Cataracts, named for pathological light scattering in the lens, are known to be associated with increased large protein aggregates, disrupted protein phase separation, and/or osmotic imbalances in ...lens cells. We have applied synchrotron phase contrast X-ray micro-computed tomography to directly examine an age-related nuclear cataract model in Cx46 knockout (Cx46KO) mice. High-resolution 3D X-ray tomographic images reveal amorphous spots and strip-like dense matter precipitates in lens cores of all examined Cx46KO mice at different ages. The precipitates are predominantly accumulated in the anterior suture regions of lens cores, and they become longer and dense as mice age. Alizarin red staining data confirms the presence of calcium precipitates in lens cores of all Cx46KO mice. This study indicates that the spatial and temporal calcium precipitation is an age-related event associated with age-related nuclear cataract formation in Cx46KO mice, and further suggests that the loss of Cx46 promotes calcium precipitates in the lens core, which is a new mechanism that likely contributes to the pathological light scattering in this age-related cataract model.
Circular RNAs (circRNAs) are involved in the regulation of many pathophysiological processes as non-coding RNAs. This study focuses on the role of circRACGAP1 in the development of non-small cell ...lung cancer (NSCLC). Expression patterns of circRACGAP1 and miR-144-5p in NSCLC tissues and cell lines were quantified by qRT-PCR analysis. Then, the function of circRACGAP1 on cell proliferation and tumorigenesis were confirmed in vitro and in vivo using CCK-8 assay, colony formation, EdU incorporation, and xenograft technique. The regulation of circRACGAP1 on Gefitinib resistance of NSCLC cells was evaluated by flow cytometry. The regulatory network of circRACGAP1/miR-144-5p/CDKL1 was verified by luciferase reporter assay and RNA pull-down. Western blotting analysis was performed to assess the biomarkers of cell cycle and apoptosis-associated proteins. CircRACGAP1 was highly expressed and miR-144-5p was inhibited both in NSCLC tissues and cell lines, suggesting their negative correlation in NSCLC. Knockdown of circRACGAP1 suppressed cell proliferation via arresting the cell cycle. miR-144-5p was identified as a downstream target to reverse circRACGAP1-mediated cell proliferation. miR-144-5p directly targeted the 3'-UTR of CDKL1 to regulate cell cycle of NSCLC cells. circRACGAP1 knockdown dramatically inhibited the tumor growth and enhanced the sensitivity of NSCLC to Gefitinib in vitro and in vivo. In summary, our study revealed a novel machinery of circRACGAP1/miR-144-5p/CDKL1 for the NSCLC tumorigenesis and development, providing potential diagnostic and therapeutic targets for NSCLC.
Among arthropod vectors, ticks transmit the most diverse human and animal pathogens, leading to an increasing number of new challenges worldwide. Here we sequenced and assembled high-quality genomes ...of six ixodid tick species and further resequenced 678 tick specimens to understand three key aspects of ticks: genetic diversity, population structure, and pathogen distribution. We explored the genetic basis common to ticks, including heme and hemoglobin digestion, iron metabolism, and reactive oxygen species, and unveiled for the first time that genetic structure and pathogen composition in different tick species are mainly shaped by ecological and geographic factors. We further identified species-specific determinants associated with different host ranges, life cycles, and distributions. The findings of this study are an invaluable resource for research and control of ticks and tick-borne diseases.
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•Six high-quality ixodid tick genomes and 678 re-sequenced tick specimens•Insights into the genetic basis of tick hematophagy and related phenotypes•Population structure and genetic diversity of six tick species•Tick-borne pathogen composition and distribution by metagenome analyses
The high-quality genomes of six ixodid tick species and resequencing of 678 tick specimens are a resource to understand the genetic diversity, population structure, and pathogen distribution of ticks with implications for control of ticks and tick-borne diseases.
The synthesis of polymers with on-demand sequence structures is very important not only for academic researchers but also for industry. However, despite the existing polymerization techniques, it is ...still difficult to achieve copolymer chains with on-demand sequence structures. Here we report a dually switchable and controlled interconvertible polymerization system; in this system, two distinct orthogonal polymerizations can be selectively switched ON/OFF independent of each other and they can be interconverted promptly and quantitatively according to external stimuli. Thus, the external stimuli can manipulate the insertion of distinct monomers into the resulting copolymer chains temporally, spatially, and orthogonally, allowing the on-demand precise arrangement of sequence structures in the resulting polymers. This dually switchable and interconvertible polymerization system provides a powerful tool for synthesizing materials that are not accessible by other polymerization methods.
As one of the most sustainable protein sources for humans, aquaculture is the fastest growing food production sector in agriculture. According to the recent FAO estimate, there are 21 principal ...aquaculture fish species around the worldwide. Among these cultured species, almost half of them belong to Cypriniformes, the species from which all have a certain number of intermuscular bones (IBs). IBs are small spicule‐like bones existing in the muscle fillet, which are existed only in lower teleost and of course have a negative effect on fish quality and aquatic product processing. Many studies have been focusing on IBs number, morphology, and more and more become focusing on its development molecular mechanism. In the review, we summarized the recent progress and discussed with following directions: (i) Controversial on the origin of IBs, ossified from tendons or ligaments? (ii) IBs counts and morphology revealed big variation among different species; (iii) Ossification patterns of IBs might be related with different swimming modes among the teleost fish, and its development belongs to intramembranous ossification without cartilaginous phase; (iv) Transcriptome/microRNA (miRNA)/proteomics and gene functional analysis had been used to investigate the molecular mechanism of IBs development and some genes showed certain regulatory roles during IBs’ development; (v) The reports showed that some breeding technologies could make a certain effect on IBs counts in fish species, but there are rare reports with success on deleting or significantly reducing IBs counts. Meanwhile, we also discuss the challenges and future directions of reducing or even deleting IBs in aquaculture.
Cyclic polymers have a number of unique physical properties compared with those of their linear counterparts. However, the methods for the synthesis of cyclic polymers are very limited, and some ...multicyclic polymers are still not accessible now. Here, we found that the five-membered cyclic structure and electron withdrawing groups make methylene in rhodanine highly active to aldehyde via highly efficient Knoevenagel reaction. Also, rhodanine can act as an initiator for anionic ring-opening polymerization of thiirane to produce cyclic polythioethers. Therefore, rhodanine can serve as both an initiator for ring-opening polymerization and a monomer in Knoevenagel polymerization. Via rhodanine-based Knoevenagel reaction, we can easily incorporate rhodanine moieties in the backbone, side chain, branched chain, etc, and correspondingly could produce cyclic structures in the backbone, side chain, branched chain, etc, via rhodanine-based anionic ring-opening polymerization. This rhodanine chemistry would provide easy access to a wide variety of complex multicyclic polymers.
Background & Aims
T‐cell receptor (TCR) repertoire is ambiguously changed in chronic hepatitis B (CHB) patients during antivirus therapy. We tried to assess TCR repertoire dynamics and its clinical ...significance upon HBeAg seroconversion in CHB patients.
Methods
Twenty CHB patients undergoing 1‐year entecavir (ETV) treatment were enrolled, including 10 complete response (CR) vs 10 non‐complete response (NCR) patients based on HBeAg seroconversion at week 48. The TCRβ complementarity‐determining region 3 (CDR3) of peripheral CD4+ and CD8+ T cells at weeks 0, 12 and 48 was analyzed by unbiased high‐throughput sequencing. The TCR repertoire profiles and their correlations with serological parameters were analyzed.
Results
The diversity of TCRβ repertoires was decreasing in CR patients but increasing in NCR patients. The distribution pattern of TCR repertoires stratified according to clonotype frequencies changed in the opposite direction between CR and NCR patients. Narrow amounts of newly appearing clonotypes in CR patients experienced a more intensive and robust expansion and this phenomenon could occur as early as week 12 for the CD4+ subset but later at week 48 for the CD8+ subset. There existed some CR‐exclusive clonotypes with a relatively low but increasing frequency at week 48. The number of unique TCRβ clonotypes was positively correlated with the ALT or HBV DNA level in CR patients but showed no or negative correlation in NCR patients.
Conclusion
Distinct TCR profiles contribute to predicting HBeAg seroconversion in CHB patients during ETV treatment and certain TCRβ CDR3 motif may be utilized for CHB immunotherapy in the future.
Chemodynamic therapy based on Fe2+-catalyzed Fenton reaction holds great promise in cancer treatment. However, low-produced hydroxyl radicals in tumor cells constitute its severe challenges because ...of the fact that Fe2+ with high catalytic activity could be easily oxidized into Fe3+ with low catalytic activity, greatly lowering Fenton reaction efficacy. Here, we codeliver CuS with the iron-containing prodrug into tumor cells. In tumor cells, the overproduced esterase could cleave the phenolic ester bond in the prodrug to release Fe2+, activating Fenton reaction to produce the hydroxyl radical. Meanwhile, CuS could act as a nanocatalyst for continuously catalyzing the regeneration of high-active Fe2+ from low-active Fe3+ to produce enough hydroxyl radicals to efficiently kill tumor cells as well as a photothermal therapy agent for generating hyperthermia for thermal ablation of tumor cells upon NIR irradiation. The results have exhibited that the approach of photothermal therapy nanomaterials boosting transformation of Fe3+ into Fe2+ in tumor cells can highly improve Fenton reaction for efficient chemodynamic therapy. This strategy was demonstrated to have an excellent antitumor activity both in vitro and in vivo, which provides an innovative perspective to Fenton reaction-based chemodynamic therapy.
Alzheimer's disease (AD) is currently ranked as the third leading cause of death for eldly people, just behind heart disease and cancer. Autophagy is declined with aging. Our study determined the ...biphasic changes of miR-331-3p and miR-9-5p associated with AD progression in APPswe/PS1dE9 mouse model and demonstrated inhibiting miR-331-3p and miR-9-5p treatment prevented AD progression by promoting the autophagic clearance of amyloid beta (Aβ).
The biphasic changes of microRNAs were obtained from RNA-seq data and verified by qRT-PCR in early-stage (6 months) and late-stage (12 months) APPswe/PS1dE9 mice (hereinafter referred to as AD mice). The AD progression was determined by analyzing Aβ levels, neuron numbers (MAP2
) and activated microglia (CD68
IBA1
) in brain tissues using immunohistological and immunofluorescent staining. MRNA and protein levels of autophagic-associated genes (
) were tested to determine the autophagic activity. Morris water maze and object location test were employed to evaluate the memory and learning after antagomirs treatments in AD mice and the Aβ in the brain tissues were determined.
MiR-331-3p and miR-9-5p are down-regulated in early-stage of AD mice, whereas up-regulated in late-stage of AD mice. We demonstrated that miR-331-3p and miR-9-5p target autophagy receptors Sequestosome 1 (
) and Optineurin (
), respectively. Overexpression of miR-331-3p and miR-9-5p in SH-SY5Y cell line impaired autophagic activity and promoted amyloid plaques formation. Moreover, AD mice had enhanced Aβ clearance, improved cognition and mobility when treated with miR-331-3p and miR-9-5p antagomirs at late-stage.
Our study suggests that using miR-331-3p and miR-9-5p, along with autophagic activity and amyloid plaques may distinguish early versus late stage of AD for more accurate and timely diagnosis. Additionally, we further provide a possible new therapeutic strategy for AD patients by inhibiting miR-331-3p and miR-9-5p and enhancing autophagy.
The mammalian ocular lens is an avascular multicellular organ that grows continuously throughout life. Traditionally, its cellular organization is investigated using dissected lenses, which ...eliminates in vivo environmental and structural support. Therefore, in vivo optical imaging methods for studying lenses in their native context in live animals are urgently needed.
Here, we demonstrated that two-photon fluorescence microscopy can visualize lens cells in vivo. To maintain subcellular resolution at depth, we used adaptive optics to correct aberrations owing to ocular and lens tissues, which led to substantial signal and resolution improvements.
Imaging lens cells up to 980 µm deep, we observed novel cellular organizations including suture-associated voids, enlarged vacuoles, and large cavities, contrary to the conventional view of a highly ordered organization. We tracked these features longitudinally over weeks and observed the incorporation of new cells during growth.
Taken together, noninvasive longitudinal in vivo imaging of lens morphology using adaptive optics two-photon fluorescence microscopy will allow us to observe the development or alterations of lens cellular organization in living animals directly.
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