N6-methyladenosine (m6A) modification is the most pervasive modification in mRNA, and has been considered as a new layer of epigenetic regulation on mRNA processing, stability and translation. ...Despite its functional significance in various physiological processes, the role of the m6A modification involved in breast cancer is yet fully understood.
We used the m6A-RNA immunoprecipitation sequencing to identify the potential targets in breast cancer. To determine the underlying mechanism for the axis of FTO-BNIP3, we performed a series of in vitro and in vivo assays in 3 breast cancer cell lines and 36 primary breast tumor tissues and 12 adjunct tissues.
We showed that FTO, a key m6A demethylase, was up-regulated in human breast cancer. High level of FTO was significantly associated with lower survival rates in patients with breast cancer. FTO promoted breast cancer cell proliferation, colony formation and metastasis in vitro and in vivo. We identified BNIP3, a pro-apoptosis gene, as a downstream target of FTO-mediated m6A modification. Epigenetically, FTO mediated m6A demethylation in the 3'UTR of BNIP3 mRNA and induced its degradation via an YTHDF2 independent mechanism. BNIP3 acts as a tumor suppressor and is negatively correlated with FTO expression in clinical breast cancer patients. BNIP3 dramatically alleviated FTO-dependent tumor growth retardation and metastasis.
Our findings demonstrate the functional significance of the m6A modification in breast cancer, and suggest that FTO may serve as a novel potential therapeutic target for breast cancer.
In this paper, by using critical point theory, the existence of infinitely many small solutions for a perturbed partial discrete Dirichlet problems including the mean curvature operator is ...investigated. Moreover, the present study first attempts to address discrete Dirichlet problems with ϕc-Laplacian operator in relative to some relative existing references. Based on our knowledge, this is the research of perturbed partial discrete bvp with ϕc-Laplacian operator for the first time. At last, two examples are used to examplify the results.
In this paper, the existence of infinitely many solutions for the partial discrete Kirchhoff-type problems involving p-Laplacian is proven by exploiting the critical point theory for the first time. ...Moreover, by using the strong maximum principle, we acquire some sufficient conditions for the presence of infinitely many positive solutions to the boundary value problems. Our major outcomes are explained with one example.
Mitofusin-2 (MFN2) is a dynamin-like GTPase that plays a central role in regulating mitochondrial fusion and cell metabolism. Mutations in MFN2 cause the neurodegenerative disease Charcot-Marie-Tooth ...type 2A (CMT2A). The molecular basis underlying the physiological and pathological relevance of MFN2 is unclear. Here, we present crystal structures of truncated human MFN2 in different nucleotide-loading states. Unlike other dynamin superfamily members including MFN1, MFN2 forms sustained dimers even after GTP hydrolysis via the GTPase domain (G) interface, which accounts for its high membrane-tethering efficiency. The biochemical discrepancy between human MFN2 and MFN1 largely derives from a primate-only single amino acid variance. MFN2 and MFN1 can form heterodimers via the G interface in a nucleotide-dependent manner. CMT2A-related mutations, mapping to different functional zones of MFN2, lead to changes in GTP hydrolysis and homo/hetero-association ability. Our study provides fundamental insight into how mitofusins mediate mitochondrial fusion and the ways their disruptions cause disease.
Phase-change materials (PCMs) are promising candidates for nonvolatile data storage and reconfigurable electronics, but high programming currents have presented a challenge to realize low-power ...operation. We controlled PCM bits with single-wall and small-diameter multi-wall carbon nanotubes. This configuration achieves programming currents of 0.5 microampere (set) and 5 microamperes (reset), two orders of magnitude lower than present state-of-the-art devices. Pulsed measurements enable memory switching with very low energy consumption. Analysis of over 100 devices finds that the programming voltage and energy are highly scalable and could be below 1 volt and single femtojoules per bit, respectively.
In recent years, the integration of graphene and related two-dimensional (2D) materials in optical fibers have stimulated significant advances in all-fiber photonics and optoelectronics. The ...conventional passive silica fiber devices with 2D materials are empowered for enhancing light-matter interactions and are applied for manipulating light beams in respect of their polarization, phase, intensity and frequency, and even realizing the active photo-electric conversion and electro-optic modulation, which paves a new route to the integrated multifunctional all-fiber optoelectronic system. This article reviews the fast-progress field of hybrid 2D-materials-optical-fiber for the opto-electro-mechanical devices. The challenges and opportunities in this field for future development are discussed.
PERK signaling is required for cancer invasion and there is interest in targeting this pathway for therapy. Unfortunately, chemical inhibitors of PERK's kinase activity cause on-target side effects ...that have precluded their further development. One strategy for resolving this difficulty would be to target downstream components of the pathway that specifically mediate PERK's pro-invasive and metastatic functions. Here we identify the transcription factor CREB3L1 as an essential mediator of PERK's pro-metastatic functions in breast cancer. CREB3L1 acts downstream of PERK, specifically in the mesenchymal subtype of triple-negative tumors, and its inhibition by genetic or pharmacological methods suppresses cancer cell invasion and metastasis. In patients with this tumor subtype, CREB3L1 expression is predictive of distant metastasis. These findings establish CREB3L1 as a key downstream mediator of PERK-driven metastasis and a druggable target for breast cancer therapy.
Objectives
The tyrosine kinase inhibitor (TKI)-sensitive mutations of the epidermal growth factor receptor (EGFR) gene is essential in the treatment of lung adenocarcinoma. To overcome the difficulty ...of EGFR gene test in situations where surgery and biopsy samples are too risky to obtain, we tried a noninvasive imaging method using radiomics features and random forest models.
Methods
Five hundred three lung adenocarcinoma patients who received surgery-based treatment were included in this study. The diagnosis and EGFR gene test were based on resections. TKI-sensitive mutations were found in 60.8% of the patients. CT scans before any invasive operation were gathered and analyzed to extract quantitative radiomics features and build random forest classifiers to identify EGFR mutants from wild types. Clinical features (sex and smoking history) were added to the image-based model. The model was trained on a set of 345 patients and validated on an independent test group (
n
= 158) using the area under the receiver operating characteristic curve (AUC), sensitivity, and specificity.
Results
The performance of the random forest model with 94 radiomics features reached an AUC of 0.802. Its AUC was further improved to 0.828 by adding sex and smoking history. The sensitivity and specificity are 60.6% and 85.1% at the best diagnostic decision point.
Conclusion
Our results showed that radiomics could not only reflect the genetic differences among tumors but also have diagnostic value and the potential to be a diagnostic tool.
Key Points
•
Radiomics provides a potential noninvasive method for the prediction of EGFR mutation status.
•
In situations where surgeries and biopsy are not available, CT image-based radiomics models could help to make treatment decisions.
•
The accuracy, sensitivity, and specificity still need to be improved before the image-based EGFR identifier could be used in clinics.
Two-dimensional layered materials like MoS2 have shown promise for nanoelectronics and energy storage, both as monolayers and as bulk van der Waals crystals with tunable properties. Here we present a ...platform to tune the physical and chemical properties of nanoscale MoS2 by electrochemically inserting a foreign species (Li+ ions) into their interlayer spacing. We discover substantial enhancement of light transmission (up to 90% in 4 nm thick lithiated MoS2) and electrical conductivity (more than 200×) in ultrathin (∼2–50 nm) MoS2 nanosheets after Li intercalation due to changes in band structure that reduce absorption upon intercalation and the injection of large amounts of free carriers. We also capture the first in situ optical observations of Li intercalation in MoS2 nanosheets, shedding light on the dynamics of the intercalation process and the associated spatial inhomogeneity and cycling-induced structural defects.
A computed scanning technology was applied to measure fracture tomography, and three-dimensional fracture meshes were established. Water flow experiments and simulations on fractures were conducted. ...Results demonstrate both Forchheimer and Izbash equations can capture the nonlinear flow behavior. As Reynolds number increases, contact obstacles and roughness of fracture increase the complexity of the velocity distribution by generating eddies or back flow. Nonlinear coefficient in Forchheimer equation increases by 1–5 orders of magnitude, ranging from 6 × 1010 to 5 × 1015. A critical Reynolds number is proposed to quantify the onset of nonlinear flow. Further quantitative analysis is conducted regarding flow path tortuosity.
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