The role of focal amplifications and extrachromosomal DNA (ecDNA) is unknown in gastric cardia adenocarcinoma (GCA). Here, we identify frequent focal amplifications and ecDNAs in Chinese GCA patient ...samples, and find focal amplifications in the GCA cohort are associated with the chromothripsis process and may be induced by accumulated DNA damage due to local dietary habits. We observe diverse correlations between the presence of oncogene focal amplifications and prognosis, where ERBB2 focal amplifications positively correlate with prognosis and EGFR focal amplifications negatively correlate with prognosis. Large-scale ERBB2 immunohistochemistry results from 1668 GCA patients show survival probability of ERBB2 positive patients is lower than that of ERBB2 negative patients when their surviving time is under 2 years, however, the tendency is opposite when their surviving time is longer than 2 years. Our observations indicate that the ERBB2 focal amplifications may represent a good prognostic marker in GCA patients.
Chromium is a common heavy metal widely present in aquatic environments. Cost-effective remediation of chromium-contaminated environment can be realized by microbial reduction of Cr(VI) to Cr(III). ...The genus Aeromonas species is one of such Cr(VI) reducers, whose reduction mechanism remains unrevealed and the main factors governing the Cr(VI) reduction pathways are unknown yet. In this work, the performances and mechanisms of Cr(VI) anaerobic reduction by Aeromonas hydrophila ATCC 7966 were investigated. This strain exhibited excellent Cr(VI) resistance and could utilize a suite of electron donors to support Cr(VI) bioreduction. The Cr(VI) bioreduction processes involved both extracellular (the metal-reducing and respiratory pathway) and intracellular reaction pathways. Adding anthraquinone-2,6-disulfonate or humic acid as a mediator substantially enhanced the Cr(VI) bioreduction. The forms and distribution of the Cr(VI) bioreduction products were affected by the medium composition. Soluble organo-Cr(III) complexes were identified as the main Cr(VI) reduction products when basal salts medium was adopted. Given the environmental ubiquity of the genus Aeromonas, the findings in this work may facilitate a better understanding about the transformation behaviors and fates of Cr(VI) in environments and provide useful clues to tune the bioremediation of chromium-contaminated environments.
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•A. hydrophila ATCC 7966 had an excellent Cr(VI) resistance and reduction ability.•Extracellular and intracellular pathways were involved in the Cr(VI) bioreduction.•Medium composition affected the formation of Cr(VI) reduction products.•Organo-Cr(III) complexes were the main Cr(VI) reduction products by Aeromonas.
Dissimilatory metal reducing bacteria (DMRB) are capable of extracellular electron transfer (EET) to insoluble metal oxides, which are used as external electron acceptors by DMRB for their anaerobic ...respiration. The EET process has important contribution to environmental remediation mineral cycling, and bioelectrochemical systems. However, the low EET efficiency remains to be one of the major bottlenecks for its practical applications for pollutant degradation. In this work, Shewanella oneidensis MR-1, a model DMRB, was used to examine the feasibility of enhancing the EET and its biodegradation capacity through genetic engineering. A flavin biosynthesis gene cluster ribD-ribC-ribBA-ribE and metal-reducing conduit biosynthesis gene cluster mtrC-mtrA-mtrB were coexpressed in S. oneidensis MR-1. Compared to the control strain, the engineered strain was found to exhibit an improved EET capacity in microbial fuel cells and potentiostat-controlled electrochemical cells, with an increase in maximum current density by approximate 110% and 87%, respectively. The electrochemical impedance spectroscopy (EIS) analysis showed that the current increase correlated with the lower interfacial charge-transfer resistance of the engineered strain. Meanwhile, a three times more rapid removal rate of methyl orange by the engineered strain confirmed the improvement of its EET and biodegradation ability. Our results demonstrate that coupling of improved synthesis of mediators and metal-reducing conduits could be an efficient strategy to enhance EET in S. oneidensis MR-1, which is essential to the applications of DMRB for environmental remediation, wastewater treatment, and bioenergy recovery from wastes.
Idiopathic pulmonary fibrosis (IPF) is an age‐related pulmonary interstitial disease with unclear etiology that poses a serious threat to human health. IPF interventions in clinical settings mainly ...involve oral medications, such as nintedanib (NIN), which exhibit limited accumulation in the lungs and neglect the epithelial micro‐environment. Inhalation is an efficient route for the treatment of pulmonary diseases. However, the mucus barrier in the trachea and the extracellular matrix (ECM) barrier in the interstitium are the two main obstacles to inhaled therapeutic agent delivery. Therefore, in this study, dual barrier‐penetrating inhaled liposomes (AN‐TR) are constructed utilizing tris‐(2‐carboxyethyl)‐phosphine (TCEP) and l‐arginine to penetrate the mucus and ECM barriers, respectively. This approach facilitates the thorough and uniform distribution of NIN and navitoclax (ABT‐263) across all five lung lobes. Furthermore, ABT‐263 can remove the senescent epithelial cells in the trachea and alveoli, thereby improving the efficiency of NIN for IPF treatment. This study suggests dual barrier‐penetrating inhaled liposomes as efficient noninvasive vehicles for first‐line clinical medications to improve the efficacy of IPF treatment.
Inhalation is a unique administration route for pulmonary diseases, especially for idiopathic pulmonary fibrosis (IPF), an irreversible and ultimately fatal disease. However, barriers in the trachea and alveoli will block the drug delivery. Herein, dual barrier‐penetrating liposomes are constructed to overcome the mucus barrier in the trachea and the extracellular matrix barrier in the alveoli to enhance drug delivery efficiency, thereby improving IPF therapy.
Cordyceps militaris is a traditional medicinal fungus contains a variety of functional ingredients and has been developed as an important mushroom food recently. Ergothioneine, one of the ...antioxidative compounds in C. militaris, is benefits on aging-related diseases and therefore became a novel functional food nutritive fortifier. Currently, the main diet source of ergothioneine is mushroom food. However, the mushroom farming faces the problems such as rather low ingredient yield and spontaneous degeneration associated fruiting body that restricts large scale production of ergothioneine. In this study, we excavated the ergothioneine synthetases in mushroom and modified the genes in C. militaris to construct a new ergothioneine synthesis pathway. By further introducing this pathway into C. militaris genome, we succeeded to increase the ingredients' production of engineering strain, the highest amount of ergothioneine and cordycepin were up to 2.5 g/kg dry weight and 2 g/L, respectively. Additionally, the expression of ergothioneine synthetase genes in the shape-mutated degenerative C. militaris could recover the ability of degenerative strain to produce high amount of ingredients, suggesting the metabolic regulation of ergothioneine might release the symptom of mushroom degeneration. This study reveals a new pathway to fulfill the market needs of functional mushroom food and food fortifier ergothioneine. It implied the mycelium of C. militaris could be engineered as a novel medicinal mushroom food which could produce higher amount of valuable ingredients.
Probing the mechanism of ultrafast thermoelastic processes is becoming increasingly important with the development of laser-assisted micro/nano machining. Although thermoelastic models containing ...temperature rate have been historically proposed, the strain rate has not been considered yet. In this work, a generalized thermoelastic model is theoretically established by introducing the strain rate in Green–Lindsay (GL) thermoelastic model with the aid of extended thermodynamics. Numerically, a semi-infinite one-dimensional problem is considered with traction free at one end and subjected to a temperature rise. The problem is solved using the Laplace transform method, and the transient responses, i.e. displacement, temperature and stresses are graphically depicted. Interestingly, it is found that the strain rate may eliminate the discontinuity of the displacement at the elastic and thermal wave front. Also, the present model is compared with Green–Naghdi (GN) models. It is found that the thermal wave speed of the present model is faster than GN model without energy dissipation, and slower than GN model with energy dissipation. In addition, the thermoelastic responses from the present model are the largest. The present model based upon GL model is free of the jump of GL model in the displacement distribution, and is safer in engineering practices than GN model. The present work will benefit the theoretical modeling and numerical prediction of thermoelastic process, especially for those under extreme fast heating.
The coordination-restricted ortho-site C–H bond activation and dehydrogenative homocoupling of 4,4′-(1,3-phenylene)dipyridine (1,3-BPyB) and 4,4′-(1,4-phenylene)dipyridine (1,4-BPyB) on different ...metal surfaces were studied by a combination of scanning tunneling microscopy, noncontact atomic force microscopy, and density functional theory calculations. The coupling products on Cu(111) exhibited certain configurations subject to the spatial restriction of robust two-fold Cu–N coordination bonds. Compared to the V-shaped 1,3-BPyB, the straight backbone of 1,4-BPyB helped to further reduce the variety of reactive products. By utilizing the three-fold coordination of Fe atoms with 1,4-BPyB molecules on Au(111), a large-scale network containing single products was constructed. Our results offer a promising protocol for controllable on-surface synthesis with the aid of robust coordination interactions.
In living organisms, daily light/dark cycles profoundly affect cellular processes. In plants, optimal growth and development, and adaptation to daily light–dark cycles, require starch synthesis and ...turnover. However, the underlying molecular mechanisms coordinating daily starch metabolism remain poorly understood.
To explore the roles of Arabidopsis thaliana light signal transduction proteins FAR-RED ELONGATED HYPOCOTYLS3 (FHY3) and FAR-RED-IMPAIRED RESPONSE1 (FAR1) in starch metabolism, the contents of starch and water-soluble polysaccharides, and the structure of starch granules were investigated in fhy3, far1 and fhy3 far1 mutant plants.
Disruption of FHY3 or FAR1 reduced starch accumulation and altered starch granule structure in the fhy3-4, far1-2, and fhy3-4 far1-2 mutant plants. Furthermore, molecular and genetic evidence revealed that the gene encoding the starch-debranching enzyme ISOAMYLASE2 (ISA2) is a direct target of FHY3 and FAR1, and functions in light-induced starch synthesis.
Our data establish the first molecular link between light signal transduction and starch synthesis, suggesting that the light-signaling proteins FHY3 and FAR1 influence starch synthesis and starch granule formation through transcriptional activation of ISA2.
In the present scenario, it is much needed of developing Al–Sc and Al–Sc–Zr alloys owing to its higher strength to weight for aerospace applications. The present study is dealt about effect of ...Scandium on micro hardness and micro structure of synthesized Al–Sc alloy and Al–Sc–Zr alloy under different weight percentage. The precipitation strengthening of as-cast structure, Al–Sc alloy and Al–Sc–Zr alloy have been analyzed during aging at 350 °C. From the experimental investigation, only little difference in micro hardness of developed alloys was observed during initial stage of aging. The peak hardness of Al–Sc–Zr alloy was maintained for a relatively longer period for producing better thermal stability. Three-dimensional atomic probing indicated that the precipitation of Zr in the precipitate at the initial stage of aging which can inhibit the growth of the precipitate’s size. TEM results showed that the Al–Sc–Zr alloy formed two precipitates of different sizes at the over-aging phase after the peak state of hardness.
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NOD-like receptors (NLRs) are a family of intracellular pattern recognition receptors (PRRs) that play critical roles in innate immunity against pathogens infection. NLRC5, the largest member of NLR ...family, has been characterized as a regulator of innate immunity and MHC class I expression. Alternative splicing of NLRC5 is only reported in human and zebrafish. However, the function of NLRC5 isoforms in the innate immune responses remains unknown. In the present study, we report the functional characterization of zfNLRC5a and zfNLRC5d, two splicing isoforms of zebrafish NLRC5. zfNLRC5a and zfNLRC5d are generated by exon skipping, and whose alternative splicing sites exist in the region of LRRs. Fluorescence microscopy showed that zfNLRC5 isoforms were located throughout the entire cell including nuclear staining. The expression of zfNLRC5 isoform was inducible in response to bacterial and viral infections. During SVCV infection, the in vitro and in vivo studies found that zfNLRC5d overexpression increased protection against viral infection; however zfNLRC5a overexpression had no significant effect on antiviral activity. Interestingly, zfNLRC5 isoforms but not zfNLRC5 were involved in transcriptional regulation of TLRs and NF-κB signaling. Overexpression of zfNLRC5 isoforms also contributed to negative regulation of antibacterial immune response, with the decreased expression of nfkbiaa (IκBα). All together, these results firstly demonstrate the function of NLRC5 isoforms in antiviral and antibacterial immune responses both in vitro and in vivo.
•zfNLRC5 isoforms are generated by exon skipping.•zfNLRC5 isoform was induced by both bacterial and viral infection.•zfNLRC5d but not zfNLRC5a increased the protection against viral infection.•zfNLRC5 isoforms were involved in transcription regulation of TLRs and NF-κB signaling during viral infection.•zfNLRC5 isoforms negatively regulated antibacterial immune response.
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