Mechanism of METTL14-mediated ERα m6A regulation of endometrial cancer metastasis

Background and purpose: Aberrant N6-methyladenosine (m6A) modification caused by dysregulation of methyltransferase-like factor 14 (METTL14) plays an important role in the progression of various cancers, and it is unclear whether it is involved in the endometrial cancer (EC) progression. This study aimed to investigate the role of aberrant m6A modification caused by dysregulation of METTL14 in EC invasion and metastasis. Methods: Ninety-six EC patients who underwent curative surgery in Qinghai Provincial People’s Hospital from 2017 to 2021 were enrolled. RNA (70 pairs) or proteins (10 pairs) were isolated from frozen tissues for real-time fluorescence quantitative polymerase chain reaction (RTFQ-PCR) or immunoblot analysis to assess METTL14 expression in EC. The expression of METTL14 and its correlation with clinicopathological features of EC were assessed. The biological effects of METTL14 in EC were determined in vitro and in vivo. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) combined with RNA sequencing (RNA-seq), and following m6A dot blot, MeRIP-RTFQ-PCR, RIP-RTFQ-PCR or dual luciferase reporter assays were employed to screen and validate the candidate targets of METTL14. Results: The mRNA expression and protein levels of METTL14 were significantly downregulated in EC compared with matched adjacent tissues. Compared with the METTL14 high expression group, the METTL14 low expression group had a significant increase in International Federation of Gynecology and Obstetrics (FIGO) stage, infiltration depth, lymphovascular invasion, lymph node metastasis and the number of cases of tumor metastasis (P<0.05). Functionally, METTL14 inhibited the proliferation and invasive capacity of EC cells in vitro and in vivo. Mechanistically, METTL14-mediated demethylation of m6A resulted in post-transcriptional repression of estrogen receptor alpha (ERα). Furthermore, compared with METTL14, ERα induced oncogenic behavior of tumors. Conclusion: METTL14 attenuates ERα expression in EC cells in a m6A-dependent manner, thereby inhibiting tumor metastasis and invasion

Characterization of Shiga toxin-producing Escherichia coli isolated from healthy pigs in China

BACKGROUND: Shiga toxin-producing Escherichia coli (STEC) is recognized as an important human diarrheal pathogen. Swine plays an important role as a carrier of this pathogen. In this study we determined the prevalence and characteristics of STEC from healthy swine collected between May 2011 and August 2012 from 3 cities/provinces in China. RESULTS: A total of 1003 samples, including 326 fecal, 351 small intestinal contents and 326 colon contents samples, was analyzed. Two hundred and fifty five samples were stx-positive by PCR and 93 STEC isolates were recovered from 62 stx-positive samples. Twelve O serogroups and 19 O:H serotypes including 6 serotypes (O100:H20/[H20], O143:H38/[H38], O87:H10, O172:H30/[H30], O159:H16, O9:H30/[H30]) rarely found in swine and ruminants were identified. All 93 STEC isolates harbored stx(2) only, all of which were stx(2e) subtype including 1 isolate being a new variant of stx(2e). 53.76%, 15.05% and 2.15% STEC isolates carried astA, hlyA and ehxA respectively. Four STEC isolates harbored the high-pathogenicity island. Of the 15 adherence-associated genes tested, 13 (eae, efa1, iha, lpfA(O113), lpfA(O157/OI-154), lpfA(O157/OI-141), toxB, saa, F4, F5, F6, F17 or F41) were all absent while 2 (paa and F18) were present in 7 and 4 STEC isolates respectively. The majority of the isolates were resistant to tetracycline (79.57%), nalidixic acid (78.49%), trimethoprim-sulfamethoxazole (73.12%) and kanamycin (55.91%). The STEC isolates were divided into 63 pulsed-field gel electrophoresis patterns and 21 sequence types (STs). Isolates of the same STs generally showed the same or similar drug resistance patterns. A higher proportion of STEC isolates from Chongqing showed multidrug resistance with one ST (ST3628) resistant to 14 antimicrobials. CONCLUSIONS: Our results indicate that swine is a significant reservoir of STEC strains in China. Based on comparison by serotypes and sequence types with human strains and presence of virulence genes, the swine STEC may have a low potential to cause human disease

Detection of the Diffuse Supernova Neutrino Background with JUNO

As an underground multi-purpose neutrino detector with 20 kton liquid scintillator, Jiangmen Underground Neutrino Observatory (JUNO) is competitive with and complementary to the water-Cherenkov detectors on the search for the diffuse supernova neutrino background (DSNB). Typical supernova models predict 2-4 events per year within the optimal observation window in the JUNO detector. The dominant background is from the neutral-current (NC) interaction of atmospheric neutrinos with 12C nuclei, which surpasses the DSNB by more than one order of magnitude. We evaluated the systematic uncertainty of NC background from the spread of a variety of data-driven models and further developed a method to determine NC background within 15\% with {\it{in}} {\it{situ}} measurements after ten years of running. Besides, the NC-like backgrounds can be effectively suppressed by the intrinsic pulse-shape discrimination (PSD) capabilities of liquid scintillators. In this talk, I will present in detail the improvements on NC background uncertainty evaluation, PSD discriminator development, and finally, the potential of DSNB sensitivity in JUNO

Real-time Monitoring for the Next Core-Collapse Supernova in JUNO

Core-collapse supernova (CCSN) is one of the most energetic astrophysical events in the Universe. The early and prompt detection of neutrinos before (pre-SN) and during the SN burst is a unique opportunity to realize the multi-messenger observation of the CCSN events. In this work, we describe the monitoring concept and present the sensitivity of the system to the pre-SN and SN neutrinos at the Jiangmen Underground Neutrino Observatory (JUNO), which is a 20 kton liquid scintillator detector under construction in South China. The real-time monitoring system is designed with both the prompt monitors on the electronic board and online monitors at the data acquisition stage, in order to ensure both the alert speed and alert coverage of progenitor stars. By assuming a false alert rate of 1 per year, this monitoring system can be sensitive to the pre-SN neutrinos up to the distance of about 1.6 (0.9) kpc and SN neutrinos up to about 370 (360) kpc for a progenitor mass of 30$M_{\odot}$ for the case of normal (inverted) mass ordering. The pointing ability of the CCSN is evaluated by using the accumulated event anisotropy of the inverse beta decay interactions from pre-SN or SN neutrinos, which, along with the early alert, can play important roles for the followup multi-messenger observations of the next Galactic or nearby extragalactic CCSN.Comment: 24 pages, 9 figure

Potential of Core-Collapse Supernova Neutrino Detection at JUNO

JUNO is an underground neutrino observatory under construction in Jiangmen, China. It uses 20kton liquid scintillator as target, which enables it to detect supernova burst neutrinos of a large statistics for the next galactic core-collapse supernova (CCSN) and also pre-supernova neutrinos from the nearby CCSN progenitors. All flavors of supernova burst neutrinos can be detected by JUNO via several interaction channels, including inverse beta decay, elastic scattering on electron and proton, interactions on C12 nuclei, etc. This retains the possibility for JUNO to reconstruct the energy spectra of supernova burst neutrinos of all flavors. The real time monitoring systems based on FPGA and DAQ are under development in JUNO, which allow prompt alert and trigger-less data acquisition of CCSN events. The alert performances of both monitoring systems have been thoroughly studied using simulations. Moreover, once a CCSN is tagged, the system can give fast characterizations, such as directionality and light curve

Protective Effects of p38 MAPK Inhibitor SB202190 against Hippocampal Apoptosis and Spatial Learning and Memory Deficits in a Rat Model of Vascular Dementia

Vascular dementia (VaD) is a common age-related neurodegenerative disease resulting from chronic hypoxia. In the present study, we examined the protective effects of p38 MAPK inhibitor SB202190 against hippocampal apoptosis and spatial learning and memory deficits in a chronic hypoperfusion rat model of VaD established by permanent bilateral carotid occlusion (2-VO). Sixty rats were randomly divided into sham-operated, VaD model, and VaD plus SB202190 groups (n=20/group). After sham/2-VO surgery, rats were administered 0.1% DMSO (sham-operated and VaD groups) or SB202190 by intracerebroventricular injection. One week after inhibitor/vehicle treatment, hippocampal p38 MAPK phosphorylation was higher in the model group than in the SB202190 group (P<0.01). Compared to the model group, the SB202190 group exhibited significantly shorter escape latencies in the Morris water maze hidden platform trials (P<0.01) and longer times in the original platform quadrant during probe trials (P<0.01). The SB202190 group also showed significantly reduced neuronal apoptosis in the hippocampus compared to VaD model rats (P<0.01) as well as higher (antiapoptotic) Bcl-2 expression and lower (proapoptotic) caspase-3 expression (P<0.01 for both). In conclusion, blockade of the p38 MAPK signaling pathway by SB202190 following permanent 2-OV reduced apoptosis of hippocampal neurons and rescued spatial learning and memory deficits

Immunological evaluation of <it>Lactobacillus casei </it>Zhang: a newly isolated strain from koumiss in Inner Mongolia, China

<p>Abstract</p> <p>Background</p> <p>There is increasing evidence to suggest an immunomodulation function both within the intestines and systemically upon consuming probiotic species. We recently isolated a novel LAB, <it>Lactobacillus casei</it>Zhang (LcZhang) from koumiss. LcZhang exhibited favorable probiotic properties, such as acid resistance, bile resistance, gastrointestinal (GI) colonization ability, etc. In order to examine the immunomodulatory qualities of LcZhang, we administered LcZhang to healthy mice with varying doses of either live or heat-killed LcZhang and measured various parameters of the host immune response.</p> <p>Results</p> <p>The study was performed in four separate experiments via oral administration of live and heat-killed LcZhang to BALB/c mice for several consecutive days. We investigated the immunomodulating capacity of LcZhang <it>in vivo </it>by analyzing the profile of cytokines, T cell subpopulations, and immunoglobulin concentrations induced in blood serum and intestinal fluid in BALB/c mice. Only live bacteria elicited a wide range of immune responses, which include the increased production of interferon-γ (IFN-γ), and depression of tumor necrosis factor-α (TNF-α) levels. In addition, interleukin-2 (IL-2) and IL-2 receptor gene transcription increased significantly, but the proportion of T cell subsets appeared to be unaffected. We also observed that LcZhang was capable of inducing gut mucosal responses by enhancing the production of secretory Immunoglobulin A (sIgA) as well influencing the systemic immunity via the cytokines released to the circulating blood.</p> <p>Conclusion</p> <p>The present work shows that the dose-dependent administration of LcZhang is capable of influencing immune responses, implying that it may be a valuable strain for probiotic use in humans.</p