Background and Aims
No effective treatments are available for liver fibrosis. Angiogenesis is deeply involved in liver fibrogenesis. However, current controversial results suggest it is difficult to ...treat liver fibrosis through vascular targeting. There are three different microvessels in liver: portal vessels, liver sinusoids, and central vessels. The changes and roles for each of the three different vessels during liver fibrogenesis are unclear. We propose that they play different roles during liver fibrogenesis, and a single vascular endothelial cell (EC) regulator is not enough to fully regulate these three vessels to treat liver fibrosis. Therefore, a combined regulation of multiple different EC regulatory signaling pathway may provide new strategies for the liver fibrosis therapy. Herein, we present a proof‐of‐concept strategy by combining the regulation of leukocyte cell‐derived chemotaxin 2 (LECT2)/tyrosine kinase with immunoglobulin‐like and epidermal growth factor–like domains 1 signaling with that of vascular endothelial growth factor (VEGF)/recombinant VEGF (rVEGF) signaling.
Approach and Results
The CCl4‐induced mouse liver fibrosis model and NASH model were both used. During fibrogenesis, vascular changes occurred at very early stage, and different liver vessels showed different changes and played different roles: decreased portal vessels, increased sinusoid capillarization and the increased central vessels the increase of portal vessels alleviates liver fibrosis, the increase of central vessels aggravates liver fibrosis, and the increase of sinusoid capillarization aggravates liver fibrosis. The combinational treatment of adeno‐associated viral vector serotype 9 (AAV9)–LECT2–short hairpin RNA (shRNA) and rVEGF showed improved therapeutic effects, but it led to serious side effects. The combination of AAV9‐LECT2‐shRNA and bevacizumab showed both improved therapeutic effects and decreased side effects.
Conclusions
Liver vascular changes occurred at very early stage of fibrogenesis. Different vessels play different roles in liver fibrosis. The combinational treatment of AAV9‐LECT2‐shRNA and bevacizumab could significantly improve the therapeutic effects on liver fibrosis.
Since December 2019, an epidemic caused by novel coronavirus (2019-nCoV) infection has occurred unexpectedly in China. As of 8 pm, 31 January 2020, more than 20 pediatric cases have been reported in ...China. Of these cases, ten patients were identified in Zhejiang Province, with an age of onset ranging from 112 days to 17 years. Following the latest
National recommendations for diagnosis and treatment of pneumonia caused by 2019-nCoV
(the 4th edition) and current status of clinical practice in Zhejiang Province, recommendations for the diagnosis and treatment of respiratory infection caused by 2019-nCoV for children were drafted by the National Clinical Research Center for Child Health, the National Children’s Regional Medical Center, Children’s Hospital, Zhejiang University School of Medicine to further standardize the protocol for diagnosis and treatment of respiratory infection in children caused by 2019-nCoV.
Ultrafast‐response (20 μs) UV detectors, which are visible‐blind and self‐powered, in devices where an n‐type ZnO nanowire partially lies on a p‐type GaN film, are demonstrated. Moreover, a ...CdSe‐nanowire red‐light detector powered by a nanoscale ZnO/GaN photovoltaic cell is also demonstrated, which extends the device function to a selective multiwavelength photodetector and shows the function of an optical logical AND gate.
Aim
East Asia exhibits complex geomorphological and climatic characteristics. The aim of this study was to test whether the so‐called three‐step landforms of China, together with the East China Sea ...(ECS), have acted to shape specific phylogeographical patterns and affected the biogeographical history of the species belonging to the East Asian Flora.
Location
China and Japan.
Taxon
Kerria japonica (L.) DC.
Methods
Three chloroplast DNA regions and 15 nuclear microsatellite (nSSR) loci were sequenced and genotyped in 576/450 individuals of K. japonica. Phylogeographical analyses were performed to assess the genetic structure, historical gene flow and demographical history of these individuals, and climatic factors were examined to determine their effects on phylogeographical breaks. Furthermore, time‐calibrated phylogenetic trees and ancestral range reconstruction were used to infer the biogeographical history of K. japonica. Potential habitats at present and during the last glacial maximum (LGM) were identified using ecological niche modelling.
Results
Distinct phylogeographical breaks were found across the ECS and along the boundary of the three‐step landforms of China. Low historical gene flow and significant climatic differences were detected in each pair of adjacent regions. The results of molecular dating and ancestral range reconstruction indicated that K. japonica originated in North America during the mid‐Miocene (14.76 Ma), and intra‐specific diversification began in the late Miocene (7.78 Ma). Compared to the relatively stable distribution range of Chinese populations, Japanese populations experienced range expansion after the LGM in response to Quaternary climate change.
Main conclusions
Kerria japonica has a complex biogeographical history, with a mid‐Miocene origin in North America and subsequent migration into East Asia via the Bering land bridge. The onset of intra‐specific diversification was probably associated with Asian monsoon intensifications, while exposure to the ECS floor facilitated the formation of the Japanese lineage in the late Miocene. The spatiotemporal population differentiation on the Chinese mainland demonstrates the significant role of biogeographical divides delineated by the three‐step landforms of China and provides clues to understand the floristic regionalization and evolutionary history of plant diversity in East Asia, especially with respect to the Hengduan Mountains, Central China and East China.
For realizing sunlight stimulated self-healing, a crosslinked polyurethane carrying disulfide in the main chain is synthesized. Its macromolecular composition and architecture are optimized so that ...the included disulfide bonds can take part in the exchange reaction simply under illumination of the low concentration UV component of sunlight. Accordingly, the damaged polymer is allowed to be repeatedly healed in the sun in terms of strength restoration as a result of photo-triggered reversible exchange of disulfide bonds. Meanwhile, the elaborately introduced hydrogen bonding helps to quickly close cracks, favoring intimate contacts of the cracked surface and subsequent interaction of dangling chains across the interface, and eventually raising the effectiveness of the photo-reaction of the disulfide bonds in the solid phase. In addition, network rearrangement due to disulfide exchange enables multiple recycling and reshaping of the polymer under sunshine. The present proof-of-concept work would be hopefully developed into a cost-effective and environmentally friendly technology of design, fabrication and application of smart photo-sensitive polymers with high mechanical strength.
Liver fibrosis is a very common condition seen in millions of patients with various liver diseases, and yet no effective treatments are available owing to poorly characterized molecular pathogenesis. ...Here, we show that leukocyte cell-derived chemotaxin 2 (LECT2) is a functional ligand of Tie1, a poorly characterized endothelial cell (EC)-specific orphan receptor. Upon binding to Tie1, LECT2 interrupts Tie1/Tie2 heterodimerization, facilitates Tie2/Tie2 homodimerization, activates PPAR signaling, and inhibits the migration and tube formations of EC. In vivo studies showed that LECT2 overexpression inhibits portal angiogenesis, promotes sinusoid capillarization, and worsens fibrosis, whereas these changes were reversed in Lect2-KO mice. Adeno-associated viral vector serotype 9 (AAV9)-LECT2 small hairpin RNA (shRNA) treatment significantly attenuates fibrosis. Upregulation of LECT2 is associated with advanced human liver fibrosis staging. We concluded that targeting LECT2/Tie1 signaling may represent a potential therapeutic target for liver fibrosis, and serum LECT2 level may be a potential biomarker for the screening and diagnosis of liver fibrosis.
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•LECT2 is a functional ligand of EC-specific orphan receptor Tie1•LECT2-Tie1 inhibits portal angiogenesis and promotes sinusoid capillarization•LECT2-Tie1 promotes liver fibrogenesis•Divergent roles of portal angiogenesis and sinusoid capillarization in liver fibrosis
Produced by hepatocytes in response to liver damage, LECT2 signals through orphan receptor Tie1 on endothelial cells to activate Tie2 signaling in endothelial cells and promote fibrosis.
Biological lignin valorization represents a promising approach contributing to sustainable and economic biorefineries. The low level of valuable lignin‐derived products remains a major challenge ...hindering the implementation of microbial lignin conversion. Lignin's properties play a significant role in determining the efficiency of lignin bioconversion. To date, despite significant progress in the development of biomass pretreatment, lignin fractionation, and fermentation over the last few decades, little efforts have gone into identifying the ideal lignin substrates for an efficient microbial metabolism. In this Minireview, emerging and state‐of‐the‐art strategies for biomass pretreatment and lignin fractionation are summarized to elaborate their roles in modifying lignin structure for bioconversion. Fermentation strategies aimed at enhancing lignin depolymerization for microbial utilization are systematically reviewed as well. With an improved understanding of the ideal lignin structure elucidated by comprehensive metabolic pathways and/or big data analysis, modifying lignin chemistry could be more directional and effective. Ultimately, together with the progress of fermentation process optimization, biological lignin valorization will become more competitive in biorefineries.
Targeting makes efforts more efficient: Lignin's structure determines its bioconversion efficiency. In‐depth understanding of ideal lignin substrates for microbial metabolism could guide modifying lignin chemistry directionally. This Minireview summarizes advances in pretreatment, fractionation, and fermentation strategies to depolymerize and modify lignin for bioconversion.
Aim: The Himalaya-Hengduan Mountain (HHM) biodiversity hotspot including the 'sky islands' of Southwest China harbour exceptional plant diversity and endemicity at subnival summits (most of them ...exceeding 4300 m a.s.l.). This study is the first using a comparative phylogeographical framework to gain insights into the temporal origin of this highly fragmented subnival flora, and the historical factors shaping its genetic architecture as exemplified by four perennial herbs. Location: Himalaya-Hengduan Mountains, China. Methods: Based on nuclear and/or chloroplast (cp) DNA sequences for each of the four studied species, we performed AMOVA and mismatch distributional analyses to assess molecular structure, diversity and demographic history in relation to current and last glacial distributions using ecological niche modelling (ENM). Time-calibrated phylogenetic reconstructions of cpDNA data were used to infer species-specific stem and crown ages. Results: Our time estimates suggest that these species originated during the Late Pliocene or early-to-mid Pleistocene, whereas their onset of diversification generally falls into the mid-Pleistocene. All four species exhibited island-like population genetic structures, with all of them showing signatures of recent population growth and/or spatial expansion based on cpDNA. By contrast, ENM indicated that species broad-scale distributions remained fairly stable over the last glacial/post-glacial cycle. Main conclusions: The temporal origin of the four subnival HHM species is likely associated with tectonic changes in the region, while their near-simultaneous onset of diversification during the 'Naynayxungla Glaciation' (0.72-0.50 Ma) could reflect initial population divergence through climate-induced habitat fragmentation. Despite a rather stable distributional history, geographical population isolation and localized range expansion/contractions likely resulted in significant genetic structure and differentiation over the last glacial/post-glacial cycle. Overall, the present results are strongly indicative of shared evolutionary histories and phylogeographical structures among subnival plants from the 'sky island system' of the HHM region.
Recent studies have shown that certain combinations of Toll-like receptor (TLR) agonists can induce synergistic immune activation. However, it remains challenging to achieve such robust responses in ...vivo in a manner that is effective, facile, and amenable for clinical translation. Here, we show that MPLA, a TLR4 agonist, and CpG, a TLR9 agonist, can be efficiently co-loaded into synthetic high-density lipoprotein nanodiscs, forming a potent adjuvant system (ND-MPLA/CpG) that can be readily combined with a variety of subunit antigens, including proteins and peptides. ND-MPLA/CpG significantly enhanced activation of dendritic cells, compared with free dual adjuvants or nanodiscs delivering a single TLR agonist. Importantly, mice immunized with physical mixtures of protein antigens ND-MPLA/CpG generated strong humoral responses, including induction of IgG responses against protein convertase subtilisin/kexin 9 (PCSK9), leading to 17–30% reduction of the total plasma cholesterol levels. Moreover, ND-MPLA/CpG exerted strong anti-tumor efficacy in multiple murine tumor models. Compared with free adjuvants, ND-MPLA/CpG admixed with ovalbumin markedly improved antigen-specific CD8+ T cell responses by 8-fold and promoted regression of B16F10-OVA melanoma (P < 0.0001). Furthermore, ND-MPLA/CpG admixed with E7 peptide antigen elicited ~20% E7-specific CD8+ T cell responses and achieved complete regression of established TC-1 tumors in all treated animals. Taken together, our work highlights the simplicity, versatility, and potency of dual TLR agonist nanodiscs for applications in vaccines and cancer immunotherapy.
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Immune thrombocytopenia (ITP) is a common bleeding disorder caused primarily by autoantibodies against platelet GPIIbIIIa and/or the GPIb complex. Current theory suggests that antibody-mediated ...platelet destruction occurs in the spleen, via macrophages through Fc-FcγR interactions. However, we and others have demonstrated that anti-GPIbα (but not GPIIbIIIa)-mediated ITP is often refractory to therapies targeting FcγR pathways. Here, we generate mouse anti-mouse monoclonal antibodies (mAbs) that recognize GPIbα and GPIIbIIIa of different species. Utilizing these unique mAbs and human ITP plasma, we find that anti-GPIbα, but not anti-GPIIbIIIa antibodies, induces Fc-independent platelet activation, sialidase neuraminidase-1 translocation and desialylation. This leads to platelet clearance in the liver via hepatocyte Ashwell-Morell receptors, which is fundamentally different from the classical Fc-FcγR-dependent macrophage phagocytosis. Importantly, sialidase inhibitors ameliorate anti-GPIbα-mediated thrombocytopenia in mice. These findings shed light on Fc-independent cytopenias, designating desialylation as a potential diagnostic biomarker and therapeutic target in the treatment of refractory ITP.
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