Nucleated red blood cells participate in myocardial regeneration in the toad Bufo Gargarizan Gargarizan

Heart regeneration is negligible in humans and mammals but remarkable in some ectotherms. Humans and mammals lack nucleated red blood cells (NRBCs), while ectotherms have sufficient NRBCs. This study used Bufo gargarizan gargarizan, a Chinese toad subspecies, as a model animal to verify our hypothesis that NRBCs participate in myocardial regeneration. NRBC infiltration into myocardium was seen in the healthy toad hearts. Heart needle-injury was used as an enlarged model of physiological cardiomyocyte loss. It recovered quickly and scarlessly. NRBC infiltration increased during the recovery. Transwell assay was done to in vitro explore effects of myocardial injury on NRBCs. In the transwell system, NRBCs could infiltrate into cardiac pieces and could transdifferentiate toward cardiomyocytes. Heart apex cautery caused approximately 5% of the ventricle to be injured to varying degrees. In the mildly to moderately injured regions, NRBC infiltration increased and myocardial regeneration started soon after the inflammatory response; the severely damaged region underwent inflammation, scarring, and vascularity before NRBC infiltration and myocardial regeneration, and recovered scarlessly in four months. NRBCs were seen in the newly formed myocardium. Enzyme-linked immunosorbent assay and Western blotting showed that the levels of tumor necrosis factor-α, interleukin- 1β, 6, and11, cardiotrophin-1, vascular endothelial growth factor, erythropoietin, matrix metalloproteinase- 2 and 9 in the serum and/or cardiac tissues fluctuated in different patterns during the cardiac injury-regeneration. Cardiotrophin-1 could induce toad NRBC transdifferentiation toward cardiomyocytes in vitro. Taken together, the results suggest that the NRBC is a cell source for cardiomyocyte renewal/regeneration in the toad; cardiomyocyte loss triggers a series of biological processes, facilitating NRBC infiltration and transition to cardiomyocytes. This finding may guide a new direction for improving human myocardial regeneration.     

AnnexinA7 promotes epithelial–mesenchymal transition by interacting with Sorcin and contributes to aggressiveness in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and metastasis is the major cause of the high mortality of HCC. In this study, we identified that AnnexinA7 (ANXA7) and Sorcin (SRI) are overexpressed and interacting proteins in HCC tissues and cells. In vitro functional investigations revealed that the interaction between ANXA7 and SRI regulated epithelial–mesenchymal transition (EMT), and then affected migration, invasion, and proliferation in HCC cells. Furthermore overexpression/knockdown of ANXA7 was remarkably effective in promoting/inhibiting tumorigenicity and EMT in vivo. Altogether, our study unveiled a mechanism that ANXA7 promotes EMT by interacting with SRI and further contributes to the aggressiveness in HCC, which provides a novel potential therapeutic target for preventing recurrence and metastasis in HCC.Subject terms: Medical research, Genetics research     

Universal Strategy with Structural and Chemical Crosslinking Interface for Efficient and Stable Perovskite Solar Cells

Due to the limited interface contact and weak interfacial interaction, planar heterojunction perovskite solar cells (PSCs) have space for further improvement. Herein, a structural and chemical crosslinking interface is proposed and constructed by introducing an extra layer, which blends tin dioxide (SnO₂) nanoparticles with chloride salts. Since the incorporated materials can be dissolved during the fabrication of perovskite, the quality of perovskite films is improved, leading to larger grain size and reduced trap-state density. Also, more chloride ions at the SnO₂/perovskite interface are observed and the interaction between Cl⁻ and Sn⁴⁺ is confirmed. It results in more pronounced n-type SnO₂ with better conductivity and deeper conduction bands, leading to preferable energy level alignment between SnO₂ and perovskite. Consequently, the open-circuit voltage and fill factor of the devices increase, and target cells present better stability, retaining 98% of initial efficiencies after >10 000 h storage in dry air (≈5% relative humidity) and maintaining 85.50% of the initial efficiency after 1000 h of operation under light. This strategy enables the achievement of 25.28% efficiency with a low bandgap (1.53 eV) perovskite composition, and it is confirmed to be universal when other related materials are utilized.     

基于DNA条形码评估西双版纳国家级自然保护区对樟科植物进化历史的保护

为评估西双版纳国家级自然保护区对樟科这一重要植物类群进化潜力的保护情况, 揭示将物种进化历史纳入生物多样性保护评估的重要性, 本研究通过对西双版纳地区长期的野外调查并查阅标本记录与文献资料, 整理出该地区樟科13属121种物种的具体分布信息, 以植物条形码ITS序列作为分子标记构建了反映整个西双版纳地区樟科植物系统发育关系的系统发育树。我们以此为基础, 从物种层面分析了各物种的进化特异性(evolutionary distinctiveness, ED), 从区域层面分析了自然保护区内、外以及32个行政乡镇的系统发育多样性(phylogenetic diversity, PD), 并结合物种丰富度(species richness, SR)与物种濒危等级, 综合探讨了西双版纳国家级自然保护区对樟科植物进化历史的保护情况。研究发现, 西双版纳国家级自然保护区仅拥有整个西双版纳地区54.5%的樟科物种数, 却保护了该地区樟科植物约88.8%的进化历史, 没有被列入保护范围但却拥有高系统发育多样性的区域有打洛镇、易武乡等。就物种而言, 进化特异性相对较高的19个物种中, 有5种(26.3%)在自然保护区内没有分布; 濒危等级高的54个物种中, 有20种(37.0%)在自然保护区没有分布, 同时拥有高进化特异性和濒危等级的物种仅有1种不在保护区内分布。结果表明, 虽然西双版纳国家级自然保护区对樟科这一植物类群的系统发育多样性以及高保护价值物种的保护较好, 但仍有部分重要樟科植物的进化历史没有涵盖在现有自然保护区范围内; 按照传统方法设定的自然保护区虽能在一定程度上保护樟科物种的进化历史, 但仍然存在与标准化系统发育多样性保护策略相矛盾的地方。因此, 今后在建立自然保护区时, 应将系统发育多样性考虑在内, 以保护生物多样性应对环境变化的潜力。     

Bacillus velezensis strain HYEB5-6 as a potential biocontrol agent against anthracnose on Euonymus japonicus

Anthracnose is a foliar disease of the Euonymus shrub caused by Colletotrichum gloeosporioides. In this study, the bacterium HYEB5-6 was isolated from inside one-year-old branches of healthy Euonymus japonicus and showed significant antifungal activities against various phytopathogenic fungi, including C. gloeosporioides s.s. HYCG2-3, in dual culture experiments. The HYEB5-6 isolate significantly decreased lesion diameter and disease index caused by C. gloeosporioides inoculation on detached leaves of E. japonicus. The effects of HYEB5-6 metabolites on the invading structure of the fungus were investigated. Bacterial metabolites inhibited conidial germination, the growth of the germ tube and appressorium formation, possibly through protease and glucanase of HYEB5-6 by managing the mycelial cell wall. The HYEB5-6 isolate also produced a massive biofilm, which might facilitate leaf colonisation. These results indicate that HYEB5-6 has the potential for use as a biological control agent against C. gloeosporioides. The HYEB5-6 isolate was identified as Bacillus velezensis based on its biochemical characteristics and its 16S rRNA gene sequence.     

The discovery of tetrahydropyridine analogs as hNav1.7 selective inhibitors for analgesia

hNav1.7 small molecular inhibitors have attracted lots of attention by its unique analgesic effect. Herein, we report the design and synthesis of a novel series of tetrahydropyridine analogs as hNav1.7 inhibitors for analgesia. Detail structural–activity relationship (SAR) studies were undertaken towards improving hNav1.7 activity, in vitro ADME, and in vivo PK profiles. These efforts resulted in the identification of compound (?)-15h, a highly potent and selective hNav1.7 inhibitor with good ADME and PK profiles.     

MARK inhibitors: Declaring a No-Go decision on a chemical series based on extensive DMPK experimentation

Attempts to optimize pharmacokinetic properties in a promising series of pyrrolopyrimidinone MARK inhibitors for the treatment of Alzheimer’s disease are described. A focus on physical properties and ligand efficiency while prosecuting this series afforded key tool compounds that revealed a large discrepancy in the rat in vitro–in vivo DMPK (Drug Metabolism/Pharmacokinetics) correlation. These differences prompted an in vivo rat disposition study employing a radiolabeled representative of the series, and the results from this experiment justified the termination of any further optimization efforts.     

Development of MBRI-001, a deuterium-substituted plinabulin derivative as a potent anti-cancer agent

Plinabulin, a drug targeting microtubule of cancer cells, has been currently tried in its phase III clinical study. However, low efficacy caused by poor pharmacokinetic (PK) properties has been considered to be the main obstacle to approved by the Food and Drug Administration. Herein, we introduced a deuterium atom as an isostere in its structure to become a new compound named (MBRI-001, No. 9 in a series of deuterium-substituted compounds). The structure of MBRI-001 was characterized by HRMS, NMR, IR and a single crystal analysis. MBRI-001 exhibited better pharmacokinetic characteristics than that of plinabulin. Additionally, its antitumor activity is in a low nanomolar level for a variety of cancer cell lines and high activity against human NCI-H460 xenograted in mice intravenous administration. Importantly, continuous administration of MBRI-001 exhibited lower toxicity compared to docetaxel. We thus suggest that MBRI-001 could be developed as a promising anti-cancer agent in near future.