of the adenoma-carcinoma sequence, single-cell deconvolution and immune repertoire analyses were conducted. Significant composition changes for innate immunity cells and decreased plasma B-cells with immunoglobulin diversity were observed, along with distinctive immunoglobulin recombination patterns. Taken together, we believe our findings suggest underlying transcriptional and immunological changes during the adenoma-carcinoma sequence, contributing to the further development of pre-diagnostic markers for CRC.
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Adenoma , Neoplasias Colorrectales , Biología Computacional , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/patología , Adenoma/genética , Adenoma/inmunología , Adenoma/patología , República de Corea , Biología Computacional/métodos , Masculino , Femenino , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Pronóstico , Persona de Mediana Edad , Anciano , Biomarcadores de Tumor/genética , Estimación de Kaplan-Meier , Perfilación de la Expresión GénicaRESUMEN
The differentiation of naive CD8+ T cells into effector cells is important for establishing immunity. However, the effect of heterogeneous naive CD8+ T cell populations is not fully understood. Here, we demonstrate that steady-state naive CD8+ T cells are composed of functionally heterogeneous subpopulations that differ in their ability to differentiate into type 17 cytotoxic effector cells (Tc17) in a context of murine inflammatory disease models, such as inflammatory bowel disease and graft-versus-host disease. The differential ability of Tc17 differentiation is not related to T-cell receptor (TCR) diversity and antigen specificity but is inversely correlated with self-reactivity acquired during development. Mechanistically, this phenomenon is linked to differential levels of intrinsic TCR sensitivity and basal Suppressor of Mothers Against Decapentaplegic 3 (SMAD3) expression, generating a wide spectrum of Tc17 differentiation potential within naive CD8+ T cell populations. These findings suggest that developmental self-reactivity can determine the fate of naive CD8+ T cells to generate functionally distinct effector populations and achieve immense diversity and complexity in antigen-specific T-cell immune responses.
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Linfocitos T CD8-positivos , Inflamación , Ratones , Animales , Modelos Animales de Enfermedad , Diferenciación Celular , Inflamación/patología , Receptores de Antígenos de Linfocitos T/metabolismoRESUMEN
BACKGROUND: Recombinant human interleukin (rhIL)-7-hyFc (efineptakin alfa; NT-I7) is a potent T-cell amplifier, with two IL-7 molecules fused to IgD/IgG4 elements. rhIL-7-hyFc promotes extensive infiltration of CD8+ T cells into the tumor, concurrently increasing the numbers of intratumoral PD-1+CD8+ T cells. The hIL-2/TCB2 complex (SLC-3010) inhibits tumor growth by preferential activation of CD122 (IL-2Rß)high CD8+ T cells and natural killer cells, over regulatory T cells (Tregs). We investigated the underlying mechanisms of rhIL-7-hyFc and hIL-2/TCB2c antitumor activity and the potential synergistic efficacy, specifically focusing on tumor-specific CD8+ cells within the tumor and the tumor-draining lymph nodes (tdLN). METHODS: MC38 and CT26 tumor-bearing mice were administered with 10 mg/kg rhIL-7-hyFc intramuscularly and 0.9 mg/kg hIL-2/TCB2c intravenously. Anti-PD-1 monoclonal antibody was administered intraperitoneally three times at 3-day intervals at a dose of 5 mg/kg. Tumor volume was measured to assess efficacy. To compare the composition of immune cells between each monotherapy and the combination therapy, we analyzed tumors and tdLNs by flow cytometry. RESULTS: Our data demonstrate that the combination of rhIL-7-hyFc and hIL-2/TCB2c increases efficacy and generates an immune-stimulatory tumor microenvironment (TME). The TME is characterized by an increased infiltration of tumor-specific CD8+ T cells, and a decreased frequency of CD39highTIM-3+ Treg cells. Most importantly, rhIL-7-hyFc increases infiltration of a CD62L+Ly108+ early progenitor population of exhausted CD8+ T cells (TPEX), which may retain long-term proliferation capacity and replenish functional effector CD8+ T cells. hIL-2/TCB2c induces differentiation of CD62L+Ly108+ TPEX rapidly into CD101+ terminally differentiated subsets (terminally exhausted T cell (TEX term)). Our study also demonstrates that rhIL-7-hyFc significantly enhances the proliferation rate of TPEX in the tdLNs, positively correlating with their abundance within the tumor. Moreover, rhIL-7-hyFc and hIL-2/TCB2c can overcome the limited therapeutic effectiveness of PD-1 blockade, culminating in the complete regression of tumors. CONCLUSIONS: rhIL-7-hyFc can expand and maintain the progenitor pool of exhausted CD8+ T cells, whereas hIL-2/TCB2c promotes their differentiation into TEX term. Together, this induces an immune-stimulatory TME that improves the efficacy of checkpoint blockade.
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Linfocitos T CD8-positivos , Interleucina-7 , Neoplasias , Proteínas Recombinantes de Fusión , Humanos , Animales , Ratones , Microambiente Tumoral , Receptor de Muerte Celular Programada 1 , Factores InmunológicosRESUMEN
BACKGROUND: Juvenile idiopathic arthritis (JIA) is one of the most prevalent rheumatic disorders in children and is classified as an autoimmune disease (AID). While a robust genetic contribution to JIA etiology has been established, the exact pathogenesis remains unclear. METHODS: To prioritize biologically interpretable susceptibility genes and proteins for JIA, we conducted transcriptome-wide and proteome-wide association studies (TWAS/PWAS). Then, to understand the genetic architecture of JIA, we systematically analyzed single-nucleotide polymorphism (SNP)-based heritability, a signature of natural selection, and polygenicity. Next, we conducted HLA typing using multi-ethnicity RNA sequencing data. Additionally, we examined the T cell receptor (TCR) repertoire at a single-cell level to explore the potential links between immunity and JIA risk. RESULTS: We have identified 19 TWAS genes and two PWAS proteins associated with JIA risks. Furthermore, we observe that the heritability and cell type enrichment analysis of JIA are enriched in T lymphocytes and HLA regions and that JIA shows higher polygenicity compared to other AIDs. In multi-ancestry HLA typing, B*45:01 is more prevalent in African JIA patients than in European JIA patients, whereas DQA1*01:01, DQA1*03:01, and DRB1*04:01 exhibit a higher frequency in European JIA patients. Using single-cell immune repertoire analysis, we identify clonally expanded T cell subpopulations in JIA patients, including CXCL13+BHLHE40+ TH cells which are significantly associated with JIA risks. CONCLUSION: Our findings shed new light on the pathogenesis of JIA and provide a strong foundation for future mechanistic studies aimed at uncovering the molecular drivers of JIA.
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Artritis Juvenil , Niño , Humanos , Artritis Juvenil/genética , Predisposición Genética a la Enfermedad/genética , Proteínas/genética , AlelosRESUMEN
Background and Objectives: This study aimed to analyze patients with rhabdomyolysis who presented to emergency departments and identify their distribution of related disease and prognostic factors. Materials and Methods: A retrospective cohort study was conducted on patients with rhabdomyolysis who presented to emergency departments over a 10-year period. Patient data, including patients' demographic variables (sex and age), mode of arrival, final diagnosis, statin use, rhabdomyolysis trigger factors, and levels of serum creatine phosphokinase (CPK), myoglobin, creatinine, sodium, potassium, phosphate, calcium, and lactate, were analyzed. Univariate and multivariate logistic regression analyses were conducted to identify the predictive factors of acute kidney injury (AKI). Results: Among the patients, 268 (65.6%) were found to have trigger factors without underlying diseases. Furthermore, 115 (28.2%) patients developed AKI. This comprehensive study sheds light on the diverse factors influencing the occurrence of AKI in rhabdomyolysis and provides insights into AKI predictive markers. Furthermore, we analyzed the cases by dividing them into six groups: occurrence of AKI, occurrence of infection, and simple or complex rhabdomyolysis. CPK time course was found to be important in clinical prognosis, such as AKI occurrence, dialysis or not, and mortality. Conclusions: Age, statin use, elevated creatinine and lactate levels, and initial serum CPK level emerged as significant predictors of AKI. CPK time course was also found to be an important factor in predicting the clinical outcomes of patients with rhabdomyolysis.
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Lesión Renal Aguda , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Humanos , Creatinina , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Diálisis Renal , Estudios Retrospectivos , Lesión Renal Aguda/epidemiología , Lesión Renal Aguda/etiología , Servicio de Urgencia en Hospital , Pronóstico , Ácido LácticoRESUMEN
Accumulating data suggest that ribosomal protein S6 kinase 1 (S6K1), an effector in the mammalian target of rapamycin (mTOR) pathway, plays pleiotropic roles in tumor progression. However, to date, while the tumorigenic function of S6K1 in tumor cells has been well elucidated, its role in the tumor stroma remains poorly understood. We recently showed that S6K1 mediates vascular endothelial growth factor A (VEGF-A) production in macrophages, thereby supporting tumor angiogenesis and growth. As macrophage-derived VEGF-A is crucial for both tumor cell intravasation and extravasation across the vascular endothelium, our previous findings suggest that stromal S6K1 signaling is required for tumor metastatic spread. Therefore, we aimed to determine the impact of host S6K1 depletion on tumor metastasis using a murine model of pulmonary metastasis (S6k1-/- mice implanted with B16F10 melanoma). The ablation of S6K1 in the host microenvironment significantly reduced the metastasized B16F10 melanoma cells on the lung surface in both spontaneous and intravenous lung metastasis mouse models without affecting the incidence of metastasis to distant lymph nodes. In addition, stromal S6K1 loss decreased the number of tumor cells circulating in the peripheral blood of mice bearing B16F10 xenografts without affecting the vascular leakage induced by VEGF-A in vivo. These observations demonstrate that S6K1 signaling in host cells other than endothelial cells is required to modulate the host microenvironment to facilitate the metastatic spread of tumors via blood circulation, thus revealing its novel role in the tumor stroma during tumor progression.
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Neoplasias Pulmonares , Melanoma , Proteínas Quinasas S6 Ribosómicas 90-kDa , Animales , Humanos , Ratones , Células Endoteliales/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Mamíferos/metabolismo , Melanoma/metabolismo , Melanoma/patología , Transducción de Señal , Microambiente Tumoral , Factor A de Crecimiento Endotelial Vascular/metabolismo , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismoRESUMEN
The µ-opioid receptor (MOR) is a class of opioid receptors characterized by a high affinity for ß-endorphin and morphine. MOR is a G protein-coupled receptor (GPCR) that plays a role in reward and analgesic effects. While expression of MOR has been well established in neurons and microglia, astrocytic MOR expression has been less clear. Recently, we have reported that MOR is expressed in hippocampal astrocytes, and its activation has a critical role in the establishment of conditioned place preference. Despite this critical role, the expression and function of astrocytic MOR from other brain regions are still unknown. Here, we report that MOR is significantly expressed in astrocytes and GABAergic neurons from various brain regions including the hippocampus, nucleus accumbens, periaqueductal gray, amygdala, and arcuate nucleus. Using the MOR-mCherry reporter mice and Imaris analysis, we demonstrate that astrocytic MOR expression exceeded 60% in all tested regions. Also, we observed similar MOR expression of GABAergic neurons as shown in the previous distribution studies and it is noteworthy that MOR expression is particularly in parvalbumin (PV)-positive neurons. Furthermore, consistent with the normal MOR function observed in the MOR-mCherry mouse, our study also demonstrates intact MOR functionality in astrocytes through iGluSnFr-mediated glutamate imaging. Finally, we show the sex-difference in the expression pattern of MOR in PV-positive neurons, but not in the GABAergic neurons and astrocytes. Taken together, our findings highlight a substantial astrocytic MOR presence across various brain regions.