The heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), telomeric repeat-containing RNA (TERRA), and protection of telomeres 1 (POT1) have been reported to orchestrate to displace replication ...protein A (RPA) from telomeric overhangs, ensuring orderly telomere replication and capping. Our previous studies further demonstrated that DNA-dependent protein kinase catalytic subunit (DNA-PKcs)-dependent hnRNPA1 phosphorylation plays a crucial role in the promotion of hnRNPA1 binding to telomeric overhangs and RPA displacement during G2-M phases. However, it is unclear that how the subsequent exchange between hnRNPA1 and POT1 is orchestrated. Here we report that the protein phosphatase 2A (PP2A) depends on its scaffold subunit, which is called PPP2R1A, to interact with and dephosphorylate hnRNPA1 in the late M phase. Furthermore, PP2A-mediated hnRNPA1 dephosphorylation and TERRA accumulation act in concert to promote the hnRNPA1-to-POT1 switch on telomeric single-stranded DNA. Consequently, defective PPP2R1A results in ataxia telangiectasia and Rad3-related (ATR)-mediated DNA damage response at telomeres as well as induction of fragile telomeres. Combined inhibition of ATR and PP2A induces entry into a catastrophic mitosis and leads to synthetic lethality of tumor cells. In addition, PPP2R1A levels correlate with clinical stages and prognosis of multiple types of cancers. Taken together, our results indicate that PP2A is critical for telomere maintenance.
This study demonstrates that the PP2A-dependent hnRNPA1 dephosphorylation and TERRA accumulation facilitates the formation of the protective capping structure of newly replicated telomeres, thus exerting essential oncogenic role in tumorigenesis.
Interferon regulatory factors (IRFs) are a family of mediators in various biological processes including immune modulation of interferon (IFN) and proinflammatory cytokine expression. However, the ...data on the complete composition of IRFs is rather limited in teleost fish. In the present study, all IRF members, i.e. IRF1‒11 with two IRF4, IRF4a and IRF4b have been characterised in an aquaculture species of fish, the mandarin fish, Siniperca chuatsi, in addition to the previous report of IRF1, IRF2, IRF3 and IRF7 from the fish. These IRFs are constitutively expressed in various organs/tissues of the fish, and their expression can be induced following the stimulation of polyinosinic:polycytidylic acid (poly(I:C)) and the infection of infectious spleen and kidney necrosis virus (ISKNV), a viral pathogen of mandarin fish in aquaculture. The ISKNV infection induced the significant increase in the expression of some IRF genes, i.e. IRF2, IRF4a, IRF7, IRF9, IRF10 at 24 or 36 h post-infection (hpi) in spleen and head-kidney, and the significant increase of some other IRF genes, e.g. IRF1, IRF3, IRF4b, IRF5, IRF6, IRF8 at later stage of infection from 72, or 96, or even 120 hpi, which may imply the inhibitory effect of ISKNV on fish immune response. It is considered that the present study provides the first detailed analysis on all IRF members in an aquaculture species of fish, and can be served as the base for further investigation on the role of IRFs in teleost fish.
•IRF1‒11 with two IRF4 have been identified in the mandarin fish Siniperca chuatsi.•All IRF genes are constitutively expressed in various organs/tissues examined.•All IRF genes are significantly induced at mRNA level following poly(I:C) stimulation.•IRF1‒11 genes can be induced following the infectious spleen and kidney necrosis virus (ISKNV) infection.•Some IRF genes have an early response, while others have a delayed response to the viral infection.
This study aimed to determine the in vitro susceptibility of commonly encountered Gram-negative bacilli (GNB) recovered from patients admitted to intensive care units (ICUs) in Taiwan against ...colistin, carbapenems, and other comparative agents.
In total, 758 nonduplicate GNB isolates were obtained from clinical specimens of ICU patients at seven medical centers in 2016. Minimum inhibitory concentrations (MICs) were determined using the Vitek 2 susceptibility system. The reference broth-microdilution method was performed to determine MICs of colistin. Five main carbapenemase genes among carbapenem-non-susceptible GNB and
-
genes among colistin non-wild-type or -resistant isolates were determined.
After exclusion 38
and 13
spp. among 361 Enterobacteriaceae isolates, 34 (9.4%) isolates were carbapenem-insusceptible, 91.1% (n=31) were colistin wild type, and three and one
isolates carried
and
-like, respectively. Carbapenem-insusceptible isolates were found in 23.4% (30 of 128) and 63.0% (87 of 138) of isolates of the
and
complex, respectively.
was detected in two (1.8%)
isolates. Very major errors between two methods of susceptibility to colistin were found in 1.5% of
, 27.5% of
, 4.7% of
, and 10.1% of
complex isolates.
In this study, 8.7% of Enterobacteriaceae isolates from ICUs were not susceptible to carbapenem, and
and
-like were found among three and one carbapenem-insusceptible
isolates, respectively. Colistin MICs determined by Vitek 2 were not reliable, especially for
and
complex isolates.
Many nonmotor symptoms (e.g., hyposmia) appear years before the cardinal motor features of Parkinson's disease (PD). It is thus desirable to be able to use noninvasive brain imaging methods, such as ...magnetic resonance imaging (MRI), to detect brain abnormalities in early PD stages. Among the MRI modalities, diffusion-tensor imaging (DTI) is suitable for detecting changes in brain tissue structure due to neurological diseases. The main purpose of this study was to investigate whether DTI signals measured from brain regions involved in early stages of PD differ from those of healthy controls. To answer this question, we analyzed whole-brain DTI data of 30 early-stage PD patients and 30 controls using improved region of interest-based analysis methods. Results showed that (i) the fractional anisotropy (FA) values in the olfactory tract (connected with the olfactory bulb: one of the first structures affected by PD) are lower in PD patients than healthy controls; (ii) FA values are higher in PD patients than healthy controls in the following brain regions: corticospinal tract, cingulum (near hippocampus), and superior longitudinal fasciculus (temporal part). Experimental results suggest that the tissue property, measured by FA, in olfactory regions is structurally modulated by PD with a mechanism that is different from other brain regions.
Purpose: RON and MET belong to a subfamily of tyrosine kinase receptors. They both can induce invasive growth, including migration,
cell dissociation, and matrix invasion. Cross-linking experiments ...show that RON and MET form a noncovalent complex on the
cell surface and cooperate in intracellular signaling. We wanted to examine the clinical significance of RON and MET expression
patterns in node-negative breast cancer.
Experimental Design: We studied the protein expressions of RON and MET in five breast cancer cell lines and a homogeneous cohort of 103 T 1-2 N 0 M 0 breast carcinoma patients, including 52 patients with distant metastases and 51 patients with no evidence of disease after
at least a 10-year follow-up.
Results: Both HCC1937 and MDA-MB-231 cancer cell lines co-overexpressed RON and MET. The MCF-7 cell line did not express RON or MET.
In multiple logistic regression analysis, RON expression (odds ratio, 2.6; P = 0.05) and MET expression (odds ratio, 4.7; P = 0.009) were independent predictors of distant relapse. RON+/MET+ and RON−/MET+ tumors resulted in a large risk increase
for 10-year disease-free survival after adjusting for tumor size, histologic grade, estrogen receptor, bcl-2, HER-2/neu, and
p53 status by multivariate Cox analysis (risk ratio, 5.3; P = 0.001 and risk ratio, 3.76; P = 0.005). The 10-year disease-free survival was 79.3% in patients with RON−/MET− tumors, was only 11.8% in patients with
RON+/MET+ tumors, and was 43.9% and 55.6% in patients with RON−/MET+ and RON+/MET− tumors.
Conclusions: Co-expression of RON and MET seems to signify an aggressive phenotype in node-negative breast cancer patients.
Major advances in resting-state functional magnetic resonance imaging (fMRI) techniques in the last two decades have provided a tool to better understand the functional organization of the brain both ...in health and illness. Despite such developments, characterizing regulation and cerebral representation of mind wandering, which occurs unavoidably during resting-state fMRI scans and may induce variability of the acquired data, remains a work in progress. Here, we demonstrate that a decrease or decoupling in functional connectivity involving the caudate nucleus, insula, medial prefrontal cortex and other domain-specific regions was associated with more sustained mind wandering in particular thought domains during resting-state fMRI. Importantly, our findings suggest that temporal and between-subject variations in functional connectivity of above-mentioned regions might be linked with the continuity of mind wandering. Our study not only provides a preliminary framework for characterizing the maintenance and cerebral representation of different types of mind wandering, but also highlights the importance of taking mind wandering into consideration when studying brain organization with resting-state fMRI in the future.
Hemorrhagic fever with renal syndrome (HFRS) is a zoonotic disease caused by the rodent-transmitted orthohantaviruses (HVs), with China possessing the most cases globally. The virus hosts in China ...are
and
, and the disease spread is strongly influenced by global climate dynamics. To assess and predict the spatiotemporal trends of HFRS from 2005 to 2098, we collected historical HFRS data in mainland China (2005-2020), historical and projected climate and population data (2005-2098), and spatial variables including biotic, environmental, topographical, and socioeconomic. Spatiotemporal predictions and mapping were conducted under 27 scenarios incorporating multiple integrated representative concentration pathway models and population scenarios. We identify the type of magistral HVs host species as the best spatial division, including four region categories. Seven extreme climate indices associated with temperature and precipitation have been pinpointed as key factors affecting the trends of HFRS. Our predictions indicate that annual HFRS cases will increase significantly in 62 of 356 cities in mainland China.
regions are predicted to be the most active, surpassing
and Mixed regions. Eighty cities are identified as at severe risk level for HFRS, each with over 50 reported cases annually, including 22 new cities primarily located in East China and
regions after 2020, while 6 others develop new risk. Our results suggest that the risk of HFRS will remain high through the end of this century, with
being the most active host, and that extreme climate indices are significant risk factors. Our findings can inform evidence-based policymaking regarding future risk of HFRS.
With semiconductor technology gradually approaching its physical and thermal limits, recent supercomputers have adopted major architectural changes to continue increasing the performance through more ...power-efficient heterogeneous many-core systems. Examples include Sunway TaihuLight that has four management processing elements (MPEs) and 256 computing processing elements (CPEs) inside one processor and Summit that has two central processing units (CPUs) and six graphics processing units (GPUs) inside one node. Meanwhile, current high-resolution Earth system models that desperately require more computing power generally consist of millions of lines of legacy code developed for traditional homogeneous multicore processors and cannot automatically benefit from the advancement of supercomputer hardware. As a result, refactoring and optimizing the legacy models for new architectures become key challenges along the road of taking advantage of greener and faster supercomputers, providing better support for the global climate research community and contributing to the long-lasting societal task of addressing long-term climate change. This article reports the efforts of a large group in the International Laboratory for High-Resolution Earth System Prediction (iHESP) that was established by the cooperation of Qingdao Pilot National Laboratory for Marine Science and Technology (QNLM), Texas A&M University (TAMU), and the National Center for Atmospheric Research (NCAR), with the goal of enabling highly efficient simulations of the high-resolution (25 km atmosphere and 10 km ocean) Community Earth System Model (CESM-HR) on Sunway TaihuLight. The refactoring and optimizing efforts have improved the simulation speed of CESM-HR from 1 SYPD (simulation years per day) to 3.4 SYPD (with output disabled) and supported several hundred years of pre-industrial control simulations. With further strategies on deeper refactoring and optimizing for remaining computing hotspots, as well as redesigning architecture-oriented algorithms, we expect an equivalent or even better efficiency to be gained on the new platform than traditional homogeneous CPU platforms. The refactoring and optimizing processes detailed in this paper on the Sunway system should have implications for similar efforts on other heterogeneous many-core systems such as GPU-based high-performance computing (HPC) systems.
Dengue virus outbreaks are increasing in number and severity worldwide. Viral transmission is assumed to require a minimum time period of viral replication within the mosquito midgut. It is unknown ...if alternative transmission periods not requiring replication are possible.
We used a mouse model of dengue virus transmission to investigate the potential of mechanical transmission of dengue virus. We investigated minimal viral titres necessary for development of symptoms in bitten mice and used resulting parameters to inform a new model of dengue virus transmission within a susceptible population.
Naïve mice bitten by mosquitoes immediately after they took partial blood meals from dengue infected mice showed symptoms of dengue virus, followed by mortality. Incorporation of mechanical transmission into mathematical models of dengue virus transmission suggest that this supplemental transmission route could result in larger outbreaks which peak sooner.
The potential of dengue transmission routes independent of midgut viral replication has implications for vector control strategies that target mosquito lifespan and suggest the possibility of similar mechanical transmission routes in other disease-carrying mosquitoes.
This study was funded by grants from the National Health Research Institutes, Taiwan (04D2-MMMOST02), the Human Frontier Science Program (RGP0033/2021), the National Institutes of Health (1R01AI143698-01A1, R01AI151004 and DP2AI152071) and the Ministry of Science and Technology, Taiwan (MOST104-2321-B-400-016).
•TRPC6 inhibition attenuated morphine withdrawal-induced hyperalgesia.•TRPC6 inhibition suppressed morphine tolerance.•TRPC6 inhibition suppressed morphine-induced increased levels of CaMKIIα and ...nNOS.•TRPC6 inhibition blocked morphine-induced neuroinflammation.
The chronic administration of opioids results in the development of morphine analgesic tolerance and withdrawl-induced hyperalgesia, which limits their clinical utility in pain treatment. However, the cellular mechanisms underlying opioid-induced tolerance and hyperalgesia are not fully understood. The transient receptor potential canonical channel TRPC6 is important for brain development and function, as it regulates cytosolic, endoplasmic reticulum, and mitochondrial Ca2+ levels in neural cells. Here, we report that TRPC6 expression in the spinal cord was up-regulated after chronic morphine treatment. Furthermore, inhibition of TRPC6 in the spinal cord blocked the induction of morphine tolerance and hyperalgesia without affecting basal pain perception. These effects were attributed to the attenuation of morphine-induced neuroimmune activation and increased levels of CaMKIIα and nNOS in the spinal cord. This data suggests that specific TRPC6 inhibitors could be utilized for the prevention of morphine-induced antinociceptive tolerance and hyperalgesia in chronic pain management.
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