microRNAs （miRNAs） are an abundant class of-22 nucleotide （nt） regulatory RNAs that are pervasive in higher eukaryotic genomes. In order to fully understand their prominence in genomes, it is ...necessary to elucidate the molecular mechanisms that can diversify miRNA activities. In this review, we describe some of the many strategies that allow novel miRNA functions to emerge, with particular emphasis on how miRNA genes evolve in animals. These mechanisms include changes in their sequence, processing, or expression pattern; acquisition of miRNA^＊ functionality or antisense processing; and de novo gene birth. The facility and versatility of miRNAs to evolve and change likely underlies how they have become dominant constituents of higher genomes.
ObjectivesDuring the COVID-19 outbreak, medical educators’ main concern has been how to prepare new physicians and medical students to meet their obligations as healthcare providers under novel ...circumstances. This study aims at exploring how trainees perceive their commitments as physicians under the threat of a pandemic.DesignA qualitative method was employed. Researchers interviewed medical students under clerkship training (fifth and sixth-year medical students) and new physicians undergoing postgraduate year (PGY) and specialty training.SettingA university hospital in Taipei, Taiwan.ParticipantsThe team conducted three focus groups for participants in three separate training stages: clerks, PGY students (PGYs), and residents. Researchers collected data from 31 March to 2 April 2020 and analysed the thematic analysis results.ResultsSeventeen medical students and new physicians took part in the focus groups, five of whom (31.25%) were female. Participants consisted of four residents, six PGYs, and seven medical students. Through their responses, the authors determined four major dimensions with corresponding subdimensions that significantly affected their sense of medical professionalism, including medical knowledge and clinical skills, sense of duty towards public health, teamwork and protection of patient rights.ConclusionsWe therefore concluded that participants grew to accept their roles after acquiring the knowledge and skills needed to care for patients with COVID-19. Alternative teaching arrangements and their impact on trainees’ clinical performance require further discussion.
Emerging research suggests that multiple tumor compartments can influence treatment responsiveness and relapse, yet the search for therapeutic resistance mechanisms remains largely focused on ...acquired genomic alterations in cancer cells. Here we show how treatment-induced changes occur in multiple tumor compartments during tumor relapse and can reduce benefit of follow-on therapies. By using serial biopsies, next-generation sequencing, and single-cell transcriptomics, we tracked the evolution of multiple cellular compartments within individual lesions during first-line treatment response, relapse, and second-line therapeutic interventions in an autochthonous model of melanoma. We discovered that although treatment-relapsed tumors remained genetically stable, they converged on a shared resistance phenotype characterized by dramatic changes in tumor cell differentiation state, immune infiltration, and extracellular matrix (ECM) composition. Similar alterations in tumor cell differentiation were also observed in more than half of our treatment-relapsed patient tumors. Tumor cell-state changes were coincident with ECM remodeling and increased tumor stiffness, which alone was sufficient to alter tumor cell fate and reduce treatment responses in melanoma cell lines in vitro. Despite the absence of acquired mutations in the targeted pathway, resistant tumors showed significantly decreased responsiveness to second-line therapy intervention within the same pathway. The ability to preclinically model relapse and refractory settings-while capturing dynamics within and crosstalk between all relevant tumor compartments-provides a unique opportunity to better design and sequence appropriate clinical interventions.
The principal goals were to identify and validate targetable metabolic drivers relevant to myxofibrosarcoma pathogenesis using a published transcriptome.
As the most significantly downregulated gene ...regulating amino acid metabolism, argininosuccinate synthetase (ASS1) was selected for further analysis by methylation-specific PCR, pyrosequencing, and immunohistochemistry of myxofibrosarcoma samples. The roles of ASS1 in tumorigenesis and the therapeutic relevance of the arginine-depriving agent pegylated arginine deiminase (ADI-PEG20) were elucidated in ASS1-deficient myxofibrosarcoma cell lines and xenografts with and without stable ASS1 reexpression.
ASS1 promoter hypermethylation was detected in myxofibrosarcoma samples and cell lines and was strongly linked to ASS1 protein deficiency. The latter correlated with increased tumor grade and stage and independently predicted a worse survival. ASS1-deficient cell lines were auxotrophic for arginine and susceptible to ADI-PEG20 treatment, with dose-dependent reductions in cell viability and tumor growth attributable to cell-cycle arrest in the S-phase. ASS1 expression was restored in 2 of 3 ASS1-deficient myxofibrosarcoma cell lines by 5-aza-2'-deoxycytidine, abrogating the inhibitory effect of ADI-PEG20. Conditioned media following ASS1 reexpression attenuated HUVEC tube-forming capability, which was associated with suppression of MMP-9 and an antiangiogenic effect in corresponding myxofibrosarcoma xenografts. In addition to delayed wound closure and fewer invading cells in a Matrigel assay, ASS1 reexpression reduced tumor cell proliferation, induced G1-phase arrest, and downregulated cyclin E with corresponding growth inhibition in soft agar and xenograft assays.
Our findings highlight ASS1 as a novel tumor suppressor in myxofibrosarcomas, with loss of expression linked to promoter methylation, clinical aggressiveness, and sensitivity to ADI-PEG20.
Aggregation in polymer composites is one of the major obstacles in the carbon nanotubes (CNTs) applications. Authentic CNTs are known to have very good electrical conductivity and mechanical ...strengths. Surface functionalization can avoid aggregation and help dispersion of CNTs, but reduces CNT’s electrical conductivities and mechanical strengths dramatically. It needs a good way to resolve the above dilemma situation; i.e., poor dispersion–good conductivity vs. good dispersion–poor conductivity. Herein, we demonstrate that in-situ polymerized polyaniline (PANI)-coated CNTs have good polymer matrix compatibility, and are superior electrically conductive fillers to nylon 6 composites. In this report, multi-walled CNTs (MWCNTs) were surface-modified with poly(acrylic acids) (PAA), followed by further coating with PANI. The electrical conductivity of (PANI-MWCNTs)-nylon 6 composite thin film was increased from 10
−12 to 7.3 × 10
−5 S/cm in the presence of 1 wt% PANI-coated MWCNTs prepared by physical mixing of PANI and PAA-grafted MWCNTs. When in-situ polymerized PANI-coated MWCNTs were added, the electrical conductivity of MWCNTs-nylon 6 composite was further enhanced by 3 orders to be 3.4 × 10
−2 S/cm at the same 1 wt% loading of MWCNTs. Both Fourier-transformed infrared and uv–visible absorption spectra indicate that there exist very strong site-specific charge transfer interactions between the quinoid rings of PANI and MWCNTs, which results in the superior electrical conductivity of MWCNT-nylon 6 composite.
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Fibroblast growth factor 1 (FGF1) binds and activates FGF receptors, thereby regulating cell proliferation and neurogenesis. Human FGF1 gene 1B promoter (−540 to +31)-driven SV40 T antigen has been ...shown to result in tumorigenesis in the brains of transgenic mice. FGF1B promoter (−540 to +31)-driven green fluorescent protein (F1BGFP) has also been used in isolating neural stem cells (NSCs) with self-renewal and multipotency from developing and adult mouse brains. In this study, we provide six lines of evidence to demonstrate that FGF1/FGFR signaling is implicated in the expression of Aurora A (AurA) and the activation of its kinase domain (Thr288 phosphorylation) in the maintenance of glioblastoma (GBM) cells and NSCs. First, treatment of FGF1 increases AurA expression in human GBM cell lines. Second, using fluorescence-activated cell sorting, we observed that F1BGFP reporter facilitates the isolation of F1BGFP(+) GBM cells with higher expression levels of FGFR and AurA. Third, both FGFR inhibitor (SU5402) and AurA inhibitor (VX680) could down-regulate F1BGFP-dependent AurA activity. Fourth, inhibition of AurA activity by two different AurA inhibitors (VX680 and valproic acid) not only reduced neurosphere formation but also induced neuronal differentiation of F1BGFP(+) GBM cells. Fifth, flow cytometric analyses demonstrated that F1BGFP(+) GBM cells possessed different NSC cell surface markers. Finally, inhibition of AurA by VX680 reduced the neurosphere formation of different types of NSCs. Our results show that activation of AurA kinase through FGF1/FGFR signaling axis sustains the stem cell characteristics of GBM cells.
This study identified a novel mechanism for the malignancy of GBM, which could be a potential therapeutic target for GBM.
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•We report that FGF1 treatment can stimulate AurA kinase expression in human GBM cells.•FGF1/FGFR signaling is involved in the activation of AurA kinase.•FGF1 sustains the self-renewal of human GBM cells and embryonic stem cells via AurA activation.
Herein, mesoporous sodium vanadium phosphate nanoparticles with highly sp(2) -coordinated carbon coatings (meso-Na3 V2 (PO4 )3 /C) were successfully synthesized as efficient cathode material for ...rechargeable sodium-ion batteries by using ascorbic acid as both the reductant and carbon source, followed by calcination at 750 °C in an argon atmosphere. Their crystalline structure, morphology, surface area, chemical composition, carbon nature and amount were systematically explored. Following electrochemical measurements, the resultant meso-Na3 V2 (PO4 )3 /C not only delivered good reversible capacity (98 mAh g(-1) at 0.1 A g(-1) ) and superior rate capability (63 mAh g(-1) at 1 A g(-1) ) but also exhibited comparable cycling performance (capacity retention: ≈74 % at 450 cycles at 0.4 A g(-1) ). Moreover, the symmetrical sodium-ion full cell with excellent reversibility and cycling stability was also achieved (capacity retention: 92.2 % at 0.1 A g(-1) with 99.5 % coulombic efficiency after 100 cycles). These attributes are ascribed to the distinctive mesostructure for facile sodium-ion insertion/extraction and their continuous sp(2) -coordinated carbon coatings, which facilitate electronic conduction.
Neutrophils are the primary immune cells in innate immunity, which are related to various inflammatory diseases.
is a Chinese medicinal herb used to treat various oxidative stress-related ...inflammatory diseases. However, there are limited studies that elucidate the effects of
in human neutrophils. In this study, we used isolated human neutrophils activated by various stimulants to investigate the anti-inflammatory effects of
water extract (AWE). Cell-free assays were used to examine free radicals scavenging capabilities on superoxide anion, reactive oxygen species (ROS), and nitrogen-centered radicals. Imiquimod (IMQ) induced psoriasis-like skin inflammation mouse model was used for investigating anti-psoriatic effects. We found that AWE inhibited superoxide anion production, ROS generation, and elastase release in human neutrophils, which exhibiting a direct anti-neutrophil effect. Moreover, AWE exerted a ROS scavenging ability in the 2,2'-Azobis (2-amidinopropane) dihydrochloride assay, but not superoxide anion in the xanthine/xanthine oxidase assay, suggesting that AWE exhibited anti-oxidation and anti-inflammatory capabilities by both scavenging ROS and by directly inhibiting neutrophil activation. AWE also reduced CD11b expression and adhesion to endothelial cells in activated human neutrophils. Meanwhile, in mice with psoriasis-like skin inflammation, administration of topical AWE reduced both the affected area and the severity index score. It inhibited neutrophil infiltration, myeloperoxidase release, ROS-induced damage, and skin proliferation. In summary, AWE exhibited direct anti-inflammatory effects by inhibiting neutrophil activation and anti-psoriatic effects in mice with IMQ-induced psoriasis-like skin inflammation. Therefore, AWE could potentially be a pharmaceutical Chinese herbal medicine to inhibit neutrophilic inflammation for anti-psoriasis.
In recent years, multi-level cell flash memory (MLC) has been widely adopted in solid state drives (SSD's) as the major storage medium due to its lower cost and higher density, compared with ...single-level cell flash memory (SLC). However, MLC has reliability concerns since it has lower endurance and higher disturb failure rate. Researchers thus proposed SLC/MLC hybrid SSD to exploit the advantages of SLC and MLC by separating frequently updated data in SLC and seldom modified data in MLC. In this paper, we propose an adaptive error correction code (ECC) scheme with four ECC levels to enhance the reliability of SSD's. Different from past researches, SLC is dedicated for the management of ECC, not for the user data. Since ECC is maintained in the data area of SLC (2 KB), rather than the spare area of MLC (128 Bytes), ECC capability is no longer confined by the limited size of the spare area. With adaptive management, ECC capability for a page would be upgraded whenever the current ECC cannot guarantee its reliability. A quantitative analysis is conducted to explore the impacts of different settings. The experiment results show that the lifetime of SSD can be extended by 318 percent for the trace of OLTP applications with our adaptive ECC scheme.
KRAS mutant tumors are largely recalcitrant to targeted therapies. Genetically engineered mouse models (GEMMs) of Kras mutant cancer recapitulate critical aspects of this disease and are widely used ...for preclinical validation of targets and therapies. Through comprehensive profiling of exomes and matched transcriptomes of >200 KrasG12D-initiated GEMM tumors from one lung and two pancreatic cancer models, we discover that significant intratumoral and intertumoral genomic heterogeneity evolves during tumorigenesis. Known oncogenes and tumor suppressor genes, beyond those engineered, are mutated, amplified, and deleted. Unlike human tumors, the GEMM genomic landscapes are dominated by copy number alterations, while protein-altering mutations are rare. However, interspecies comparative analyses of the genomic landscapes demonstrate fidelity between genes altered in KRAS mutant human and murine tumors. Genes that are spontaneously altered during murine tumorigenesis are also among the most prevalent found in human indications. Using targeted therapies, we also demonstrate that this inherent tumor heterogeneity can be exploited preclinically to discover cancer-specific and genotype-specific therapeutic vulnerabilities. Focusing on Kras allelic imbalance, a feature shared by all three models, we discover that MAPK pathway inhibition impinges uniquely on this event, indicating distinct susceptibility and fitness advantage of Kras-mutant cells. These data reveal previously unknown genomic diversity among KrasG12D-initiated GEMM tumors, places them in context of human patients, and demonstrates how to exploit this inherent tumor heterogeneity to discover therapeutic vulnerabilities.
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