Abstract
Background
Inactivation of the tumor suppressor p53 is critical for pathogenesis of glioma, in particular glioblastoma multiforme (GBM). MDM2, the main negative regulator of p53, binds to ...and forms a stable complex with p53 to regulate its activity. Hitherto, it is unclear whether the stability of the p53/MDM2 complex is affected by lncRNAs, in particular circular RNAs that are usually abundant and conserved, and frequently implicated in different oncogenic processes.
Methods
RIP-seq and RIP-qPCR assays were performed to determine the most enriched lncRNAs (including circular RNAs) bound by p53, followed by bioinformatic assays to estimate the relevance of their expression with p53 signaling and gliomagenesis. Subsequently, the clinical significance of
CDR1as
was evaluated in the largest cohort of Chinese glioma patients from CGGA (
n
= 325), and its expression in human glioma tissues was further evaluated by RNA FISH and RT-qPCR, respectively. Assays combining RNA FISH with protein immunofluorescence were performed to determine co-localization of
CDR1as
and p53, followed by CHIRP assays to confirm RNA-protein interaction. Immunoblot assays were carried out to evaluate protein expression, p53/MDM2 interaction and p53 ubiquitination in cells in which
CDR1as
expression was manipulated. After
AGO2
or
Dicer
was knocked-down to inhibit miRNA biogenesis, effects of
CDR1as
on p53 expression, stability and activity were determined by immunoblot, RT-qPCR and luciferase reporter assays. Meanwhile, impacts of
CDR1as
on DNA damage were evaluated by flow cytometric assays and immunohistochemistry. Tumorigenicity assays were performed to determine the effects of
CDR1as
on colony formation, cell proliferation, the cell cycle and apoptosis (in vitro), and on tumor volume/weight and survival of nude mice xenografted with GBM cells (in vivo).
Results
CDR1as
is found to bind to p53 protein.
CDR1as
expression decreases with increasing glioma grade and it is a reliable independent predictor of overall survival in glioma, particularly in GBM. Through a mechanism independent of acting as a miRNA sponge,
CDR1as
stabilizes p53 protein by preventing it from ubiquitination.
CDR1as
directly interacts with the p53 DBD domain that is essential for MDM2 binding, thus disrupting the p53/MDM2 complex formation. Induced upon DNA damage,
CDR1as
may preserve p53 function and protect cells from DNA damage. Significantly,
CDR1as
inhibits tumor growth in vitro and in vivo, but has little impact in cells where p53 is absent or mutated.
Conclusions
Rather than acting as a miRNA sponge,
CDR1as
functions as a tumor suppressor through binding directly to p53 at its DBD region to restrict MDM2 interaction. Thus,
CDR1as
binding disrupts the p53/MDM2 complex to prevent p53 from ubiquitination and degradation.
CDR1as
may also sense DNA damage signals and form a protective complex with p53 to preserve p53 function. Therefore,
CDR1as
depletion may play a potent role in promoting tumorigenesis through down-regulating p53 expression in glioma. Our results broaden further our understanding of the roles and mechanism of action of circular RNAs in general and
CDR1as
in particular, and can potentially open up novel therapeutic avenues for effective glioma treatment.
We report the first genome-wide association study in 1000 bipolar I patients and 1000 controls, with a replication of the top hits in another 409 cases and 1000 controls in the Han Chinese ...population. Four regions with most strongly associated single-nucleotide polymorphisms (SNPs) were detected, of which three were not found in previous GWA studies in the Caucasian populations. Among them, SNPs close to specificity protein 8 (SP8) and ST8 α-N-acetyl- neuraminide α-2,8-sialyltransferase (ST8SIA2) are associated with Bipolar I, with P-values of 4.87 × 10(-7) (rs2709736) and 6.05 × 10(-6) (rs8040009), respectively. We have also identified SNPs in potassium channel tetramerization domain containing 12 gene (KCTD12) (rs2073831, P=9.74 × 10(-6)) and in CACNB2 (Calcium channel, voltage-dependent, β-2 subunit) gene (rs11013860, P=5.15 × 10(-5)), One SNP nearby the rs1938526 SNP of ANK3 gene and another SNP nearby the SNP rs11720452 in chromosome 3 reported in previous GWA studies also showed suggestive association in this study (P=6.55 × 10(-5) and P=1.48 × 10(-5), respectively). This may suggest that there are common and population-specific susceptibility genes for bipolar I disorder.
To describe the infection control preparedness measures undertaken for coronavirus disease (COVID-19) due to SARS-CoV-2 (previously known as 2019 novel coronavirus) in the first 42 days after ...announcement of a cluster of pneumonia in China, on December 31, 2019 (day 1) in Hong Kong.
A bundled approach of active and enhanced laboratory surveillance, early airborne infection isolation, rapid molecular diagnostic testing, and contact tracing for healthcare workers (HCWs) with unprotected exposure in the hospitals was implemented. Epidemiological characteristics of confirmed cases, environmental samples, and air samples were collected and analyzed.
From day 1 to day 42, 42 of 1,275 patients (3.3%) fulfilling active (n = 29) and enhanced laboratory surveillance (n = 13) were confirmed to have the SARS-CoV-2 infection. The number of locally acquired case significantly increased from 1 of 13 confirmed cases (7.7%, day 22 to day 32) to 27 of 29 confirmed cases (93.1%, day 33 to day 42; P < .001). Among them, 28 patients (66.6%) came from 8 family clusters. Of 413 HCWs caring for these confirmed cases, 11 (2.7%) had unprotected exposure requiring quarantine for 14 days. None of these was infected, and nosocomial transmission of SARS-CoV-2 was not observed. Environmental surveillance was performed in the room of a patient with viral load of 3.3 × 106 copies/mL (pooled nasopharyngeal and throat swabs) and 5.9 × 106 copies/mL (saliva), respectively. SARS-CoV-2 was identified in 1 of 13 environmental samples (7.7%) but not in 8 air samples collected at a distance of 10 cm from the patient's chin with or without wearing a surgical mask.
Appropriate hospital infection control measures was able to prevent nosocomial transmission of SARS-CoV-2.
The nodal-line semimetals have attracted immense interest due to the unique electronic structures such as the linear dispersion and the vanishing density of states as the Fermi energy approaching the ...nodes. Here, we report temperature-dependent transport and scanning tunneling microscopy (spectroscopy) STM(S) measurements on nodal-line semimetal ZrSiSe. Our experimental results and theoretical analyses consistently demonstrate that the temperature induces Lifshitz transitions at 80 and 106 K in ZrSiSe, which results in the transport anomalies at the same temperatures. More strikingly, we observe a V-shaped dip structure around Fermi energy from the STS spectrum at low temperature, which can be attributed to co-effect of the spin-orbit coupling and excitonic instability. Our observations indicate the correlation interaction may play an important role in ZrSiSe, which owns the quasi-two-dimensional electronic structures.
Nematic order is the breaking of rotational symmetry in the presence of translational invariance. While originally defined in the context of liquid crystals, the concept of nematic order has arisen ...in crystalline matter with discrete rotational symmetry, most prominently in the tetragonal Fe-based superconductors where the parent state is four-fold symmetric. In this case the nematic director takes on only two directions, and the order parameter in such ‘Ising-nematic’ systems is a simple scalar. Here, using a spatially resolved optical polarimetry technique, we show that a qualitatively distinct nematic state arises in the triangular lattice antiferromagnet Fe1/3NbS2. The crucial difference is that the nematic order on the triangular lattice is a Z3 or three-state Potts-nematic order parameter. As a consequence, the anisotropy axes of response functions such as the resistivity tensor can be continuously reoriented by external perturbations. This discovery lays the groundwork for devices that exploit analogies with nematic liquid crystals.A spatially resolved optical polarimetry technique is used to identify a three-state Potts-nematic order parameter in a triangular lattice antiferromagnetic material.
Electronic structures of graphene oxide (GO) and hydro-thermally reduced graphene oxides (rGOs) processed at low temperatures (120-180°C) were studied using X-ray absorption near-edge structure ...(XANES), X-ray emission spectroscopy (XES) and resonant inelastic X-ray scattering (RIXS). C K-edge XANES spectra of rGOs reveal that thermal reduction restores C = C sp(2) bonds and removes some of the oxygen and hydroxyl groups of GO, which initiates the evolution of carbonaceous species. The combination of C K-edge XANES and Kα XES spectra shows that the overlapping π and π* orbitals in rGOs and GO are similar to that of highly ordered pyrolytic graphite (HOPG), which has no band-gap. C Kα RIXS spectra provide evidence that thermal reduction changes the density of states (DOSs) that is generated in the π-region and/or in the gap between the π and π* levels of the GO and rGOs. Two-dimensional C Kα RIXS mapping of the heavy reduction of rGOs further confirms that the residual oxygen and/or oxygen-containing functional groups modify the π and σ features, which are dispersed by the photon excitation energy. The dispersion behavior near the K point is approximately linear and differs from the parabolic-like dispersion observed in HOPG.
This study examined the prevalence of major depressive disorder (MDD), and the correlations and co-morbid conditions associated with MDD, in the adult Taiwanese population, which a previous estimate ...in the 1980s had found to be at the lower end of the spectrum worldwide. Possible explanations for the reported low prevalence of MDD were evaluated.
As part of a survey of common psychiatric disorders in a nationally representative sample of individuals aged ≥ 18 years who were non-institutionalized civilians in Taiwan, a face-to-face interview using the paper version of the World Mental Health Survey of the World Health Organization (WHO) Composite International Diagnostic Interview (WMH-CIDI) was conducted between 2003 and 2005. Functional impairment and help-seeking behaviors were compared between Taiwanese subjects with MDD and their counterparts in the USA.
Among the 10 135 respondents, the lifetime prevalence of MDD was 1.20% standard error (S.E.)=0.2%. Individuals who were divorced or widowed, aged ≤ 40 years, and female were at increased risk, whereas rural residents were at lower risk for MDD. The proportion of MDD cases co-morbid with other psychiatric disorders in this study was much lower than in the US study. Only one-third of Taiwanese individuals with MDD sought help despite having twice the number of lost workdays compared with the US sample.
Despite the low prevalence of MDD in Taiwanese adults, the pattern of low help-seeking behavior and profound functional impairment indicates much room for improvement in the early detection of and intervention in major depression in this population.
Quantum heat engines are expected to outperform the classical counterparts due to quantum coherences involved. Here we experimentally execute a single-ion quantum heat engine and demonstrate, for the ...first time, the dynamics and the enhanced performance of the heat engine originating from the Liouvillian exceptional points (LEPs). In addition to the topological effects related to LEPs, we focus on thermodynamic effects, which can be understood by the Landau-Zener-Stückelberg process under decoherence. We witness a positive net work from the quantum heat engine if the heat engine cycle dynamically encircles a LEP. Further investigation reveals that a larger net work is done when the system is operated closer to the LEP. We attribute the enhanced performance of the quantum heat engine to the Landau-Zener-Stückelberg process, enabled by the eigenenergy landscape in the vicinity of the LEP, and the exceptional point-induced topological transition. Therefore, our results open new possibilities toward LEP-enabled control of quantum heat engines and of thermodynamic processes in open quantum systems.
Chemotherapy and radiation not only trigger cancer cell apoptosis but also damage stromal cells in the tumour microenvironment (TME), inducing a senescence-associated secretory phenotype (SASP) ...characterized by chronic secretion of diverse soluble factors. Here we report serine protease inhibitor Kazal type I (SPINK1), a SASP factor produced in human stromal cells after genotoxic treatment. DNA damage causes SPINK1 expression by engaging NF-κB and C/EBP, while paracrine SPINK1 promotes cancer cell aggressiveness particularly chemoresistance. Strikingly, SPINK1 reprograms the expression profile of cancer cells, causing prominent epithelial-endothelial transition (EET), a phenotypic switch mediated by EGFR signaling but hitherto rarely reported for a SASP factor. In vivo, SPINK1 is expressed in the stroma of solid tumours and is routinely detectable in peripheral blood of cancer patients after chemotherapy. Our study substantiates SPINK1 as both a targetable SASP factor and a novel noninvasive biomarker of therapeutically damaged TME for disease control and clinical surveillance.