RESUMEN
Purpose: To clarify the significance of mitochondria-related differentially expressed genes (MTDEGs) in UC carcinogenesis through a bioinformatics analysis and provide potential therapeutic targets for patients with UC associated colorectal cancer. Methods: Microarray GSE37283 was utilized to investigate differentially expressed genes (DEGs) in UC and UC with neoplasia (UCN). MTDEGs were identified by intersecting DEGs with human mitochondrial genes. Utilizing LASSO and random forest analyses, we identified three crucial genes. Subsequently, using ROC curve to investigate the predictive ability of three key genes. Following, three key genes were confirmed in AOM/DSS mice model by Real-time PCR. Finally, single-sample gene set enrichment analysis (ssGSEA) was employed to explore the correlation between the hub genes and immune cells infiltration in UC carcinogenesis. Results: The three identified hub MTDEGs (HMGCS2, MAVS, RDH13) may exhibit significant diagnostic specificity in the transition from UC to UCN. Real-time PCR assay further confirmed that the expressions of HMGCS2 and RDH13 were significantly downregulated in UCN mice than that in UC mice. ssGSEA analysis revealed the hub genes were highly associated with CD56dim natural killer cells. Conclusion: RDH13, HMGCS2, and MAVS may become diagnostic indicators and potential biomarkers for UCN. Our research has the potential to enhance our understanding of the mechanisms underlying carcinogenesis in UC.
Asunto(s)
Colitis Ulcerosa , Neoplasias Colorrectales , Colitis Ulcerosa/genética , Colitis Ulcerosa/patología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Animales , Ratones , Humanos , Mitocondrias/metabolismo , Mitocondrias/genética , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Masculino , Biología ComputacionalRESUMEN
Ten-eleven translocation (TET) 2 is an enzyme that catalyzes DNA demethylation to regulate gene expression by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine, functioning as an essential epigenetic regulator in various biological processes. However, the regulation and function of TET2 in adipocytes during obesity are poorly understood. In this study, we demonstrate that leptin, a key adipokine in mammalian energy homeostasis regulation, suppresses adipocyte TET2 levels via JAK2-STAT3 signaling. Adipocyte Tet2 deficiency protects against high-fat diet-induced weight gain by reducing leptin levels and further improving leptin sensitivity in obese male mice. By interacting with C/EBPα, adipocyte TET2 increases the hydroxymethylcytosine levels of the leptin gene promoter, thereby promoting leptin gene expression. A decrease in adipose TET2 is associated with obesity-related hyperleptinemia in humans. Inhibition of TET2 suppresses the production of leptin in mature human adipocytes. Our findings support the existence of a negative feedback loop between TET2 and leptin in adipocytes and reveal a compensatory mechanism for the body to counteract the metabolic dysfunction caused by obesity.
Asunto(s)
Dioxigenasas , Leptina , Animales , Humanos , Masculino , Ratones , Adipocitos/metabolismo , Peso Corporal , Dioxigenasas/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Retroalimentación , Leptina/metabolismo , Mamíferos/metabolismo , Obesidad/genética , Obesidad/metabolismoRESUMEN
T cell infiltration into white adipose tissue (WAT) drives obesity-induced adipose inflammation, but the mechanisms of obesity-induced T cell infiltration into WAT remain unclear. Our single-cell RNA sequencing reveals a significant impact of adipose stem cells (ASCs) on T cells. Transplanting ASCs from obese mice into WAT enhances T cell accumulation. C-C motif chemokine ligand 5 (CCL5) is upregulated in ASCs as early as 4 weeks of high-fat diet feeding, coinciding with the onset of T cell infiltration into WAT during obesity. ASCs and bone marrow transplantation experiments demonstrate that CCL5 from ASCs plays a crucial role in T cell accumulation during obesity. The production of CCL5 in ASCs is induced by tumor necrosis factor alpha via the nuclear factor κB pathway. Overall, our findings underscore the pivotal role of ASCs in regulating T cell accumulation in WAT during the early phases of obesity, emphasizing their importance in modulating adaptive immunity in obesity-induced adipose inflammation.
Asunto(s)
Tejido Adiposo , Linfocitos T , Ratones , Animales , Linfocitos T/metabolismo , Tejido Adiposo/metabolismo , Obesidad/metabolismo , Inflamación/patología , Células Madre/metabolismoRESUMEN
CRISPR-Cas9-mediated genome editing depends on PAM recognition to initiate DNA unwinding. PAM mutations can abolish Cas9 binding and prohibit editing. Here, we identified a Cas9 from the thermophile Alicyclobacillus tengchongensis for which the PAM interaction can be robustly regulated by DNA topology. AtCas9 has a relaxed PAM of N4CNNN and N4RNNA (R = A/G) and is able to bind but not cleave targets with mutated PAMs. When PAM-mutated DNA was in underwound topology, AtCas9 exhibited enhanced binding affinity and high cleavage activity. Mechanistically, AtCas9 has a unique loop motif, which docked into the DNA major groove, and this interaction can be regulated by DNA topology. More importantly, AtCas9 showed near-PAMless editing of supercoiled plasmid in E. coli. In mammalian cells, AtCas9 exhibited broad PAM preference to edit plasmid with up to 72% efficiency and effective base editing at four endogenous loci, representing a potentially powerful tool for near-PAMless editing.
Asunto(s)
Sistemas CRISPR-Cas , Escherichia coli , Animales , Escherichia coli/genética , Escherichia coli/metabolismo , Edición Génica , ADN/genética , Plásmidos , Mamíferos/metabolismoRESUMEN
The VB2-air battery is currently known for its highest theoretical specific capacity, up to 4060 mA h g-1. This together with the excellent environmental compatibility and high security endues with promising application prospects for the battery. However, the self-discharge of the anode caused by hydrogen evolution corrosion results in a severe capacity loss during discharge. In this work, we studied the FeNi-LDH intercalation for suppressing the self-discharge of the VB2-air battery. We adopt the vertical FeNi-LDH arrays to modify VB2 particles. Hydroxyl ions participating in the discharge reaction are transported along adsorbed water molecules and hydroxide host layers through a rapid hydrogen bond formation and cleavage to the VB2 surface, while the depolarizer hydrogen ions are isolated. The hydrogen evolution corrosion on the VB2 anode is effectively suppressed. As a result, the discharge specific capacity of the battery is increased by 700 mA h g-1.
RESUMEN
Serpins are evolutionarily conserved serine protease inhibitors that are widely distributed in animals, plants and microbes. In this study, we reported the cloning and functional characterizations of two novel serpin genes, HlSerpin-a and HlSerpin-b, from the hard tick Haemaphysalis longicornis of China. Recombinant HlSerpin-a and HlSerpin-b displayed protease inhibitory activities against multiple mammalian proteases. Similar to other tick serpins, HlSerpin-a and HlSerpin-b suppressed the expression of inflammatory cytokines such as TNF-α, interleukin (IL)-6 and IL-1ß from lipopolysaccharide-stimulated mouse bone-marrow-derived macrophages (BMDMs) or mouse bone-marrow-derived dendritic cells (BMDCs). The minimum active region (reaction centre loop) of HlSerpin-a, named SA-RCL, showed similar biological activities as HlSerpin-a in the protease inhibition and immune suppression assays. The immunosuppressive activities of full-length HlSerpin-a and SA-RCL are impaired in Cathepsin G or Cathepsin B knockout mouse macrophages, suggesting that the immunomodulation functions of SA and SA-RCL are dependent on their protease inhibitory activity. Finally, we showed that both full-length HlSerpins and SA-RCL can relieve the joint swelling and inflammatory response in collagen-induced mouse arthritis models. These results suggested that HlSerpin-a and HlSerpin-b are two functional arthropod serpins, and the minimal reactive peptide SA-RCL is a potential candidate for drug development against inflammatory diseases.
Asunto(s)
Artritis Experimental/prevención & control , Proteínas de Artrópodos/farmacología , Células Dendríticas/efectos de los fármacos , Inmunosupresores/farmacología , Ixodidae/metabolismo , Articulaciones/efectos de los fármacos , Macrófagos/efectos de los fármacos , Serpinas/farmacología , Animales , Artritis Experimental/inmunología , Artritis Experimental/metabolismo , Artritis Experimental/patología , Proteínas de Artrópodos/genética , Proteínas de Artrópodos/aislamiento & purificación , Citocinas/metabolismo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Inmunosupresores/aislamiento & purificación , Ixodidae/genética , Articulaciones/inmunología , Articulaciones/metabolismo , Articulaciones/patología , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos DBA , Conformación Proteica , Células RAW 264.7 , Saliva/metabolismo , Serpinas/genética , Serpinas/aislamiento & purificación , Relación Estructura-ActividadRESUMEN
The vanadium boride (VB2) air battery is currently known as a primary battery with the highest theoretical specific capacity, 4060 mA h g-1, which originates from an extraordinary 11 electrons per VB2 molecule oxidation process. However, the parasitical reaction between VB2 and hydroxide ions in the alkaline electrolyte leads to obvious self-discharge, which results in severe capacity loss during discharge. In this work, we applied the polydopamine (PDA) membrane to modify the surface of VB2 particles, which contains amine groups and phenolic hydroxyl groups exhibiting fully reversible, pH-switchable permselectivity. The "smart" membrane with pH-switching characteristics successfully coordinated the conflict between the electrolyte and VB2 in the open circuit to avoid corrosion but also ensured that the hydroxide ions can enter the VB2 particle surface to participate in the reaction during discharge. According to the corrosion suppression test, the remaining amount of VB2@PDA is 90 wt % stored at 65 °C for 2 weeks, which is 10 wt % more than the uncoated VB2. The assembled pouch cell with the VB2@PDA anode can deliver a high capacity of 325 mA h at 250 mA g-1, retaining an improved Coulombic efficiency of 86.3%, which is 18.7% higher than that of the cell with the raw VB2 anode. Moreover, the 0.05 V higher discharge voltage of the VB2@PDA-based cell further shows that the PDA membrane can effectively conduct hydroxide ions during discharge.
RESUMEN
Cysticercosis is a parasitic infection caused by adult tapeworms, and it constantly plagues the livelihoods of people from subsistence farming communities in developing countries. Diagnosis of Cysticercosis typically requires both central nervous system imaging and serological testing. The most common methods in serological testing are Enzyme-linked Immunosorbent Assay (ELISA) and Enzyme Immuno-electrotransfer Blot (EITB). Both ELISA and EITB methods are excessively time-consuming and labor-intensive. Recent research indicates that a shorter assay time and/or higher sensitivity can be achieved by integrating alternate current electrokinetics (ACEK) with biosensing. However, the raw time-series data is very noisy and the size of the dataset is extremely small, which would bring two potential challenges. On one hand, traditional statistical methods cannot extract features robust enough for high sensitivity as well as high specificity. On the other hand, the small data size limits the usage of automatic feature extractors such as deep neural networks. In this paper, we propose a linear unmixing based approach by exploiting the possibility that the time-series biological signals can be represented as linear combinations of source signals. This paper makes distinctive contributions to the field of bio-signal by introducing the unmixing model from the image processing domain to the time-series domain. Experimental results on the classification of Cysticercosis using 123 samples demonstrate the robustness and superior performance of the linear unmixing method over other conventional classifiers in handling small datasets.
Asunto(s)
Cisticercosis , Animales , Cisticercosis/diagnóstico , Ensayo de Inmunoadsorción Enzimática , Humanos , Taenia soliumRESUMEN
Ticks, blood-feeding arthropods, and secrete immunosuppressive molecules that inhibit host immune responses and provide survival advantages to pathogens. In this study, we characterized the immunosuppressive function of a novel tick salivary protein, DsCystatin, from Dermacentor silvarum of China. DsCystatin directly interacted with human Cathepsins L and B and inhibited their enzymatic activities. DsCystatin impaired the expression of inflammatory cytokines such as IL1ß, IFNγ, TNFα, and IL6 from mouse bone marrow-derived macrophages (BMDMs) that had been stimulated with LPS or Borrelia burgdorferi. Consistently, DsCystatin inhibited the activation of mouse BMDMs and bone marrow-derived dendritic cells by downregulating the surface expression of CD80 and CD86. Mechanically, DsCystatin inhibited LPS- or B. burgdorferi-induced NFκB activation. For the first time, we identified that DsCystatin-attenuated TLR4 signaling by targeting TRAF6. DsCystatin enhanced LPS-induced autophagy, mediated TRAF6 degradation via an autophagy dependent manner, thereby impeded the downstream phosphorylation of IκBα and the nuclear transport of NFκB. Finally, DsCystatin relieved the joint inflammation in B. burgdorferi or complete Freund's adjuvant induced mouse arthritis models. These data suggested that DsCystatin is a novel immunosuppressive protein and can potentially be used in the treatment of inflammatory diseases.