Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers worldwide and the fourth most lethal cancer in China. However, although genomic studies have identified some mutations ...associated with ESCC, we know little of the mutational processes responsible. To identify genome-wide mutational signatures, we performed either whole-genome sequencing (WGS) or whole-exome sequencing (WES) on 104 ESCC individuals and combined our data with those of 88 previously reported samples. An APOBEC-mediated mutational signature in 47% of 192 tumors suggests that APOBEC-catalyzed deamination provides a source of DNA damage in ESCC. Moreover, PIK3CA hotspot mutations (c.1624G>A p.Glu542Lys and c.1633G>A p.Glu545Lys) were enriched in APOBEC-signature tumors, and no smoking-associated signature was observed in ESCC. In the samples analyzed by WGS, we identified focal (<100 kb) amplifications of CBX4 and CBX8. In our combined cohort, we identified frequent inactivating mutations in AJUBA, ZNF750, and PTCH1 and the chromatin-remodeling genes CREBBP and BAP1, in addition to known mutations. Functional analyses suggest roles for several genes (CBX4, CBX8, AJUBA, and ZNF750) in ESCC. Notably, high activity of hedgehog signaling and the PI3K pathway in approximately 60% of 104 ESCC tumors indicates that therapies targeting these pathways might be particularly promising strategies for ESCC. Collectively, our data provide comprehensive insights into the mutational signatures of ESCC and identify markers for early diagnosis and potential therapeutic targets.
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•Diaryl-substituted thiosemicarbazones effective inhibit NDM-1.•1c restored antibacterial effect of meropenem on bacteriaharboring NDM-1.•The inhibitor cooperated with meropenem to ...kill clinically resistant E .coli in vivo.
The superbug infection caused by New Delhi metallo-β-lactamase (NDM-1) has become an emerging public health threat. Inhibition of NDM-1 has proven challenging due to its shuttling between pathogenic bacteria. A potent scaffold, diaryl-substituted thiosemicarbazone, was constructed and assayed with metallo-β-lactamases (MβLs). The obtained twenty-six molecules specifically inhibited NDM-1 with IC50 0.038–34.7 µM range (except 1e, 2e, and 3d), and 1c is the most potent inhibitor (IC50 = 0.038 µM). The structure-activity relationship of synthetic thiosemicarbazones revealed that the diaryl-substitutes, specifically 2-pyridine and 2-hydroxylbenzene improved inhibitory activities of the inhibitors. The thiosemicarbazones exhibited synergistic antimycobacterial actions against E. coli-NDM-1, resulted a 2–512-fold reduction in MIC of meropenem, while 1c restored 16–256-, 16-, and 2-fold activity of the antibiotic on clinical isolates ECs, K. pneumonia and P. aeruginosa harboring NDM-1, respectively. Also, mice experiments showed that 1c had a synergistic antibacterial ability with meropenem, reduced the bacterial load clinical isolate EC08 in the spleen and liver. This work provided a highly promising scaffold for the development of NDM-1 inhibitors.
Benzoapyrene (BaP) is a polycyclic aromatic hydrocarbon compound that is generated during combustion processes, and is present in various substances such as foods, tobacco smoke, and burning ...emissions. BaP is extensively acknowledged as a highly carcinogenic substance to induce multiple forms of cancer, such as lung cancer, skin cancer, and stomach cancer. Recently it is shown to adversely affect the reproductive system. Nevertheless, the potential toxicity of BaP on oocyte quality remains unclear. In this study, we established a BaP exposure model via mouse oral gavage and found that BaP exposure resulted in a notable decrease in the ovarian weight, number of GV oocytes in ovarian, and oocyte maturation competence. BaP exposure caused ribosomal dysfunction, characterized by a decrease in the expression of RPS3 and HPG in oocytes. BaP exposure also caused abnormal distribution of the endoplasmic reticulum (ER) and induced ER stress, as indicated by increased expression of GRP78. Besides, the Golgi apparatus exhibited an abnormal localization pattern, which was confirmed by the GM130 localization. Disruption of vesicle transport processes was observed by the abnormal expression and localization of Rab10. Additionally, an enhanced lysosome and LC3 fluorescence intensity indicated the occurrence of protein degradation in oocytes. In summary, our results suggested that BaP exposure disrupted the distribution and functioning of organelles, consequently affecting the developmental competence of mouse oocytes.
•BaP exposure induces RPS3-related ribosomal dysfunction and protein biosynthesis in oocytes.•BaP exposure causes ER distribution and induced ER stress in oocytes.•BaP exposure disrupts Golgi apparatus and Rab10-based vesicle transport in oocytes.•BaP exposure enhances LC3-based autophagy and lysosome dysfunction in oocytes.
Ultrasonic melt processing of magnesium (Mg) alloys has received widespread attention. However, the cavitation behavior and microstructure evolution are difficult to be directly observed in high ...temperature melts. In this work, single-frequency ultrasonic field (SUF) and dual-frequency ultrasonic field (DUF) were introduced into succinonitrile (SCN) melt and real-time images of dendrite growth and evolution were captured to explore the regulation mechanism of DUF on melt solidification structure. Numerical simulation and corresponding experiments were performed to investigate the acoustic pressure distribution and cavitation area of DUF in Mg alloy melt. Ultrasonic treatment increased the SCN dendrite growth rate and refined the solidification microstructure, and a higher efficiency was achieved by DUF when compared to SUF when the total electric power was the same. DUF decreased sound pressure attenuation and enlarged cavitation area. A result of this improvement was that its grain refinement efficiency was 13.8% and 25.6% higher than SUF at 15 kHz and 20 kHz, respectively. The input power ratio plays a crucial part in improving the grain refinement efficiency of DUF. While ensuring the symmetrical distribution of cavitation area, the grain refinement efficiency can be significantly optimized by appropriately increasing the power share of 15 kHz ultrasound is optimal at a power ratio of 2:1.
Understanding the host impact on its symbiotic microbiota is important in redirecting the rumen microbiota and thus improving animal performance. The current study aimed to understand how rumen ...microbiota were altered and re-established after being emptied and receiving content from donor, thus to understand the impact of such process on rumen microbial fermentation and to explore the microbial phylotypes with higher manipulation potentials.
Individual animal had strong effect on the re-establishment of the bacterial community according to the observed profiles detected by both fingerprinting and pyrosequencing. Most of the bacterial profile recovery patterns and extents at genus level varied among steers; and each identified bacterial genus responded to transfaunation differently within each host. Coriobacteriaceae, Coprococcus, and Lactobacillus were found to be the most responsive and tunable genera by exchanging rumen content. Besides, the association of 18 bacterial phylotypes with host fermentation parameters suggest that these phylotypes should also be considered as the regulating targets in improving host feed efficiency. In addition, the archaeal community had different re-establishment patterns for each host as determined by fingerprint profiling: it was altered after receiving non-native microbiome in some animals, while it resumed its original status after the adaptation period in the other ones.
The highly individualized microbial re-establishment process suggested the importance of considering host genetics, microbial functional genomics, and host fermentation/performance assessment when developing effective and selective microbial manipulation methods for improving animal feed efficiency.
The dried rhizome of Atractylodes lancea (Thumb.) DC. (Compositae) has been prescribed in folk medicine for the management of various inflammatory conditions such as rheumatic diseases, gastritis and ...hepatitis. However, the molecular mechanisms underlying the beneficial properties of this herb remain elusive.
In this study, we investigated the anti-gastritis activities of Al-EE (an ethanolic extract of the herb) and explored the mechanism of action.
An ethanolic extract of the Atractylodes lancea (Thumb.) DC. (Compositae) rhizome, Al-EE, was prepared with ethanol (95%) and quality controlled using HPLC analysis. To determine the in vivo effects of this extract, we utilised a HCl/EtOH-induced gastritis rat model. In vitro assays were carried out using a lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cell model. MTT assays were used to examine cell viability, while Griess assays were carried out to measure nitric oxide (NO) production. Messenger RNA expression was examined by real-time PCR. Prostaglandin E2 (PGE2) production was examined using ELISA assays. To examine protein expression and enzymatic activities, we employed western blot analysis. Nuclear transcription factor (NF)-κB activity was determined by Luciferase reporter assays.
The content of atractylenolide (AT)-1 and AT-2 in Al-EE was 0.45% and 5.07% (w/w), respectively (Supplementary Fig. 1). Al-EE treatment suppressed the production of NO and PGE2, reduced the mRNA expression of inducible NO synthase (iNOS), cyclooxygenase (COX)-2 and tumor necrosis factor (TNF)-α, while also reducing the protein levels of iNOS and COX-2 in RAW264.7 macrophage cells. Furthermore, Al-EE inhibited the nuclear protein levels of NF-κB (p65) and NF-κB-driven luciferase reporter gene activity in RAW264.7 macrophage cells. Critically, intra-gastric injection of Al-EE (25 mg/kg) attenuated HCl/EtOH-induced gastric damage in SD rats, while the phosphorylation of Akt and IκBα was suppressed by Al-EE in vitro and in vivo.
In summary, Al-EE has significant anti-gastritis effects in vivo and in vitro, which can be associated with the inhibition of the Akt/IκBα/NF-κB signalling pathway. This mechanistic finding provides a pharmacological basis for the use of the A. lancea rhizome in the clinical treatment of various inflammatory conditions.
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Optical modulators can have high modulation speed and broad bandwidth, while being compact. However, these optical modulators usually work for low-intensity light beams. Here we present an ultrafast, ...plasma-based optical modulator, which can directly modulate high-power lasers with intensity up to 10(16) W cm(-2) to produce an extremely broad spectrum with a fractional bandwidth over 100%, extending to the mid-infrared regime in the low-frequency side. This concept relies on two co-propagating laser pulses in a sub-millimetre-scale underdense plasma, where a drive laser pulse first excites an electron plasma wave in its wake while a following carrier laser pulse is modulated by the plasma wave. The laser and plasma parameters suitable for the modulator to work are based on numerical simulations.
We report on the analysis of the 10-1000 TeV large-scale sidereal anisotropy of Galactic cosmic rays (GCRs) with the data collected by the Tibet Air Shower Array from 1995 October to 2010 February. ...In this analysis, we improve the energy estimate and extend the decl. range down to −30°. We find that the anisotropy maps above 100 TeV are distinct from that at a multi-TeV band. The so-called tail-in and loss-cone features identified at low energies get less significant, and a new component appears at ∼100 TeV. The spatial distribution of the GCR intensity with an excess (7.2 pre-trial, 5.2 post-trial) and a deficit (−5.8 pre-trial) are observed in the 300 TeV anisotropy map, in close agreement with IceCube's results at 400 TeV. Combining the Tibet results in the northern sky with IceCube's results in the southern sky, we establish a full-sky picture of the anisotropy in hundreds of TeV band. We further find that the amplitude of the first order anisotropy increases sharply above ∼100 TeV, indicating a new component of the anisotropy. All these results may shed new light on understanding the origin and propagation of GCRs.
Given the widespread demand for digital health services, a systematic study on the quality of digital health services is essential. Based on the current situation of tertiary hospitals in central ...China providing digital health services via social media, we used the Cronbach and Bayesian Best and Worst methods to evaluate the quality of hospital digital health services and conduct an empirical study of several hospitals. Based on the results of the empirical study, we propose a path for constructing a digital health service platform, suggesting that hospitals focus on building business function services of social media and accelerate the development of Internet hospitals. Hospitals should also improve the operation and maintenance of social media, optimize the intelligence of online guidance, and simplify the design logic of function menus. In terms of content information services, hospitals need to design targeted content according to the characteristics of different social media, improve content quality, and ensure the appropriate proportion of various types of information. With such measures, hospitals can guide users to use social media through business function services and retain users through content information services to increase the influence of hospitals and the quality of social health welfare.
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![Benzo[a]pyrene exposure dis...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/0147-6513/small "Benzo[a]pyrene exposure disrupts the organelle distribution and function of mouse oocytes")
