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Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), such as Erlotinib, have demonstrated remarkable efficacy in the treatment of non-small cell lung cancer (NSCLC) patients with mutated EGFR. However, the efficacy of EGFR-TKIs in wild-type (wt) EGFR tumours has been shown to be marginal. Methods that can sensitize Erlotinib to EGFR wild-type NSCLC remain rare. Herein, we developed a multifunctional superparamagnetic nanotheranostic agent as a novel strategy to potentiate Erlotinib to EGFR-wt NSCLCs. Our results demonstrate that the nanoparticles can co-escort Erlotinib and a vascular epithermal growth factor (VEGF) inhibitor, Bevacizumab (Bev), to EGFR-wt tumours. The nanotheranostic agent exhibits remarkable effects as an inhibitor of EGFR-wt tumour growth. Moreover, Bev normalizes the tumour embedded vessels, further promoting the therapeutic efficacy of Erlotinib. In addition, the tumour engagement of the nanoparticles and the vascular normalization could be tracked by magnetic resonance imaging (MRI). Collectively, our study, for the first time, demonstrated that elaborated nanoparticles could be employed as a robust tool to potentiate Erlotinib to EGFR-wt NSCLC, paving the way for imaging-guided nanotheranostics for refractory NSCLCs expressing EGFR wild-type genes.

Metastasis and chemo-resistance are still important factors that limit the overall efficacy of colorectal cancer treatment. Understanding the detailed molecular mechanism and identifying potential biomarkers are of great value in prognosis prediction and risk stratification. We investigated the role of miR-582-5p in colorectal cancer pathogenesis, progression and chemo-resistance. Furthermore, we explored the underlying molecular mechanism of miR-582-5p in modulation of malignant behaviors of colorectal cancer cells. Clinical samples and colorectal cancer cell lines were applied to explore miR-582-5p expression level and its significance on tumor cell metastasis and chemo-resistance. Transwell study and cellular survivability study were performed to explore the influences of miR-582-5p expression modulation on tumor cell chemo-resistance and invasion/migration. Dual-luciferase reporter gene assay was conducted to explore the influences of miR-582-5p on its target gene TNKS2. Colorectal cancer patients with lymph node or distal organ metastatic diseases exhibited significantly lower level of miR-582-5p. In vitro studies have indicated that miR-582-5p inhibition significantly increased migration and chemo-resistant capabilities of tumor cells. And dual-luciferase reporter gene assay demonstrated that miR-582-5p exhibited its influences on the biological behavior of tumor cells by targeting TNKS2. Our study demonstrated for the first time that miR-582-5p played an important role for colorectal tumor cell metastasis and chemo-resistance. Our research also indicated that miR-582-5p and its target gene TNKS2 could be novel biomarkers for metastatic disease prediction, overall prognosis evaluation, as well as potential therapeutic target for colorectal cancer patients.

Iron dyshomeostasis is associated with hepatocellular carcinoma (HCC) development. However, the role of iron in HCC metastasis is unknown. This study aimed to elucidate the underlying mechanisms of iron’s enhancement activity on HCC metastasis. In addition to the HCC cell lines and clinical samples in vitro, iron deficient (ID) mouse models were generated using iron-free diet and transferrin receptor protein knock out, followed by administration of HCC tumors through either orthotopic or ectopic route. Clinical metastatic HCC samples showed significant ID status, accompanied by overexpression of sphingosine-1-phosphate transporter spinster homologue 2 (SPNS2). Mechanistically, ID increased SPNS2 expression, leading to HCC metastasis in both cell cultures and mouse models. ID not only altered the anti-tumor immunity, which was indicated by phenotypes of lymphatic subsets in the liver and lung of tumor-bearing mice, but also promoted HCC metastasis in a cancer cell autonomous manner through the SPNS2. Since germline knockout of globe SPNS2 showed significantly reduced HCC metastasis, we further developed hepatic-targeting recombinant adeno-associated virus vectors to knockdown SPNS2 expression and to inhibit iron-regulated HCC metastasis. Our observation indicates the role of iron in HCC pulmonary metastasis and suggests SPNS2 as a potential therapeutic target for the prevention of HCC pulmonary metastasis.

Spot blotch caused by Cochliobolus sativus has become an important disease in the wheat-growing regions in China that has resulted from changes in the regional climate, agricultural cultivation patterns, and the susceptible wheat varieties that are widely grown. Little information is available about virulence variability and pathogenic specialization of the C. sativus isolates from major wheat-growing regions in China. Here, 12 representative wheat varieties and foundation breeding stocks were selected to characterize the pathotypes of C. sativus isolates from infected wheat plants. Based on the infection phenotypes in the 12 differential genotypes at the seedling stage, 70 Chinese pathotypes were identified from 110 isolates and clustered into three virulence groups. The high virulence isolates were collected from wheat leaves, crowns, and roots, with most (10 of 14) from the Henan province in the Huang-Huai plain. No relationship was evident between virulence variability of C. sativus isolates and their geographic origins or types of diseased wheat tissues. C. sativus showed a significant pathogenic specialization in hosts of wheat and barley. Most of the wheat isolates (50 of 65) were avirulent to all the differential barley genotypes, and a few were virulent only to highly susceptible barley genotypes. These results indicated that C. sativus isolates from the wheat-growing regions in China varied considerably for their virulence in wheat varieties, and showed significant pathogenic specialization to the wheat and barley hosts.

Benzimidazole (BI)/triphenylamine (TPA)-based compounds (AL-1 to AL-7) were synthesized and evaluated for their cytotoxic activity in the different cell lines. Among them, AL-1 is demonstrated good cytotoxic activity in all the chosen cell lines, as observed from the MTT results. The antiproliferative activity of AL-1 against various cancer cells indicates that this BI-TPA-based compound may be applicable as a potential multi cancer inhibitor. AL-1 has a low IC50 value to kill H446, demonstrating the efficacy of the selected BI-TPA derivatives against the highly aggressive cancer cells (H446, small cell lung cancer - SCLC). The cytotoxicity performance is correlated with the presence of two redox peaks in the cyclic voltammetry (CV) analysis. It can be found in insilico analysis that, AL-1 has a good Gscore towards mutant receptor tyrosine kinase (RTK), PDGFRɑ. And it has a high stability for mutant EGFR (4RJ5) in the molecular dynamics simulation study. The small binding free energy from MM-GBSA is correlated with the formation of a stable complex structure. These studies suggest that BI-TPA-based compounds (e.g., AL-1) can be used as prospective anticancer agents to treat cancer cells and their mutant variants (resistant cancer cells).

Severe Helicobacter pylori-linked gastric disorders are especially prevalent in the East Asia region. The ability of H. pylori to cause different clinical outcomes is thought to be associated with unique sets of its genetic features. However, only few genetic features have been definitively linked to specific gastrointestinal pathologies. Genome heterogeneity of clinical H. pylori strains from patients with four different gastric disorders was studied to explore the population structure and molecular genomic features and their association with pathogenicity. Population analysis showed that 92.9% of the Shanghai H. pylori isolates were clustered in the East Asia group. Among 2,866 genes detected in all genomes, 1,146 genes formed the core genome, whereas 209 unique genes were detected in individual disease groups. The unique genes of peptic ulcer and gastric cancer groups represented the inorganic ion transport and metabolism function gene clusters. Sixteen virulence genes were detected with statistically different detection rates among the four disease groups. Furthermore, 127 clustered regularly interspaced short palindromic repeats were found with significantly different rates in the four disease groups. A total of 337 putative genomic islands were identified, and three genomic islands were individually found in more than 10% of strains. The genomic islands included several metabolism-associated genes and many genes with unknown function. In total, 88 sequence types were detected among the 112 Shanghai H. pylori isolates. Our study provides an essential milestone in the mapping of specific genomic features and their functions to identify factors needed to induce specific gastric disorders in H. pylori.

Background. ANLN and miR-30a-5p may be involved in the progression of lung adenocarcinoma (LUAD). However, their underlying mechanism in LUAD has not been completely comprehended. Methods. Differential expression analysis, binding site prediction, and survival analysis were conducted by bioinformatics approaches. ANLN mRNA and miR-30a-5p expression were detected by qRT-PCR. ANLN protein expression was detected by western blot. Cell behaviors in LUAD were examined by functional experiments. Results. ANLN was activated in LUAD cells in terms of mRNA and protein. High ANLN level was positively correlated with poor prognosis. Enforced ANLN stimulated protumorigenesis LUAD cell behaviors. miR-30a-5p could target ANLN mRNA, as revealed and verified through assays. Remarkably low miR-30a-5p expression was observed in LUAD cells, and it could repress ANLN expression. The accelerated cell behaviors by overexpression of ANLN were counteracted by upregulating miR-30a-5p. Conclusion. Overall, miR-30a-5p remarkably restrained the malignant progression of LUAD cells by constraining ANLN expression. Thus, ANLN and miR-30a-5p could be novel therapeutic targets of LUAD.

Human embryonic stem cells (hESCs) are self-renewing and pluripotent cells that originate from the inner cell mass of the blastocyst. Mitosis is fundamental to organism survival and reproduction and is responsible for the equal distribution of duplicated chromosomes into daughter cells. Mitotic dysfunction is associated with a wide variety of human diseases, not least cancer. hESCs have a unique cell cycle distribution, but it is unclear exactly how the mitotic activity of hESCs is related to their proliferation and differentiation. Here, we established a cell line of hESCs stably expressing GFP-α-tubulin and mCherry-H2B by lentiviral infection to analyze and visualize mitosis in detail. During metaphase, the mitotic spindle was smaller and wider and contained a greater proportion of astral microtubules than normal cells. In addition, spindle microtubules were more stable, and chromosome alignment was faster in hESCs than in somatic cells. We also found that the spindle assembly checkpoint was functional in hESCs. These findings thus reveal a specialized mitotic behavior of hESCs.

BACKGROUND Human spermatogonial stem cells (SSCs) are the basis of spermatogenesis. However, little is known about the developmental regulatory mechanisms of SSC due to sample origin and species differences. AIM To investigates the mechanisms involved in the proliferation of human SSC. METHODS The expression of mitogen-activated protein kinase kinase 7 (MKK7) in human testis was identified using immunohistochemistry and western blotting (WB). MKK7 was knocked down using small interfering RNA, and cell proliferation and apoptosis were detected by WB, EdU, cell counting kit-8 and fluorescence-activated cell sorting. After bioinformatic analysis, the interaction of MKK7 with c-Jun N-terminal kinases ( JNKs ) was verified by protein co-immunoprecipitation and WB. The phosphorylation of JNKs was inhibited by SP600125, and the phenotypic changes were detected by WB, cell counting kit-8 and fluorescence-activated cell sorting. RESULTS MKK7 is mainly expressed in human SSCs, and MKK7 knockdown inhibits SSC proliferation and promotes their apoptosis. MKK7 mediated the phosphorylation of JNKs, and after inhibiting the phosphorylation of JNKs, the phenotypic changes of the cells were similar to those after MKK7 downregulation. The expression of MKK7 was significantly downregulated in patients with abnormal spermatogenesis, suggesting that abnormal MKK7 may be associated with spermatogenesis impairment. CONCLUSION MKK7 regulates the proliferation and apoptosis of human SSC by mediating the phosphorylation of JNKs.

Birds’ activities may cause short-circuit damages of transmission line (TL), especially in the areas without tall trees and other vegetation. ± 400 kV Qaidam-Lhasa DC TL with an average altitude of about 4650 m in China is the highest DC TL in the world. Since November 2011 to the end of January 2017, there have been a total of 102 short-circuit damages, including 95 damages caused by birds. The damages were mainly caused by the defecation of birds. This paper analyzes the characteristics and causes of flashover damages of the Project. Moreover, A survey of birds along the TL was carried out by using line transect method and point count method, and then the comprehensive improvement measures for such bird-related outages were put forward. The results show that a total of 26 species of birds are involved in the damages, mainly including large or clustered birds such as Gyps himalayensis, Aegypius monachus, Buteo hemilasius, Buteo buteo and Corvus corax. The damages often occur at night in winter and spring. The prevention measures shall be dominated by guiding type and supplemented by isolation type and expulsion type, and focus on the treatment of tension tower. Through improvement, the outages have been greatly reduced from 2018 to now.

Plum pox, or Sharka disease, caused by infection with plum pox virus (PPV), results in enormous economic losses to the stone fruit industry. However, the frequency and distribution of PPV remain unclear in China, the world’s largest stone fruit producer. Systemic visual surveys were performed on stone fruit trees in China from 2008 to 2018, and the results suggest that plum pox disease is widely distributed on common apricots (Prunus armeniaca) and Japanese apricots (Prunus mume), with an average symptoms incidence rate >30% in the latter. In samples collected from Beijing, Nanjing, Shanghai, Wuhan, Wuxi, and Yuncheng, PPV was detected in 77% (85 of 110) of collected samples by immunochromatographic (IC) strip tests and reverse transcription PCR, and 96% (67 of 70) of samples showing Sharka symptoms were PPV positive. Transmission electron microscopy revealed filamentous particles of ∼640 × 12.5 nm (n = 19) in size and pinwheel inclusions in symptomatic plants but not in the asymptomatic and PPV-negative plants. Full-length genomes were determined for four isolates (three from Japanese apricot and one from common apricot), and phylogenetic analyses indicated that all four isolates belong to a clade PPV-D, despite slight differences in genome size. These findings not only highlight the widespread occurrence and distribution of PPV in China but also provide detailed information about the genomic characteristics and evolutionary position of PPV isolates in China.

In this work, a new species of the genus Tylototriton is described from Guangdong, southern China. Tylototriton sini sp. nov. was recorded as T. asperrimus for decades, and was indicated to represent an independent lineage based on recent molecular phylogenetic analyses. After detailed molecular analysis and morphological comparisons, Tylototriton sini sp. nov. is recognized as a distinct species which can be clearly distinguished from all known congeners by a combination of morphological characteristics and the significant divergence in the mitochondrial gene. Because the genus Tylototriton is of high conservation concern and all formally described members are protected by law, we also provide first data on the conservation status and recommendations for IUCN categorization for Tylototriton sini sp. nov. A suggestion on the species groups division of the genus Tylototriton is also provided based on their morphological differences and phylogenetic relationships.

Iodine plays a key role in maintaining thyroid homeostasis, which is influenced by hormones through almost all nucleated cells and is essential for growth and metabolism. The most common kinds of thyroid dysfunction, hypothyroidism and hyperthyroidism, are markedly related to iodine intake. In addition, the prevalence and incidence of hypothyroidism and hyperthyroidism are much higher in women than in men. However, the association between thyroid homeostasis and the gut microbiota is not yet completely clear, especially when comparing women and men. In this study, differences in the gut microbiota compositions, metabolic syndromes, and molecular mechanisms of female and male mice were investigated after iodine supplementation. The gut microbiota in male mice was changed more than that of female mice. The abundances of Muribacium intestinale, Barnesiella, Alloprevotella, Enterococcus, Desulfovibrionaceae, and Clostridium were significantly increased in female mice. This finding indicates that the high risk of thyroid disease in women could be related to the gut microbiota composition.

This study aimed to investigate the effect of repeated batch fermentation of cocultured Saccharomyces bayanus Y4 and Torulaspora delbrueckii Y7 on the quality of greengage wine. The acidity, as well as citric acid and L-malic acid content, decreased significantly with the batches. The citric acid content of the single culture in each batch was 58.59, 26.27, and 8.45 g/L, respectively. Additionally, the ester content increased with the batches. The respective values were 1627.93, 2249.46, and 2491.17 μg/L for the prophase of coculture. However, volatile content in the fresh wine of Y4 yeast in each batch was high. Ketone and terpene contents in the first batch of coculture significantly increased from 31.64 to 95.60 μg/L and 58.58–95.13 μg/L, respectively. Furthermore, a significant difference was observed between the microbial communities fermented using single culture and coculture. The change in fungal community diversity for coculture pattern was higher than that in the mash-inoculated single strain, which decreased the abundance of dominant fungi. Pichia, Stropharia, Suillus, Malassezia, Trichoderma, Faecalibacterium, and Butyricicoccus were associated with esters, terpenes, phenylethyl alcohol, and β-ionone. Our study provides a new avenue to improve the flavour and quality of wine brewed using a characteristic fruit.

The axonemal central pair (CP) are non-centrosomal microtubules critical for planar ciliary beat. How they form, however, is poorly understood. Here, we show that mammalian CP formation requires Wdr47, Camsaps, and microtubule-severing activity of Katanin. Katanin severs peripheral microtubules to produce central microtubule seeds in nascent cilia. Camsaps stabilize minus ends of the seeds to facilitate microtubule outgrowth, whereas Wdr47 concentrates Camsaps into the axonemal central lumen to properly position central microtubules. Wdr47 deficiency in mouse multicilia results in complete loss of CP, rotatory beat, and primary ciliary dyskinesia. Overexpression of Camsaps or their microtubule-binding regions induces central microtubules in Wdr47−/− ependymal cells but at the expense of low efficiency, abnormal numbers, and wrong location. Katanin levels and activity also impact the central microtubule number. We propose that Wdr47, Camsaps, and Katanin function together for the generation of non-centrosomal microtubule arrays in polarized subcellular compartments., Ciliary beating is mediated by the axonemal central pair microtubules, though how these non-centrosomal microtubules form is poorly understood. Here the authors show that a trio of proteins act cooperatively to initiate central microtubule formation in mammals.

This study aimed to explore the possibility of miR‐423‐5p modified adipose‐derived stem cell (ADSCs) therapy on streptozotocin (STZ)‐induced diabetes mellitus erectile dysfunction (DMED) rats. MiR‐423‐5p was knocked down in ADSCs. ADSCs, NC‐miR‐ADSCs and miR‐ADSCs were co‐cultured with human umbilical vein endothelial cells (HUVECs). Normal and high glucose media were supplemented. The supernatant and HUVECs were collected for assessment of eNOS and VEGFa expression, cell proliferation, and apoptosis. HUVECs co‐cultured with ADSCs or miR‐ADSCs exhibited higher eNOS and VEGFa protein expression levels compared to DM groups. MiR‐ADSCs enhanced HUVEC proliferation compared to the ADSCs and NC‐miR‐ADSCs. Lower apoptotic rates were observed when HUVECs were co‐cultured with miR‐ADSCs, compared to ADSCs and NC‐miR‐ADSCs. Fifteen male Sprague‐Dawley (SD) rats aged 12 weeks were induced to develop diabetes mellitus by intraperitoneal injection with STZ, and five healthy SD rats were used as normal controls. Eight weeks after developing diabetes, the rats received ADSCs and miR‐ADSCs via injection into the corpora cavernosa, whereas normal controls and DM controls were injected with saline. Erectile function and histological assessment of penile tissues were performed 8 weeks after injection. The ICP/MAP indicated that erectile function was impaired in the DM rats compared with the normal group. Injection of ADSCs and miR‐ADSCs improved erectile function significantly and was associated with the overexpression of eNOS and VEGFa. MiR‐423‐5p knockdown in ADSCs ameliorated high glucose‐mediated damage to HUVECs and improved erectile function in DM rats by inducing eNOS and VEGFa overexpression, indicating that miR‐423‐5p may be a potential target in the treatment of DMED.

A total of 791 citrus samples were collected from 10 citrus cultivars from nine different citrus-producing areas in China, the occurrence of citrus leaf blotch virus (CLBV) was detected by RT-PCR, and the coat protein (CP) genes of CLBV were amplified to analyze the variability of the CP genes. Results showed that in China, the incidence of CLBV was 7.7%, while CLBV was found in all sample locations and detected positive in 9 out of 10 citrus cultivars, indicating that CLBV is common in China. The CLBV isolates showed low diversity in their CP genes, and phylogenetic analysis revealed that CLBV isolates in this study were separated into different branches, indicating no clear relationship between their variation and citrus cultivar or geographic origin. The findings from this study provide important information for further research towards the population structure and epidemiology of CLBV.

Fe3O4 nanoparticles (NPs) have potential effects on the anaerobic digestion of excess sludge. The effects of different concentrations of Fe3O4 NPs (0, 100, 200, 400 and 600 mg/L) on enzymes and microorganisms in anaerobic digestion were studied to explore the mechanism of the effect of Fe3O4 NPs on anaerobic digestion. The results showed that 100, 200 and 400 mg/L Fe3O4 NPs could promote anaerobic digestion, and 200 mg/L Fe3O4 NPs had the most obvious promoting effect. The activities of protease, cellulase, dehydrogenase, acetic kinase and coenzyme F420 in the 200 mg/L Fe3O4 NPs group reached 120 U/mg VS, 71.75 U/g VS, 135 U/mL, 94 mol/L, 1.37 umol/g VSS, respectively, which were 3.8 times, 1.5 times, 1.2 times, 1.2 times and 1.6 times of the blank group, respectively. However, when the concentration of Fe3O4 NPs reached 600 mg/L, the activities of cellulase, dehydrogenase and acetic kinase were lower than those of the blank group, and anaerobic digestion was inhibited. The above conclusions can also be confirmed by high-throughput sequencing. The abundance of longilinea and ornatilina in the 200 mg/L Fe3O4 NPs group was 8.8% and 4.1% respectively, and methanthrix abundance was 69%, which was more conducive to decomposition acetic acid into CH4.

Aflatoxin B1 (AFB1) induced intestinal epithelial damage in rodent models, which indicates that long-term exposure to AFB1 may cause chronic gut disorders. In this study, we tested the hypothesis that AFB1-induced adverse effects on gut is mediated by gut-microbiota, which is partially reflected by the changes of fecal microbiome and metabolome. F344 rats were orally exposed to AFB1 of 0, 5, 25, and 75 µg kg−1 body weight for 4 weeks and fecal samples were collected. An ion-fragmentation-spectrum-based metabolomics approach was developed to investigate the fecal microbiota-associated metabolic changes in fecal samples. We found that AFB1 inhibited the hepatic and intestinal metabolism of bile constituents. As compared with the controls, bile acid synthesis-associated cholesterols in rats treated with 25 µg kg−1 (the middle-dose group) were significantly decreased in the fecal samples, for example, lathosterol (45% reduction), cholesterol ester (21% reduction), chenodeoxycholic acid (20% reduction), dihydroxycholesterol (55% reduction), hydroxycholesterol (20% reduction), and 5-cholestene (29% reduction). Although disease-associated lipids were not detectable in the feces of the control group, they were found in AFB1-treated groups, including diglyceride, monoacylglyceride, 19,20-dihydroxy-docosapentaenoic acid, and phosphatidylethanolamine. Metabolisms of carbohydrates and production of short-chain fatty acids were remarkedly decreased in all treated groups. Moreover, an inflammatory-bowel-disease (IBD)-associated taxonomic structure of fecal microbiota was observed as ∼25% Lachnospiraceae, ∼25% Ruminococcaceae, and

The centrosome is a membrane-less organelle consisting of a pair of barrel-shaped centrioles and pericentriolar material and functions as the major microtubule-organizing center and signaling hub in animal cells. The past decades have witnessed the functional complexity and importance of centrosomes in various cellular processes such as cell shaping, division, and migration. In addition, centrosome abnormalities are linked to a wide range of human diseases and pathological states, such as cancer, reproductive disorder, brain disease, and ciliopathies. Herein, we discuss various functions of centrosomes in development and health, with an emphasis on their roles in germ cells, stem cells, and immune responses. We also discuss how centrosome dysfunctions are involved in diseases. A better understanding of the mechanisms regulating centrosome functions may lead the way to potential therapeutic targeting of this organelle in disease treatment.

Background and purpose: Low-dose of carbon monoxide delivered by CO-releasing molecule-2 (CORM-2) had been confirmed having anti-inflammatory efficacy in some inflammatory diseases. Herein, we assessed the usefulness of CORM-2 in correcting intracerebral hemorrhage (ICH)-mediated inflammation.Methods: Healthy male Sprague Dawley (SD) rats randomly entered into four groups: sham-ICH, ICH, ICH+CORM-2, and ICH+ inactive carbon monoxide releasing molecule 2 (iCORM-2). ICH was induced by 50 μl of autologous arterial blood injected in situ in the rat brain. Neuro-functions of the ICH rats were evaluated with Garcia 18 scores at the 6th, 24th , 48th hou, and the fifthh day post-ICH. And brain tissues surrounding the hematoma area were collected from all ICH rats and assayed with Western blot and immunofluoresence analysis.Results: Neuro-dysfunctions in ICH rats were very severe than those in ICH +CORM-2 rats. Compared to sham group, the levels of HO-1, IKKβ, NF-κB, and TNF-α in ICH group began to elevate at the 6th hour, and reached to peak at the 48th hour post-ICH, all p < 0.05. While in ICH +CORM-2 group, the expressions of IKKβ, NF-κB, and TNF-α were very weaker than that in ICH group at every time points mentioned above; however, this phenomenon was not reproduced in ICH + iCORM-2 group. HO-1 in ICH+CORM-2 group highlighted in perihematomal area with many activated microglia (Iba-1-positive cells) and co-expressed with TNF-α, all of which were diminished at the fifth day post-ICH.Conclusion: CORM-2 may attenuate ICH-mediated inflammation by inhibiting microglial activation, which may involve the IKK/NF-κB pathway.AbbreviationsICH: intracerebral hemorrhage; CO: carbon monoxide; CORM-2: carbon monoxide releasing molecule-2; iCORM-2: inactive carbon monoxide releasing molecule-2; HO-1: heme oxygenase 1; IKKβ: inhibitor of IκB kinases β; NF-κB: nuclear factor-κB; TNF-α: tumor necrosis factor-α; Iba-1: ionized calcium binding adaptor molecule-1; IκB: inhibitor of NF-κB; iNOS: inducible nitric oxide synthase; Keap1: Kelch-like ECH-associated protein 1; Nrf2: NF-E2-related factor 2; DMSO: dimethylsulfoxide.

Background Trisomy 18 syndrome (Edwards syndrome, ES) is a type of aneuploidy caused by the presence of an extra chromosome 18. Aneuploidy is the leading cause of early pregnancy loss, intellectual disability, and multiple congenital anomalies. The research of trisomy 18 is progressing slowly, and the molecular characteristics of the disease mechanism and phenotype are still largely unclear. Results In this study, we used the commercial Chromium platform (10× Genomics) to perform sc-ATAC-seq to measure chromatin accessibility in 11,611 single umbilical cord blood cells derived from one trisomy 18 syndrome patient and one healthy donor. We obtained 13 distinct major clusters of cells and identified them as 6 human umbilical cord blood mononuclear cell types using analysis tool. Compared with the NC group, the ES group had a lower ratio of T cells to NK cells, the ratio of monocytes/DC cell population did not change significantly, and the ratio of B cell nuclear progenitor and megakaryocyte erythroid cells was higher. The differential genes of ME-0 are enriched in Human T cell leukemia virus 1 infection pathway, and the differential peak genes of ME-1 are enriched in apopotosis pathway. We found that CCNB2 and MCM3 may be vital to the development of trisomy 18. CCNB2 and MCM3, which have been reported to be essential components of the cell cycle and chromatin. Conclusions We have identified 6 cell populations in cord blood. Disorder in megakaryocyte erythroid cells implicates trisomy 18 in perturbing fetal hematopoiesis. We identified a pathway in which the master differential regulatory pathway in the ME-0 cell population involves human T cell leukemia virus 1 infection, a pathway that is dysregulated in patients with trisomy 18 and which may increase the risk of leukemia in patients with trisomy 18. CCNB2 and MCM3 in progenitor may be vital to the development of trisomy 18. CCNB2 and MCM3, which have been reported to be essential components of the cell cycle and chromatin, may be related to chromosomal abnormalities in trisomy 18.

Wenhan Huang, Feifeng Ren, Lei Luo, Jun Zhou, Dongmei Huang, Lin Tang Department of Rheumatology and Immunology of the Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Lin TangDepartment of Rheumatology and Immunology of the Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, People’s Republic of ChinaEmail hopetang@163.comObjective: Clinical characterization of lipid metabolism in untreated patients with anti-melanoma differentiation-associated gene 5 antibodies-positive (anti-MDA5+).Methods: Body-mass index (BMI), autoantibodies, lipid levels, and serum ferritin levels in 57 anti-MDA5+ patients were determined in the Department of Rheumatology and Immunology of the Second Affiliated Hospital of Chongqing Medical University.Results: Plasma high-density lipoprotein (HDL) and apolipoprotein A1 (ApoA1) levels were significantly lower in deceased group than in the survival group (P < 0.05). Plasma levels of HDL and ApoA1 were significantly lower in patients who were simultaneously anti-MDA5+ and anti-Ro-52+ than in patients who were anti-MDA5+ alone (P < 0.05). Plasma levels of total cholesterol, low-density lipoprotein, HDL, and ApoA1 were significantly decreased in patients with high levels of serum ferritin compared with patients with low levels (P < 0.05). There were no significant differences in blood lipid levels between patients grouped according to BMI.Conclusion: 1) HDL and ApoA1 levels are important indicators of poor prognosis in anti-MDA5+ patients; 2) Dysregulated lipid metabolism in anti-MDA5+ patients is closely associated with anti-Ro-52 antibody and ferritin levels but independent of BMI; 3) HDL involvement in inflammation and immune regulation merits close attention by rheumatologists.Keywords: anti-melanoma differentiation-associated gene 5 antibodies, anti-Ro-52 antibody, lipid, high-density lipoprotein, apolipoprotein A1

Adenosine-to-inosine (A-to-I) RNA editing is a widespread posttranscriptional modification that has been shown to play an important role in tumorigenesis. Here, we evaluated a total of 19,316 RNA editing sites in the tissues of 80 lung adenocarcinoma (LUAD) patients from our Nanjing Lung Cancer Cohort (NJLCC) and 486 LUAD patients from the TCGA database. The global RNA editing level was significantly increased in tumor tissues and was highly heterogeneous across patients. The high RNA editing level in tumors was attributed to both RNA (ADAR1 expression) and DNA alterations (mutation load). Consensus clustering on RNA editing sites revealed a new molecular subtype (EC3) that was associated with the poorest prognosis of LUAD patients. Importantly, the new classification was independent of classic molecular subtypes based on gene expression or DNA methylation. We further proposed a simplified model including eight RNA editing sites to accurately distinguish the EC3 subtype in our patients. The model was further validated in the TCGA dataset and had an area under the curve (AUC) of the receiver operating characteristic curve of 0.93 (95%CI: 0.91-0.95). In addition, we found that LUAD cell lines with the EC3 subtype were sensitive to four chemotherapy drugs. These findings highlighted the importance of RNA editing events in the tumorigenesis of LUAD and provided insight into the application of RNA editing in the molecular subtyping and clinical treatment of cancer.

Background The cylindromatosis (CYLD) tumor suppressor is a microtubule‐associated deubiquitinase that plays a critical role in the regulation of cell signaling and contributes to a variety of physiological and pathological processes. However, the functions of CYLD in zebrafish are less well known, particularly with regard to their development and physiology. In this context, we investigated the loss of function of CYLD in zebrafish via transcription activator‐like effector nuclease (TALEN)‐based gene deletion. Methods Semi‐quantitative RT‐PCR was used to quantify CYLD mRNA expression in zebrafish embryos at various developmental stages. We also performed whole‐mount in situ hybridization to further assess the dynamic expression and distribution of CYLD in the entire zebrafish embryos at different stages. In addition, we deleted CYLD in zebrafish with TALENs to investigate its potential impact on embryonic development. Results The expression of CYLD mRNA varied during early embryonic development. The CYLD mRNA localized to the brain and notochord of developing zebrafish embryos. Homozygous deletion of CYLD resulted in embryonic death before 8 h post‐fertilization. Conclusions CYLD appears to play an important role in central nervous system development in zebrafish. Although severe embryonic death restricted analysis of homozygous mutants, further research into the role of CYLD in central nervous system development is warranted., Cylindromatosis (CYLD) has important pathophysiological roles in humans. More than just a tumor suppressor, CYLD has many potential functions. We exploited the zebrafish model to investigate dynamic changes in CYLD expression during embryonic development. In doing so, we discovered a potential role for CYLD in brain and notochord development, providing experimental evidence for a novel pathophysiological role in central nervous system development.

Purpose RC48 contains the novel humanized anti-HER2 antibody hertuzumab conjugated to MMAE via a cleavable linker. A phase I study was initiated to evaluate the toxicity, MTD, PK, and antitumor activity of RC48 in patients with HER2-overexpressing locally advanced or metastatic solid carcinomas, particularly gastric cancer. Patients and methods This was a 2-part phase I study. Successive cohorts of patients received escalating doses of RC48 (0.1 mg/kg, 0.5 mg/kg, 1.0 mg/kg, 2.0 mg/kg, 2.5 mg/kg, and 3.0 mg/kg). Dose expansion proceeded at the dose of 2.0 mg/kg Q2W. The efficacy and safety set included all patients who received at least one dose of RC48. Results Fifty-seven patients were enrolled, the MTD was unavailable due to termination of 3.0 mg/kg cohort; 2.5 mg/kg Q2W was declared the RP2D. RC48 was well tolerated, the most frequent grade 3 or worse TRAEs included neutropenia (19.3%), leukopenia (17.5%), hypoesthesia (14.0%), and increased conjugated blood bilirubin (8.8%). Four deaths occurred during the whole study, three of which were believed to be related to RC48. Overall, ORR and DCR were 21.0% (12/57) and 49.1% (28/57). Notably, patients who were HER2 IHC2+/FISH- responded similarly to those who were IHC2+/FISH+ and IHC3+, with ORRs of 35.7% (5/14), 20% (2/10), and 13.6% (3/22), respectively. In patients who were pretreated with HER2-targeted drugs, RC48 also showed promising efficacy, with ORR of 15.0% (3/20) and DCR of 45.0% (9/20). Conclusion RC48 was well tolerated and showed promising antitumor activity in HER2-positive solid tumors, including gastric cancer with HER2 IHC 2+/FISH- status. Clinical trial information NCT02881190.

Our previous studies have shown that the Adipose‐derived mesenchymal stem cells (ADSCs) can regulate metastasis and development of ovarian cancer. However, its specific mechanism has yet to be fully revealed. In this study, an RNA‐seq approach was adopted to compare the differences in mRNA levels in ovarian cancer cells being given or not given ADSCs. The mRNA level of paired box 8 (PAX8) changed significantly and was confirmed as an important factor in tumour‐inducing effect of ADSCs. In comparison with the ovarian cancer cells cultured in the common growth medium, those cultured in the medium supplemented with ADSCs showed a significant increase of the PAX8 level. Moreover, the cancer cell growth could be restricted, even in the ADSC‐treated group (P

Sensory perception and metabolic homeostasis are known to deteriorate with ageing, impairing the health of aged animals, while mechanisms underlying their deterioration remain poorly understood. The potential interplay between the declining sensory perception and the impaired metabolism during ageing is also barely explored. Here, we report that the intraflagellar transport (IFT) in the cilia of sensory neurons is impaired in the aged nematode Caenorhabditis elegans due to a daf-19/RFX-modulated decrease of IFT components. We find that the reduced IFT in sensory cilia thus impairs sensory perception with ageing. Moreover, we demonstrate that whereas the IFT-dependent decrease of sensory perception in aged worms has a mild impact on the insulin/IGF-1 signalling, it remarkably suppresses AMP-activated protein kinase (AMPK) signalling across tissues. We show that upregulating daf-19/RFX effectively enhances IFT, sensory perception, AMPK activity and autophagy, promoting metabolic homeostasis and longevity. Our study determines an ageing pathway causing IFT decay and sensory perception deterioration, which in turn disrupts metabolism and healthy ageing., Sensory perception and metabolic homeostasis are known to deteriorate with ageing, while mechanisms underlying their deterioration remain poorly understood. Here, the authors demonstrate that decrease of intraflagellar transport in the cilia of sensory neurons impairs sensory perception and metabolism in ageing C. elegans.

For marine invertebrates with no adaptive immune system, ferritin is a major intracellular iron‐storage protein with a critical role in innate immunity. Here, we present the crystal structures of two novel ferritins [Fer147 and Phascolosoma esculenta ferritin (PeFer)] from the marine invertebrate P. esculenta, which resides in muddy‐bottom coastal regions. Fer147 and PeFer exhibit the 4‐3‐2 symmetry of cage‐like hollow shells containing 24 subunits, similar to other known ferritins. Fer147 and PeFer contain both the conserved ferroxidase center and threefold channels. Subtle structural differences in the putative nucleation sites suggest possible routes of metal ion movement in the protein shells. However, the marked variation in the electrostatic potential of the threefold channels in Fer147 and the fourfold channels in PeFer suggests significant diversity between Fer147 and PeFer in terms of metal ion aggregation and cation exclusion. In summary, the presented crystal structures may serve as references for studies of the iron‐storage mechanism of additional ferritins from marine invertebrates., In this study, we present the crystal structures of two novel ferritins from the marine invertebrate Phascolosoma esculenta, which resides in muddy‐bottom coastal regions. They contain both the conserved ferroxidase center and 3‐fold channels, but exhibit marked variation in the electrostatic potential of the 3‐fold channels in Fer147 and the 4‐fold channels in PeFer.

Guanine quadruplex nucleic acids (G4s) are involved in key biological processes such as replication or transcription. Beyond their biological relevance, G4s find applications as biotechnological tools since they readily bind hemin and enhance its peroxidase activity, creating a G4-DNAzyme. The biocatalytic properties of G4-DNAzymes have been thoroughly studied and used for biosensing purposes. Despite hundreds of applications and massive experimental efforts, the atomistic details of the reaction mechanism remain unclear. To help select between the different hypotheses currently under investigation, we use extended explicit-solvent molecular dynamics (MD) simulations to scrutinize the G4/hemin interaction. We find that besides the dominant conformation in which hemin is stacked atop the external G-quartets, hemin can also transiently bind to the loops and be brought to the external G-quartets through diverse delivery mechanisms. The simulations do not support the catalytic mechanism relying on a wobbling guanine. Similarly, catalytic role of the iron-bound water molecule is not in line with our results, however, given the simulation limitations, this observation should be considered with some caution. The simulations rather suggest tentative mechanisms in which the external G-quartet itself could be responsible for the unique H2O2-promoted biocatalytic properties of the G4/hemin complexes. Once stacked atop a terminal G-quartet, hemin rotates about its vertical axis while readily sampling shifted geometries where the iron transiently contacts oxygen atoms of the adjacent G-quartet. This dynamics is not apparent from the ensemble-averaged structure. We also visualize transient interactions between the stacked hemin and the G4 loops. Finally, we investigated interactions between hemin and on-pathway folding intermediates of the parallel-stranded G4 fold. The simulations suggest that hemin drives the folding of parallel-stranded G4s from slip-stranded intermediates, acting as a G4 chaperone. Limitations of the MD technique are briefly discussed.For Table of Contents Only

Background Cataracts are defects of the lens that cause progressive visual impairment and ultimately blindness in many vertebrate species. Most cataracts are age-related, but up to one third have an underlying genetic cause. Cataracts are common in captive zoo animals, but it is often unclear whether these are congenital or acquired (age-related) lesions. Results Here we used a functional candidate gene screening approach to identify mutations associated with cataracts in a captive giant panda (Ailuropoda melanoleuca). We screened 11 genes often associated with human cataracts and identified a novel missense mutation (c.686G > A) in the MIP gene encoding major intrinsic protein. This is expressed in the lens and normally accumulates in the plasma membrane of lens fiber cells, where it plays an important role in fluid transport and cell adhesion. The mutation causes the replacement of serine with asparagine (p.S229N) in the C-terminal tail of the protein, and modeling predicts that the mutation induces conformational changes that may interfere with lens permeability and cell–cell interactions. Conclusion The c.686G > A mutation was found in a captive giant panda with a unilateral cataract but not in 18 controls from diverse regions in China, suggesting it is most likely a genuine disease-associated mutation rather than a single-nucleotide polymorphism. The mutation could therefore serve as a new genetic marker to predict the risk of congenital cataracts in captive giant pandas.

Interferon regulatory factor 4 (IRF4) rearrangement is commonly detected in patients with a range of lymphoproliferative malignancies, including myelomas, large B cell lymphomas and low-grade B cell neoplasms. However, IRF4 rearrangement is generally a relatively rare finding in these latter two cancer types. In the present article, we describe and summarize the clinicopathological and genetic features of 13 cases of B cell lymphoma with IRF4 rearrangement, including 12 cases of large B cell lymphoma and one case of low-grade lymphoma exhibiting such rearrangement. These cases were detected in six females and seven males between 14 and 71 years of age. From a morphological perspective, large B cell lymphoma tumors included in this analysis exhibited large neoplastic cells in diffuse or follicular patterns, while the case of low-grade lymphoma mainly composed of small lymphocytes. All analyzed cases exhibited a split in the IRF4 gene consistent with IRF4 translocation. Three of six analyzed large B cell lymphoma cases harbored IGLL5 mutations. Mutations in SAMHD1 were detected in the low-grade lymphoma with IRF4 rearrangement case. In summary, our results offer further insight into the morphological and molecular heterogeneity of cases of B cell lymphoma exhibiting IRF4 rearrangements.

The clinical notably success of immunotherapy fosters an enthusiasm in developing drugs by enhancing antitumor immunity in the tumor microenvironment (TME). Epimedium, is a promising herbal medicine for tumor immunotherapy due to the pharmacological actions in immunological function modulation and antitumor. Here, we developed a novel systems pharmacology strategy to explore the polypharmacology mechanism of Epimedium involving in targeting TME of non-small cell lung cancer (NSCLC). This strategy integrates the active compounds screening, target predicting, network pharmacology analysis and onco-immune interacting to predict the potential active compounds that trigger the antitumor immunity. Icaritin (ICT), a major active ingredient of Epimedium, was predicted to have good drug-like properties and target immune microenvironment in NSCLC via regulating multiple targets and pathways. Then, we evidenced that the ICT effectively inhibited tumor growth in LLC tumor-bearing mice and increases the infiltration of CD8+ T cells in TME. In addition, we demonstrated that ICT promotes infiltration of CD8+ T cells in TME by downregulating the immunosuppressive cytokine (TNF-α, IL10, IL6) and upregulating chemotaxis (CXCL9 and CXCL10). Overall, the systems pharmacology strategy offers an important paradigm to understand the mechanism of polypharmacology of natural products targeting TME.

Solid-gas-water phase partitioning of mercury (Hg) and the processes governing its diffusivity within soils are poorly studied. In this study, landscape and forest species dependences of gaseous elemental Hg (Hg(0)) in soil profiles (0-50 cm) were investigated over four seasons in eight subtropical (130 days) and temperate (96 days) forest plots. The vertical soil pore Hg(0) concentrations differed between subtropical (Masson pine, broad-leaved forest, and open field) and temperate (Chinese pine, larch, mixed broad-leaf forests, and open field) catchments, with annual averages ranging from 6.73 to 15.8 and 0.95 to 2.08 ng m-3, respectively. The highest Hg(0) concentrations in soil gas consistently occurred in the upper mineral or organic horizons, indicating immobilization of Hg(0) in mineral soils. A strongly positive relationship between pore Hg(0) concentrations and ratios of Hg to organic matter (SOM) in soils suggests that the vertical distribution of Hg(0) is related to soil Hg(0) formation by Hg(II) reduction and sorption to SOM. Temperature was also an important driver of Hg(0) production in soil pores. Based on measurements of soil-air Hg(0) exchange, diffusion coefficients (Ds) of Hg(0) between soil and atmosphere were calculated for field sites, providing a foundation for future development and validation of terrestrial Hg models.

Translation occurring on cytoplasmic mRNA is precisely governed at three consecutive stages, including initiation, elongation and termination. A growing body of evidence has revealed that an emerging epitranscriptomic code N6-methyladenosine (m6A), asymmetrically present in a large subset of coding and non-coding transcripts, is crucially required for mediating the translatomic stability. Through recruiting translation machinery proteins, serving as a physical barrier, or directing RNA structural rearrangement and mRNA looping formation, m6A has been decoded to modulate translational dynamics through potentially influencing the progress of different stages, thereby forming an additional layer of complexity to the regulation of translation. In this review, we summarize the current understanding of how m6A guides mRNA translation under normal and stress conditions, highlighting the divergent molecular mechanisms of multifarious regulation of m6A-mediated translation.

Long noncoding RNAs (lncRNAs) have been identified as prognostic biomarkers and functional regulators in human tumors. In our study, we aim to investigate the roles of lncRNA SND1-IT1 (SND1-IT1) in retinoblastoma (RB). We observed that SND1-IT1 was highly expressed in both RB specimens and cells, and associated with poorer prognosis of RB patients. Functional investigation revealed that downregulation of SND1-IT1 suppressed RB cell proliferation, migration and invasion in vitro and restrained RB tumorigenesis in vivo. MiR-132-3p was predicted to interact with SND1-IT1. RT-qPCR and dual-luciferase reporter assays verified the regulation of miR-132-3p by SND1-IT1 in RB cells. In addition, SND1-IT1 enhanced the expression of SMAD2 by sponging miR-132-3p. Rescue experiments revealed that knockdown of miR-132-3p reversed the inhibiting effects of miR-132-3p knockdown on RB cells. Overall, SND1-IT1 can promote the progression of RB cells through miR-132-3p/SMAD2 axis, suggesting that l SND1-IT1 might be a novel biomarker and potential target for RB., Graphical abstract

Background Peptide drugs provide promising regimes in bladder cancer. In order to identify potential bioactive peptides involved in bladder cancer, we performed the present study. Methods Liquid chromatography/mass spectrometry assay was used to compare the endogenous peptides between bladder cancer and normal control. The potential biological functions of these dysregulated peptides are assessed by GO analysis and KEGG pathway analysis of their precursors. The SMART and UniProt databases are used to identify the sequences of the dysregulated peptides located in the functional domains. The Open Targets Platform database was used to investigate the precursors related to metabolic diseases. Results A total of 9 up-regulated peptides and 110 down-regulated peptides in bladder cancer compared with normal control were identified (fold change > 1.2, P < 0.05). The MW of these dysregulated peptides ranged from 500 Da to 2500 Da and the MW of all identified peptides was below 3500 Da. The GO and KEGG pathway analysis indicated that these dysregulated peptides could play an important role in bladder cancer. Our further analysis revealed that 45HFNPRFNAHGDAN 57 derived from LGALS1 and those peptides derived from P4HB and SERPINA1 might be the promising diagnostic biomarkers and therapeutic targets of bladder cancer. Conclusion In the present study, we have identified the profile of the peptides significantly dysregulated in bladder cancer. Moreover, using bioinformatic analysis, we found the peptides derived from LGALS1, P4HB and SERPINA1 could be the promising diagnostic biomarkers and therapeutic targets of bladder cancer.

The geographic and biological diversity of China has resulted in the differential adaptation of the eastern honeybee, Apis cerana, to these varied habitats. A. cerana were collected from 14 locations in China. Their genomes were sequenced, and nucleotide polymorphisms were identified at more than 9 million sites. Both STRUCTURE and principal component analysis placed the bees into seven groups. Phylogenomic analysis groups the honeybees into many of the same clusters with high bootstrap values (91%–100%). Populations from Tibet and South Yunnan are sister taxa and together represent the earliest diverging lineage included in this study. We propose that the evolutionary origin of A. cerana in China was in the southern region of Yunnan Province and expanded from there into the southeastern regions and into the northeastern mountain regions. The Cold‐Temperate West Sichuan Plateau and Tropical Diannan populations were compared to identify genes under adaptive selection in these two habitats. Pathway enrichment analysis showing genes under selection, including the Hippo signaling pathway, GABAergic pathway, and trehalose‐phosphate synthase, indicates that most genes under selection pressure are involved in the process of signal transduction and energy metabolism. qRT‐PCR analysis reveals that one gene under selection, the AcVIAAT gene, involved in the GABAergic pathway, is responding to cold temperature stress. Through homologous recombination, we show that the AcVIAAT gene is able to replace the CNAG_01904 gene in the fungus Cryptococcus neoformans and that it makes the fungus less sensitive to conditions of oxidative stress and variations in temperature. Our results contribute to our understanding of the evolutionary origin of A. cerana in China and the molecular basis of environmental adaptation., We identified the Asian honeybee as seven genetic lineages and clarified their genetic relationship and then proposed that the origin of Chinese honeybee in the southern Asian geographic region including south Tibet, south Yunnan, and Himalaya–Hengduan Mountains. We found many genes in response to the abiotic stress were under selection for the genetic population in the regions of higher altitudes. Among these selective genes, based on homologous recombination in C. neoformans, we firstly clarified the gene involved in the pathway of transporting gamma‐aminobutyrate has contribution to tolerate the abiotic stress.

Melolonthinae are the largest group of scarab beetles, causing destructive damage to human economy for the larvae attacking a wide variety of crops, pastures and turfs. Rhizotrogina are one of the most specious groups, with their larval taxonomy far from satisfactory. In this study, the larvae of Pseudosymmachia tumidifrons and Brahmina faldermanni were studied through rearing and direct observations using light and scanning electron microscopy. The larvae share the following morphological characters: three pairs clypeal setae, six minute sensilla on haptomerum, and absence of any stridulatory structures on mandibles. The larvae also exhibit distinct morphological differences, such as the number of heli, presence or absence of proplegmatia, size arrangement of spiracles, and the arrangement of palidia on raster. The dramatically morphological differences between these two closely related genera indicate the heterogeneity of the subtribe Rhizotrogina. The morphological and functional diversity of raster were briefly discussed.

Tripartite motif–containing protein 21 (TRIM21) is a cytosolic antibody receptor that targets the internalized virus–antibody complex to the proteasome for degradation. However, the precise mechanism regulating TRIM21 activity is unknown. Here we show that TRIM21 is a substrate of histone deacetylase 6 (HDAC6) and that its function is regulated by acetylation. HDAC6 interacts with TRIM21 through its PRYSPRY motif and deacetylates TRIM21 at lysine 385 and lysine 387, thus promoting its homodimerization. Inhibiting HDAC6 activity increases TRIM21 acetylation, and hyperacetylation blocks TRIM21 dimerization and ubiquitination, preventing its binding to the virus–antibody complex and its degradation via the ubiquitin–proteasome pathway. HDAC6 depletion or inhibition increases virus accumulation in cells, indicative of an impaired capacity for antibody-dependent intracellular neutralization of viruses, whereas TRIM21 acetylation-deficient K385/387R mutant rescues HDAC6 depletion–caused ADIN impairment. These findings provide evidence for HDAC6 as a novel regulator of TRIM21-mediated intracellular innate immunity.

Ferritin is an important hub of iron metabolism because it stores iron during times of iron overload and releases iron during iron deficiency. Here, we present the first crystal structure of ferritin from the marine invertebrate Dendrorhynchus zhejiangensis with a 2.3 A resolution. D. zhejiangensis ferritin (DzFer) exhibits a common cage-shaped hollow sphere with 24 subunits containing the ferroxidase centers and 3-fold and 4-fold channels. The structure of DzFer shows highly conserved catalytic residues in the ferroxidase center. The metal wire formed by ferrous ions in the 3-fold channel reveals the path that iron ions use to enter and translocate into the ferroxidase site to be oxidized and finally arrive at the nucleation site. However, the electrostatic environment of the channels and pores exhibits significant and extensive variability, suggesting that ferritins execute diverse functions in different environments.

We report on a comprehensive analysis of the gut microbiomes of patients with gastrointestinal (GI) cancer receiving anti–PD-1/PD-L1 treatment. The human gut microbiota has been associated with clinical responses to anti–PD-1/PD-L1 immunotherapy in melanoma, non–small cell lung cancer, and renal cell carcinoma. We aimed to investigate this association in GI cancers. We also identified bacterial taxa with patient stratification potential. We recruited 74 patients with advanced-stage GI cancer receiving anti–PD-1/PD-L1 treatment and collected their fecal samples prior to and during immunotherapy, along with clinical evaluations. Our 16S rRNA taxonomy survey on the fecal samples revealed an elevation of the Prevotella/Bacteroides ratio in patients, with a preferred response to anti–PD-1/PD-L1 treatment, and a particular subgroup of responders harboring a significantly higher abundance of Prevotella, Ruminococcaceae, and Lachnospiraceae. The shotgun metagenomes of the same samples showed that patients exhibiting different responses had differential abundance of pathways related to nucleoside and nucleotide biosynthesis, lipid biosynthesis, sugar metabolism, and fermentation to short-chain fatty acids (SCFA). Gut bacteria that were capable of SCFA production, including Eubacterium, Lactobacillus, and Streptococcus, were positively associated with anti–PD-1/PD-L1 response across different GI cancer types. We further demonstrated that the identified bacterial taxa were predictive of patient stratification in both our cohort and melanoma patients from two previously published studies. Our results thus highlight the impact of gut microbiomes on anti–PD-1/PD-L1 outcomes, at least in a subset of patients with GI cancer, and suggest the potential of the microbiome as a marker for immune-checkpoint blockade responses. See articles by Tomita et al., p. 1236, and Hakozaki et al., p. 1243

Breast cancer (BC) is the most frequently diagnosed malignant tumors and the leading cause of death due to cancer in women around the world. A growing body of studies have documented that microRNA (miR)-135-5p is associated with the development and progression of BC. Considering that sekelsky mothers against dpp3 (SMAD3) plays a crucial role in transforming growth factor (TGF)-β/SMAD pathway and epithelial-mesenchymal transition (EMT) process, it is critical to elucidate the crosstalk and underlying regulatory mechanisms between miR-135-5p and SMAD3 in controlling TGF-β-mediated EMT in BC metastasis. Our results revealed a reciprocal expression pattern between miR-135-5p and SMAD3 mRNA in BC tissues and cell lines. Moreover, miR-135-5p was decreased in BC tissues compared to adjacent breast tissues; more interesting, miR-135-5p mRNA levels (Tumor/Normal, T/N) was further decreased in BC patients with lymph node metastasis, while SMAD3 mRNA levels were increased. Gain- and loss-of-function assays indicated that overexpression of miR-135-5p inhibited TGF-β-mediated EMT and BC metastasis in vitro and in vivo. Furthermore, knockdown of SMAD3 produced a consistent phenotype of miR-135-5p overexpression in breast cancer cells. Mechanistically, SMAD3, a pivotal transcriptional modulator of TGF-β/SMAD pathway, for the first time, was analyzed and identified as a target gene of miR-135-5p by bioinformatic algorithms and dual-luciferase reporter assays. Taken together, we clarified that miR-135-5p suppressed TGF-β-mediated EMT and BC metastasis by negatively regulating SMAD3 and TGF-β/SMAD signaling. Our findings supported that miR-135-5p may serve as a tumor suppressor, and be a valuable diagnostic biomarker for the treatment of BC.

Didymocarpus lobulatus, a new species endemic to Zhejiang province, eastern China, is described and illustrated with photographs. The new species is morphologically similar to D. heucherifolius, D. cortusifolius and D. salviiflorus in leaf morphology, but can be easily distinguished by a combination of characters, including the shape of bracts, calyx and calyx lobes.

To evaluate the association of multidrug resistance 1 (MDR1) polymorphism and the expression of P-glycoprotein (Pgp) in Chinese refractory lupus nephritis (LN) patients. Polymerase chain reaction-direct sequencing was used to analyze MDR1 polymorphism. The genotype distribution of MDR1 polymorphism in 132 SLE (systemic lupus erythematosus) patients was evaluated. ELISA was used to measure the expression of Pgp. Relationship among Pgp expression, MDR1 polymorphism, SLEDAI (SLE disease activity index), and kidney pathological score was analyzed by using One-way ANOVA and Pearson linear correlation. The frequency distribution of the MDR1 gene was consistent with the Hardy-Weinberg equilibrium. Compared with CT and CC, patients with T/T homozygote in MDR1 C3435T had significantly increased Pgp expression in the refractory group (p p p MDR1 C3435T polymorphism is significantly associated with Pgp expression in patients with refractory LN. Pgp expression is closely related to SLEDAI and renal pathological score. Thus, Pgp may be useful in evaluation of the prognosis of patients with refractory LN.