The ten–eleven translocation (TET) family of methylcytosine dioxygenases initiates demethylation of DNA and is associated with tumorigenesis in many cancers; however, the mechanism is mostly unknown. ...Here we identify upstream activators and downstream effectors of TET1 in breast cancer using human breast cancer cells and a genetically engineered mouse model. We show that depleting the architectural transcription factor high mobility group AT-hook 2 (HMGA2) induces TET1 . TET1 binds and demethylates its own promoter and the promoter of homeobox A (HOXA) genes, enhancing its own expression and stimulating expression of HOXA genes including HOXA7 and HOXA9 . Both TET1 and HOXA9 suppress breast tumor growth and metastasis in mouse xenografts. The genes comprising the HMGA2–TET1–HOXA9 pathway are coordinately regulated in breast cancer and together encompass a prognostic signature for patient survival. These results implicate the HMGA2–TET1–HOX signaling pathway in the epigenetic regulation of human breast cancer and highlight the importance of targeting methylation in specific subpopulations as a potential therapeutic strategy.
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Previous studies have shown that depression is often accompanied by an increase in mtDNA copy number and a decrease in ATP levels; however, the exact regulatory mechanisms remain unclear.
In the ...present study, Western blot, cell knockdown, immunofluorescence, immunoprecipitation and ChIP-qPCR assays were used to detect changes in the Ahi1/GR-TFAM-mtDNA pathway in the brains of neuronal Abelson helper integration site-1 (Ahi1) KO mice and dexamethasone (Dex)-induced mice to elucidate the pathogenesis of depression. In addition, a rescue experiment was performed to determine the effects of regular exercise on the Ahi1/GR-TFAM-mtDNA-ATP pathway and depression-like behavior in Dex-induced mice and Ahi1 KO mice under stress.
In this study, we found that ATP levels decreased and mitochondrial DNA (mtDNA) copy numbers increased in depression-related brain regions in Dex-induced depressive mice and Ahi1 knockout (KO) mice. In addition, Ahi1 and glucocorticoid receptor (GR), two important proteins related to stress and depressive behaviors, were significantly decreased in the mitochondria under stress. Intriguingly, GR can bind to the D-loop control region of mitochondria and regulate mitochondrial replication and transcription. Importantly, regular exercise significantly increased mitochondrial Ahi1/GR levels and ATP levels and thus improved depression-like behaviors in Dex-induced depressive mice but not in Ahi1 KO mice under stress.
In summary, our findings demonstrated that the mitochondrial Ahi1/GR complex and TFAM coordinately regulate mtDNA copy numbers and brain ATP levels by binding to the D-loop region of mtDNA Regular exercise increases the levels of the mitochondrial Ahi1/GR complex and improves depressive behaviors. Video Abstract.
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Lithium metal batteries (LMBs) with Ni-rich cathode materials providing ultra-high energy density (∼500 W h kg−1) are expected to be the next generation of batteries. However, high-voltage LMBs ...exhibit inferior electrochemical performance at elevated temperatures, due to severe dendrite growth in lithium metal anodes and the structural degradation of Ni-rich cathodes, which should be paid attention to in terms of their practical application. Herein, by introducing 1,3-propane sultone (PS) into the carbonate electrolytes, satisfying cycling stability of Li‖LiNi0.8Co0.1Mn0.1O2 (NCM811) batteries at a high cut-off voltage of 4.45 V and an elevated temperature of 45 °C was achieved, which also shows higher ionic conductivity, wettability and thermodynamic stability. This approach enables uniform lithium plating/stripping at elevated temperatures, because of the construction of a LiF/Li2SO3-rich interphase layer. Besides, PS inhibits drastic structural change and interfacial side reactions on NCM811. It is also noteworthy that Li‖NCM811 full cells delivered decent performance at high-load cathodes, ultra-thin lithium anodes and lean electrolytes cycling at 4.45 V and 45 °C. This strategy provides a feasible solution for boosting high energy density LMBs under extreme conditions.
Sepsis is a clinical syndrome that resulting from a dysregulated inflammatory response to infection that leads to organ dysfunction. The dysregulated inflammatory response transitions from a ...hyper-inflammatory phase to a hypo-inflammatory or immunosuppressive phase. Currently, no phase-specific molecular-based therapies are available for monitoring the complex immune response and treating sepsis due to individual variations in the timing and overlap of the dysregulated immune response in most patients. Glucocorticoid-induced leucine zipper (GILZ), is broadly present in multiple tissues and circumvent glucocorticoid resistance (GCR) or unwanted side effects. Recently, the characteristics of GILZ downregulation during acute hyperinflammation and GILZ upregulation during the immunosuppressive phase in various inflammatory diseases have been well documented, and the protective effects of GILZ have gained attention in the field of sepsis. However, whether GILZ could be a promising candidate biomarker for monitoring and treating septic patients remains unknown. Here, we discuss the effect of GILZ in sepsis and sepsis-induced immunosuppression.
The RAS/RAF/MEK/ERK and PI3K/AKT/mTOR signaling pathways all belong to mitogen-activated protein kinase (MAPK) signaling pathways, Mutations in any one of the upstream genes (such as the
gene or the
...gene) may be transmitted to the protein through transcription or translation, resulting in abnormal activation of the signaling pathway. This study investigated the relationship between the
gene mutation and the clinicopathological features and prognosis of colorectal cancer (CRC), and the effect of
mutations on its associated proteins in CRC, with an aim to clarify the cause of tumor progression and drug resistance caused by mutation of the
gene.
To investigate the
gene and RAS pathway signaling molecules in CRC and to analyze their relationship with clinicopathological features and prognosis.
Colorectal cancer tissue specimens from 196 patients were analyzed for
mutations using quantitative polymerase chain reaction and for KRAS, BRAF, MEK, and ERK protein expression levels using immunohistochemistry of tumor microarrays. To analyze differences of RAS pathway signaling molecule expression levels in different
gene status, the relationships between these parameters and clinicopathological features, 4-year progression-free survival, and overall survival were analyzed by independent sample
test, Kaplan-Meier plots, and the log-rank test. Predictors of overall and disease-free survival were assessed using a Cox proportional hazards model.
Of the 196 patients, 62 (32%) carried mutations in codon 12 (53/62) or codon 13 (9/62) in exon 2 of the
gene. KRAS, BRAF, ERK, and MEK protein expression was detected in 71.4%, 78.8%, 64.3%, and 50.8% of CRC tissues, respectively. There were no significant differences between
mutation status and KRAS, BRAF, MEK, or ERK protein levels. Positive expression of KRAS and ERK was associated with poor tumor differentiation, and KRAS expression was also associated with age < 56 years. MEK expression was significantly associated with distant metastasis (
< 0.05). The 4-year progression-free survival rate, but not overall survival rate, was significantly higher in patients with KRAS-negative tumors than in those with KRAS-positive tumors (
< 0.05), whereas BRAF, MEK, and ERK expression was unrelated to survival. Multivariate analysis showed that only the expression of KRAS protein was a risk factor for tumor recurrence (
< 0.05). No other clinicopathological factors correlated with KRAS, BRAF, MEK, or ERK expression.
gene mutations do not affect downstream protein expression in CRC. KRAS protein is associated with poor tumor differentiation, older age, and a risk of tumor recurrence.
Acne inversa (AI), also known as hidradenitis suppurativa, is a chronic, recurrent, inflammatory disease of hair follicles that often runs in families. We studied six Chinese families with features ...of AI as well as additional skin lesions on back, face, nape, and waist and found independent loss-of-function mutations in PSENEN, PSEN1, or NCSTN, the genes encoding essential components of the γ-secretase multiprotein complex. Our results identify the γ-secretase component genes as the culprits for a subset of familial AI, implicate the γ-secretase-Notch pathway in the molecular pathogenesis of AI, and demonstrate that familial AI can be an allelic disorder of early-onset familial Alzheimer's disease.
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The protein kinase C (PKC) isoforms, which play an essential role in transmembrane signal conduction, can be viewed as a family of "memory kinases." Evidence is emerging that they are critically ...involved in memory acquisition and maintenance, in addition to their involvement in other functions of cells. Deficits in PKC signal cascades in neurons are one of the earliest abnormalities in the brains of patients suffering from Alzheimer's disease. Their dysfunction is also involved in several other types of memory impairments, including those related to emotion, mental retardation, brain injury, and vascular dementia/ischemic stroke. Inhibition of PKC activity leads to a reduced capacity of many types of learning and memory, but may have therapeutic values in treating substance abuse or aversive memories. PKC activators, on the other hand, have been shown to possess memory-enhancing and antidementia actions. PKC pharmacology may, therefore, represent an attractive area for developing effective cognitive drugs for the treatment of many types of memory disorders and dementias.
Fragile X syndrome (FXS), an X-chromosome linked intellectual disability, is the leading monogenetic cause of autism spectrum disorder (ASD), a neurodevelopmental condition that currently has no ...specific drug treatment. Building upon the demonstrated therapeutic effects on spatial memory of bryostatin-1, a relatively specific activator of protein kinase C (PKC)ε, (also of PKCα) on impaired synaptic plasticity/maturation and spatial learning and memory in FXS mice, we investigated whether bryostatin-1 might affect the autistic phenotypes and other behaviors, including open field activity, activities of daily living (nesting and marble burying), at the effective therapeutic dose for spatial memory deficits. Further evaluation included other non-spatial learning and memory tasks. Interestingly, a short period of treatment (5 weeks) only produced very limited or no therapeutic effects on the autistic and cognitive phenotypes in the Fmr1 KO2 mice, while a longer treatment (13 weeks) with the same dose of bryostatin-1 effectively rescued the autistic and non-spatial learning deficit cognitive phenotypes. It is possible that longer-term treatment would result in further improvement in these fragile X phenotypes. This effect is clearly different from other treatment strategies tested to date, in that the drug shows little acute effect, but strong long-term effects. It also shows no evidence of tolerance, which has been a problem with other drug classes (mGluR5 antagonists, GABA-A and -B agonists). The results strongly suggest that, at appropriate dosing and therapeutic period, chronic bryostatin-1 may have great therapeutic value for both ASD and FXS.
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In this paper, we propose a new hybrid mesoscale eddy tracking method to enhance the eddy tracking accuracy from global satellite altimeter data. This method integrates both physical and geometric ...eddy properties (including the distance between eddies, the area and amplitude of eddy, and the shape of the eddy edge) via the output of detection and the calculation of Hausdorff distance, which could describe the similarity between eddy boundaries. We applied the proposed hybrid method to several previously reported eddies and compared the results with those from two traditional tracking methods. A quantitative comparison indicates that the hybrid algorithm can better reveal eddy signals in terms of their spatial scale, amplitude, lifespan, and splitting. The hybrid method was used for global mesoscale eddies tracking from 1993 to 2015. Global distributions of net eddy numbers revealed that the sources of eddies are located along the eastern boundaries of the world oceans, while the sinks of eddies are located along the western boundaries. The lifespan distribution of eddies exhibited steep growth from high and low latitudes to middle latitudes. A clear divergent pathway demonstrates that cyclonic/anticyclonic eddies tend to travel poleward/equatorward in the world oceans.
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Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder clinically characterized by cognitive impairment, abnormal behavior, and social deficits, which is intimately ...linked with excessive β-amyloid (Aβ) protein deposition along with many other misfolded proteins, neurofibrillary tangles formed by hyperphosphorylated tau protein aggregates, and mitochondrial damage in neurons, leading to neuron loss. Currently, research on the pathological mechanism of AD has been elucidated for decades, still no effective treatment for this complex disease was developed, and the existing therapeutic strategies are extremely erratic, thereby leading to irreversible and progressive cognitive decline in AD patients. Due to gradually mental dyscapacitating of AD patients, AD not only brings serious physical and psychological suffering to patients themselves, but also imposes huge economic burdens on family and society. Accordingly, it is very imperative to recapitulate the progress of gene editing-based precision medicine in the emerging fields. In this review, we will mainly focus on the application of CRISPR/Cas9 technique in the fields of AD research and gene therapy, and summarize the application of CRISPR/Cas9 in the aspects of AD model construction, screening of pathogenic genes, and target therapy. Finally, the development of delivery systems, which is a major challenge that hinders the clinical application of CRISPR/Cas9 technology will also be discussed.
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