Zika virus (ZIKV) has evolved into a global health threat because of its unexpected causal link to microcephaly. Phylogenetic analysis reveals that contemporary epidemic strains have accumulated ...multiple substitutions from their Asian ancestor. Here we show that a single serine-to-asparagine substitution Ser139→Asn139 (S139N) in the viral polyprotein substantially increased ZIKV infectivity in both human and mouse neural progenitor cells (NPCs) and led to more severe microcephaly in the mouse fetus, as well as higher mortality rates in neonatal mice. Evolutionary analysis indicates that the S139N substitution arose before the 2013 outbreak in French Polynesia and has been stably maintained during subsequent spread to the Americas. This functional adaption makes ZIKV more virulent to human NPCs, thus contributing to the increased incidence of microcephaly in recent ZIKV epidemics.
Silent information regulator 1 (Sirt1) is a deacetylase, which plays an important role in the occurrence and development of diabetic nephropathy (DN). Our previous study shows that Yin yang 1 (YY1), ...a widely expressed zinc finger DNA/RNA-binding transcription factor, is a novel regulator of renal fibrosis in diabetic nephropathy. Since the activity of YY1 is regulated via acetylation and deacetylation modification, this study aimed to explore whether Sirt1-induced deacetylation of YY1 mediated high glucose (HG)-induced renal tubular epithelial-mesenchymal transition (EMT) and renal fibrosis in vivo and in vitro. We first confirmed that Sirt1 expression level was significantly decreased in the kidney of db/db mice and in HG-treated HK-2 cells. Diabetes-induced Sirt1 reduction enhanced the level of YY1 acetylation and renal tubular EMT. Then, we manipulated Sirt1 expression in vivo and in vitro by injecting resveratrol (50 mg·kg
·d
. ip) to db/db mice for 2 weeks or application of SRT1720 (2.5 μM) in HG-treated HK-2 cells, we found that activation of Sirt1 reversed the renal tubular EMT and YY1 acetylation induced by HG condition. On the contrary, Sirt1 was knocked down in db/m mice or EX527 (1 μM) was added in HK-2 cells, we found that inhibition of Sirt1 exacerbated renal fibrosis in diabetic mice and enhanced level of YY1 acetylation in HK-2 cells. Furthermore, knockdown of YY1 inhibited the ameliorating effect of resveratrol on renal tubular EMT and renal fibrosis in db/db mice. In conclusion, this study demonstrates that Sirt1 plays an important role in renal tubular EMT of DN through mediating deacetylation of YY1.
Measurement-device-independent quantum key distribution (MDI-QKD), based on two-photon interference, is immune to all attacks against the detection system and allows a QKD network with untrusted ...relays. Since the MDI-QKD protocol was proposed, fiber-based implementations aimed at longer distance, higher key rates, and network verification have been rapidly developed. However, owing to the effect of atmospheric turbulence, MDI-QKD over a free-space channel remains experimentally challenging. Herein, by developing a robust adaptive optics system, high-precision time synchronization and frequency locking between independent photon sources located far apart, we realized the first free-space MDI-QKD over a 19.2-km urban atmospheric channel, which well exceeds the effective atmospheric thickness. Our experiment takes the first step toward satellite-based MDI-QKD. Moreover, the technology developed herein opens the way to quantum experiments in free space involving long-distance interference of independent single photons.
There is increasing evidence that bone morphogenetic proteins (BMP) are involved in the proliferation and drug tolerance of kidney cancer. However, the molecular mechanism of BMP8A in renal cell ...proliferation and drug tolerance is not clear. Here we showed that BMP8A was highly expressed in renal cell carcinoma, which suggests a poor prognosis of ccRCC. Promotion of cell proliferation and inhibition of apoptosis were detected by CCK‐8 assay, Trypan Blue staining, flow cytometry and bioluminescence. BMP8A promoted resistance of As2O3 by regulating Nrf2 and Wnt pathways in vitro and in vivo. Mechanistically, BMP8A enhanced phosphorylation of Nrf2, which, in turn, inhibited Keap1‐mediated Nrf2 ubiquitination and, ultimately, promoted nuclear translocation and transcriptional activity of Nrf2. Nrf2 regulates the transcription of TRIM24 detected by ChIP‐qPCR. BMP8A was highly expressed in ccRCC, which suggests a poor prognosis. BMP8A was expected to be an independent prognostic molecule for ccRCC. On the one hand, activated Nrf2 regulated reactive oxygen balance, and on the other hand, by regulating the transcription level of TRIM24, it was involved in the regulation of the Wnt pathway to promote the proliferation, invasion and metastasis of ccRCC and the resistance of As2O3. Taken together, our findings describe a regulatory axis where BMP8A promotes Nrf2 phosphorylation and activates TRIM24 to promote survival and drug resistance in ccRCC.
BMP8A can promote Nrf2 phosphorylation and nuclear translocation to exert antioxidative stress and transcriptional activity. At the same time, Nrf2 acts as a transcription factor of TRIM24, promotes the expression of TRIM24, activates the Wnt pathway and increases chemotherapy tolerance.
Abstract
Background
The Makorin ring finger protein 1 (
MKRN1
) gene, also called RNF61, is located on the long arm of chromosome 7 and is a member of the RING finger protein family. The E3 ubiquitin ...ligase MKRN1 is closely linked to tumour development, but the exact mechanism needs to be elucidated. In this study, we aimed to investigate the specific mechanism and role of
MKRN1
in colorectal cancer (CRC) development.
Methods
MKRN1
expression in CRC was analysed using the Cancer Cell Line Encyclopaedia and the Cancer Genome Atlas (TCGA) databases. Rectal tumour tissues were frozen to explore the MKRN1 expression in CRC and its clinical significance. The impact of
MKRN1
on CRC cell proliferation and migration was observed using CCK8, colony formation, wound healing, and transwell assays. A combination of MKRN1 quantitative proteomics, ubiquitination modification omics analysis, and a string of in vitro and in vivo experiments revealed the potential mechanisms by which
MKRN1
regulates CRC metastasis.
Results
MKRN1
expression was significantly elevated in CRC tissues compared to paracancerous tissues and was positively linked with prognosis (
P
< 0.01).
MKRN1
downregulation inhibits CRC cell proliferation, migration, and invasion. Conversely,
MKRN1
overexpression promotes the proliferation, migration, and invasion of CRC cells. Mechanistically,
MKRN1
induces epithelial-mesenchymal transition (EMT) in CRC cells via ubiquitination and degradation of Smad nuclear-interacting protein 1 (SNIP1). Furthermore, SNIP1 inhibits transforming growth factor-β (TGF-β) signalling, and
MKRN1
promotes TGF-β signalling by degrading SNIP1 to induce EMT in CRC cells. Finally, using conditional knockout mice, intestinal lesions and metastatic liver microlesions were greatly reduced in the intestinal knockout
MKRN1
group compared to that in the control group.
Conclusions
High
MKRN1
levels promote TGF-β signalling through ubiquitination and degradation of SNIP1, thereby facilitating CRC metastasis, and supporting
MKRN1
as a CRC pro-cancer factor. The MKRN1/SNIP1/TGF-β axis may be a potential therapeutic target in CRC.
Background and Purpose
Renal fibrosis is the final common outcome in most forms of chronic kidney disease (CKD). However, the underlying causal mechanisms remain obscure. The present study examined ...whether transmembrane member 16A (TMEM16A), a Ca2+‐activated chloride channel, contributes to the progression of renal fibrosis.
Experimental Approach
Masson staining, western blot and immunohistochemistry were used to measure renal fibrosis and related proteins expression. MQAE was used to evaluate the intracellular Cl− concentration.
Key Results
TMEM16A expression was significantly up‐regulated in fibrotic kidneys of unilateral ureteral obstruction (UUO) and high‐fat diet murine models and in renal samples of IgA nephropathy patients. In vivo knockdown of TMEM16A with adenovirus harbouring TMEM16A‐shRNA or inhibition of TMEM16A channel activity with inhibitors CaCCinh‐A01 or T16Ainh‐A01 effectively prevented UUO‐induced renal fibrosis and decreased protein expression of fibronectin, α‐SMA and collagen in the obstructed kidneys. In cultured HK2 cells, knockdown or inhibition of TMEM16A suppressed TGF‐β1‐induced epithelial–mesenchymal transition, reduced snail1 expression and phosphorylation of Smad2/3 and ERK1/2, whereas overexpression of TMEM16A showed the opposite effects. TGF‐β1 increased Cl−i in HK2 cells, which was inhibited by knockdown or inhibition of TMEM16A. Reducing Cl−i significantly blunted TGF‐β1‐induced Smad2/3 phosphorylation and profibrotic factors expression. The profibrotic effects of TGF‐β1 were also reduced by inhibition of serum‐ and glucocorticoid‐inducible protein kinase 1 (SGK1). SGK1 was also suppressed by reducing Cl−i.
Conclusion and Implications
Blockade of TMEM16A prevented the progression of kidney fibrosis, likely by suppressing Cl−i/SGK1/TGF‐β1 signalling pathway. TMEM16A may be a potential new therapeutic target against renal fibrosis.
As one of the most induced genes in activated macrophages, immune-responsive gene 1 (IRG1) encodes a mitochondrial metabolic enzyme catalysing the production of itaconic acid (ITA). Although ITA has ...an anti-inflammatory property, the underlying mechanisms are not fully understood. Here we show that ITA is a potent inhibitor of the TET-family DNA dioxygenases. ITA binds to the same site on TET2 as the co-substrate α-ketoglutarate, inhibiting TET2 catalytic activity. Lipopolysaccharide treatment, which induces Irg1 expression and ITA accumulation, inhibits Tet activity in macrophages. Transcriptome analysis reveals that TET2 is a major target of ITA in suppressing lipopolysaccharide-induced genes, including those regulated by the NF-κB and STAT signalling pathways. In vivo, ITA decreases the levels of 5-hydroxymethylcytosine, reduces lipopolysaccharide-induced acute pulmonary oedema as well as lung and liver injury, and protects mice against lethal endotoxaemia, depending on the catalytic activity of Tet2. Our study thus identifies ITA as an immune modulatory metabolite that selectively inhibits TET enzymes to dampen the inflammatory responses.
The depth-dependent structural changes in oxidized graphite have not been precisely revealed because of its friable nature. Here, micro-focused X-ray diffraction is used to measure the structural ...changes of oxidized graphite. An improved polishing method is then applied to observe the friable microstructures via scanning electron microscope. The (002) peak intensity and peak width is found to be very sensitive to local weight loss. The peak width decreases with the increase of weight loss, indicating an oxidation-induced increase of the average coherent length. High-resolution depth profiles of oxidized graphite structures are obtained for the first time. A double-layer oxidation mechanism is revealed. In the inner oxidation layer, oxidation happened preferentially to the binder regions and defective filler particles and leaves complicated paths which greatly increased the active surface area. It is observed that the original pore structures maintained in the inner oxidation layer. The outer oxidation layer showed a depletion of the binder regions and was oxidized in a much slower rate. However, the graphite grains could fall off easily, which causes a rapid drop of (002) peak intensity at the very surface.
Graphical abstract
Sugarcane ratoon stunting disease (RSD) caused by Leifsonia xyli subsp. xyli (Lxx) is a common destructive disease that occurs around the world. Lxx is an obligate pathogen of sugarcane, and previous ...studies have reported some physiological responses of RSD-affected sugarcane. However, the molecular understanding of sugarcane response to Lxx infection remains unclear. In the present study, transcriptomes of healthy and Lxx-infected sugarcane stalks and leaves were studied to gain more insights into the gene activity in sugarcane in response to Lxx infection. RNA-Seq analysis of healthy and diseased plants transcriptomes identified 107,750 unigenes. Analysis of these unigenes showed a large number of differentially expressed genes (DEGs) occurring mostly in leaves of infected plants. Sugarcane responds to Lxx infection mainly via alteration of metabolic pathways such as photosynthesis, phytohormone biosynthesis, phytohormone action-mediated regulation, and plant-pathogen interactions. It was also found that cell wall defense pathways and protein phosphorylation/dephosphorylation pathways may play important roles in Lxx pathogeneis. In Lxx-infected plants, significant inhibition in photosynthetic processes through large number of differentially expressed genes involved in energy capture, energy metabolism and chloroplast structure. Also, Lxx infection caused down-regulation of gibberellin response through an increased activity of DELLA and down-regulation of GID1 proteins. This alteration in gibberellic acid response combined with the inhibition of photosynthetic processes may account for the majority of growth retardation occurring in RSD-affected plants. A number of genes associated with plant-pathogen interactions were also differentially expressed in Lxx-infected plants. These include those involved in secondary metabolite biosynthesis, protein phosphorylation/dephosphorylation, cell wall biosynthesis, and phagosomes, implicating an active defense response to Lxx infection. Considering the fact that RSD occurs worldwide and a significant cause of sugarcane productivity, a better understanding of Lxx resistance-related processes may help develop tools and technologies for producing RSD-resistant sugarcane varieties through conventional and/or molecular breeding.
A new ionic current rectification device responsive to a broad range of pH stimuli is established using highly ordered nanochannels of porous anodic alumina membrane with abrupt surface charge ...discontinuity. The asymmetric surface charge distribution is achieved by patterning the nanochannels with surface amine functional groups at designed positions using a two‐step anodization process. Due to the protonation/deprotonation of the patterned amine and the remaining intrinsic hydroxyl groups upon solution pH variation, the nanochannel‐array‐based device is able to regulate ion transport selectivity and has ionic current rectification properties. The rectification ratio of the device is mainly determined by the nanochannel size, and the rectification ratio is less sensitive to the patterned length of the amine groups when the nanochannels size is defined. Thus, the isoelectric point of nanochannels can be easily estimated to be the pH value with a unit rectification ratio. The present ionic device is promising for biosensing, molecular transport and separation, and drug delivery in confined environments.
A new ionic current rectification device responsive to a broad range of pH stimuli is established using highly ordered nanochannels of porous anodic alumina membrane with abrupt surface charge discontinuity. Due to the protonation/deprotonation of the patterned amine and the remaining intrinsic hydroxyl groups, the nanochannel‐array‐based device is able to regulate ion transport selectivity and has ionic current rectification properties.
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