Endothelial cells (ECs) form blood vessels through angiogenesis that is regulated by coordination of vascular endothelial growth factor (VEGF), Notch, transforming growth factor β, and other signals, but the detailed molecular mechanisms remain unclear.

Physical and chemical insult-induced bone marrow (BM) damage often leads to lethality resulting from the depletion of hematopoietic stem and progenitor cells (HSPCs) and/or a deteriorated BM stroma. Notch signaling plays an important role in hematopoiesis, but whether it is involved in BM damage remains unclear. In this study, we found that conditional disruption of RBP-J, the transcription factor of canonical Notch signaling, increased irradiation sensitivity in mice. Activation of Notch signaling with the endothelial cell (EC)-targeted soluble Dll1 Notch ligand mD1R promoted BM recovery after irradiation. mD1R treatment resulted in a significant increase in myeloid progenitors and monocytes in the BM, spleen and peripheral blood after irradiation. mD1R also enhanced hematopoiesis in mice treated with cyclophosphamide, a chemotherapeutic drug that induces BM suppression. Mechanistically, mD1R increased the proliferation and reduced the apoptosis of myeloid cells in the BM after irradiation. The β chain cytokine receptor Csf2rb2 was identified as a downstream molecule of Notch signaling in hematopoietic cells. mD1R improved hematopoietic recovery through up-regulation of the hematopoietic expression of Csf2rb2. Our findings reveal the role of Notch signaling in irradiation- and drug-induced BM suppression and establish a new potential therapy of BM- and myelo-suppression induced by radiotherapy and chemotherapy.

Macrophages have been recognized as an important inflammatory component in choroidal neovascularization (CNV). However, it is unclear how these cells are activated and polarized, how they affect angiogenesis and what the underlining mechanisms are during CNV. Notch signaling has been implicated in macrophage activation. Previously we have shown that inducible disruption of RBP-J, the critical transcription factor of Notch signaling, in adult mice results in enhanced CNV, but it is unclear what is the role of macrophage-specific Notch signaling in the development of CNV. In the current study, by using the myeloid specific RBP-J knockout mouse model combined with the laser-induced CNV model, we show that disruption of Notch signaling in macrophages displayed attenuated CNV growth, reduced macrophage infiltration and activation, and alleviated angiogenic response after laser induction. The inhibition of CNV occurred with reduced expression of VEGF and TNF-α in infiltrating inflammatory macrophages in myeloid specific RBP-J knockout mice. These changes might result in direct inhibition of EC lumen formation, as shown in an in vitro study. Therefore, clinical intervention of Notch signaling in CNV needs to pinpoint myeloid lineage to avoid the counteractive effects of global inhibition.

TLR8 is an important sensor of single-stranded RNA (ssRNA) from the viral genome and plays an essential role in innate antiviral responses via the recognition of conserved viral molecular patterns. In this report, TLR8 in the Chinese raccoon dog was characterized and analyzed for the first time. The full-length sequence of raccoon dog TLR8 (RdTLR8) cDNA was cloned by rapid amplification of cDNA ends (RACE) and is 3191bp with a 3117-bp open reading frame (ORF) encoding 1038 amino acids. The putative protein exhibits typical features of the TLR families, with 19 leucine-rich repeats (LRRs) in the extracellular domain and a cytoplasmic TIR domain. Comparative analyses of the RdTLR8 amino acid sequence indicated a 73.6-99.4% sequence identity with dog, horse, pig, sheep, cattle, human and mouse TLR8. Phylogenetic analysis grouped 71 mammalian TLR proteins into five sub-families, wherein RdTLR8 was clustered into a monophyletic TLR8 clade in the TLR9 family, which was completely coincident with the evolutionary relationship among mammals. Quantitative real-time PCR analysis revealed extensive expression of RdTLR8 in tissues from healthy Chinese raccoon dogs with the highest expression in the peripheral blood mononuclear cells (PBMCs) and the lowest expression in the skeletal muscle. HEK293 cells cotransfected with a RdTLR8 expression plasmid and an NF-κB-luciferase reporter plasmid significantly responded to the agonist 3M-002, indicating a functional TLR8 homolog. In addition, raccoon dog PBMCs exposed to the canine distemper virus (CDV) wild strain CDV-PS and the TLR8 agonist 3M-002 showed significant upregulation of RdTLR8 mRNA and proinflammatory cytokines TNF-α and IFN-α, suggesting that RdTLR8 might play an important role in the immune response to viral infections in the Chinese raccoon dog.

Indicator organisms and antibiotic resistance were used as a proxy to measure microbial water quality of ballast tanks of ships, and surface waters in a tropical harbor. The survival of marine bacteria in ballast tanks appeared to diminish over longer water retention time, with a reduction of cell viability observed after a week based on heterotrophic plate counts. Pyrosequencing of 16S rRNA genes showed distinct differences in microbial composition of ballast and harbor waters. The harbor waters had a higher abundance of operational taxonomic units (OTUs) assigned to Cyanobacteria (Synechococcus spp.) and α-proteobacteria (SAR11 members), while marine hydrocarbon degraders such as γ-proteobacteria (Ocenspirillaes spp., Thiotrchales spp.) and Bacteroidetes (Flavobacteriales spp.) dominated the ballast water samples. Screening of indicator organisms found Escherichia coli (E. coli), Enterococcus and Pseudomonas aeruginosa (P. aeruginosa) in two or more of the ballast and harbor water samples tested. Vibrio spp. and Salmonella spp. were detected exclusively in harbor water samples. Using quantitative PCR (qPCR), we screened for 13 antibiotic resistant gene (ARG) targets and found higher abundances of sul1 (4.13-3.44 x 102 copies/mL), dfrA (0.77-1.80 x10 copies/mL) and cfr (2.00-5.21 copies/mL) genes compared to the other ARG targets selected for this survey. These genes encode for resistance to sulfonamides, trimethoprim and chloramphenicol-florfenicol antibiotics, which are also known to persist in sediments of aquaculture farms and coastal environments. Among the ARGs screened, we found significant correlations (P<0.05) between ereA, ermG, cfr and tetO genes to one or more of the indicator organisms detected in this study, which may suggest that these members contribute to the environmental resistome. This study provides a baseline water quality survey, quantitatively assessing indicators of antibiotic resistance, potentially pathogenic organisms and a broad-brush description of difference in microbial composition and diversity between open oceans and tropical coastal environments through the use of next generation sequencing technology.

The melanocortin-5 receptor (MC(5)) of the dogfish Squalus acanthias (SacMC(5) receptor) can be functionally expressed in CHO cells in the absence of the co-expression of an exogenous MRAP cDNA. Both human ACTH(1-24) and dogfish ACTH(1-25) were much better stimulators of the SacMC(5) receptor than any of the mammalian or dogfish MSH ligands that were tested. The order of ligand selectivity for the dogfish melanocortins was ACTH(1-25)>αMSH>γ-MSH=δ-MSH>β-MSH. Unlike mammalian MC(5) receptors, the functional expression of the SacMC(5) receptor was not negatively impacted when the receptor was co-expressed with a cartilaginous fish (Callorhinchus milii) MRAP2 cDNA. However, co-expression with either mouse mMRAP1 or zebrafish zfMRAP1 increased the sensitivity of SacMC(5) receptor for hACTH(1-24) by at least one order of magnitude. Hence, SacMC(5) receptor has the potential to interact with MRAP1 orthologs and in this regard behaved more like a melanocortin MC(2) receptor ortholog than a melanocortin MC(5) receptor ortholog. These observations are discussed in light of the evolution of the melanocortin receptor gene family in cartilaginous fish, and the physiological implications of these observations are considered.

The definition of deep tissue injury was derived from multiple clinical cases as "A purple or maroon localized area of discolored intact skin or blood-filled blister due to damage of underlying soft tissue from pressure and/or shear". Acidic fibroblast growth factor (aFGF) significantly improves wound healing under diabetic conditions. However, to date, the therapeutic application of aFGF has been limited, due to its low delivery efficiency and short half-life.

TNF-α, one of the most potent pro-inflammatory cytokines, plays a critical role in inhibition of osteoblast differentiation and bone regeneration in persistent inflammatory microenvironment. To explore the mechanism, quantitative proteomics based on iTRAQ and MRM was employed. The results showed 6 proteins involved in BMP-2 induced osteoblast differentiation inhibition by TNF-α: Periostin, Protein S100-A4, ATPase inhibitor, Cytochrome b5, SERCA3, and ELP2. The altered proteins were involved in molecular transport, tissue development, energy metabolism, and inflammation. One specific protein, ELP2 (STAT3-interacting protein 1, StIP1) up-regulated in the inhibition of osteoblast differentiation by TNF-α was verified to play a critical role in STAT3 pathway. Overexpression or knockdown of ELP2 in C2C12 and MC3T3-E1 cells affected osteoblast differentiation inhibition induced by TNF-α. These results highlight the function of ELP2 in inflammatory microenvironment, ELP2 up-regulation and STAT3 pathway activation may down-regulate BMPR2, then BMP-2 was blocked and osteoblast differentiation inhibited. The protein-expression profile revealed here should offer at least partly new clues to understand the mechanism of osteoblast differentiation inhibition by inflammation.

As widely recognized, agarwood formation in Aquilaria trees is induced by external wounding. Because agarwood usually harbors specific microbes, the function of microbes in agarwood formation has been debated for almost a century. In this study, two wounding methods, the burning-chisel-drilling method (BCD) and the whole-tree agarwood-inducing method (Agar-Wit), were used under the non-contamination of environmental microorganisms. After pyrosequencing the small rRNA subunits of the wounds induced by the BCD and Agar-Wit, no substantial variation was observed either in fungal and bacterial enrichment and diversity or in the relative abundances of taxa. By contrast, significant variations in fungal and bacterial communities were detected following the partial tree pruning (PTP)-wounding. The wound-induced sesquiterpene biosynthesis and vessel-occlusion formation, however, were found to be similar in all types of wounded trunks. We thus infer that wounding in the absence of variations in microbial communities may induce agarwood formation. This result does not support the long-standing notion that agarwood formation depends on microbes.

The Chinese Antibody Society (CAS) convened the second annual conference in Cambridge, MA, USA on 29 April 2018. More than 600 members from around the world attended the meeting. Invited speakers discussed the latest advancements in therapeutic antibodies with an emphasis on the progress made in China. The meeting covered a vast variety of topics including the current status of therapeutic antibodies, the progress of immuno-oncology, and biosimilars in China. The conference presentations also included the development of several novel antibodies such as antibodies related to weight loss, T-cell receptor-mimicking antibodies that target intracellular antigens, and tumor-targeting antibodies that utilize both innate and adaptive immune pathways. At the meeting, the CAS announced the launch of its official journal-Antibody Therapeutics-in collaboration with Oxford University Press. The conference was concluded by a panel discussion on how to bring a therapeutic drug developed in China to the USA for clinical trials.

Papillary renal cell carcinoma (PRCC) accounts for 15‑20% of all kidney neoplasms and continually attracts attention due to the increase in the incidents in which it occurs. The molecular mechanism of PRCC remains unclear and the efficacy of drugs that treat PRCC lacks sufficient evidence in clinical trials. Therefore, it is necessary to investigate the underlying mechanism in the development of PRCC and identify additional potential anti‑PRCC drugs for its treatment. The differently expressed genes (DEGs) of PRCC were identified, followed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses for functional annotation. Then, potential drugs for PRCC treatment were predicted by Connectivity Map (Cmap) based on DEGs. Furthermore, the latent function of query drugs in PRCC was explored by integrating drug‑target, drug‑pathway and drug‑protein interactions. In total, 627 genes were screened as DEGs, and these DEGs were annotated using KEGG pathway analyses and were clearly associated with the complement and coagulation cascades, amongst others. Then, 60 candidate drugs, as predicted based on DEGs, were obtained from the Cmap database. Vorinostat was considered as the most promising drug for detailed discussion. Following protein‑protein interaction (PPI) analysis and molecular docking, vorinostat was observed to interact with C3 and ANXN1 proteins, which are the upregulated hub genes and may serve as oncologic therapeutic targets in PRCC. Among the top 20 metabolic pathways, several significant pathways, such as complement and coagulation cascades and cell adhesion molecules, may greatly contribute to the development and progression of PRCC. Following the performance of the PPI network and molecular docking tests, vorinostat exhibited a considerable and promising application in PRCC treatment by targeting C3 and ANXN1.

The poor 5-year survival rate in high-grade osteosarcoma (HOS) has not been increased significantly over the past 30 years. This work aimed to develop a radiomics nomogram for survival prediction at the time of diagnosis in HOS. In this retrospective study, an initial cohort of 102 HOS patients, diagnosed from January 2008 to March 2011, was used as the training cohort. Radiomics features were extracted from the pretreatment diagnostic computed tomography images. A radiomics signature was constructed with the lasso algorithm; then, a radiomics score was calculated to reflect survival probability by using the radiomics signature for each patient. A radiomics nomogram was developed by incorporating the radiomics score and clinical factors. A clinical model was constructed by using clinical factors only. The models were validated in an independent cohort comprising 48 patients diagnosed from April 2011 to April 2012. The performance of the nomogram was assessed with respect to its calibration, discrimination, and clinical usefulness. Kaplan-Meier survival analysis was performed. The radiomics nomogram showed better calibration and classification capacity than the clinical model with AUC 0.86 vs. 0.79 for the training cohort, and 0.84 vs. 0.73 for the validation cohort. Decision curve analysis demonstrated the clinical usefulness of the radiomics nomogram. A significant difference (p-value <.05; log-rank test) was observed between the survival curves of the nomogram-predicted survival and non-survival groups. The radiomics nomogram may assist clinicians in tailoring appropriate therapy.

Arboviruses have caused significant global health concerns during the past decade. In this regard, continuous viral surveillance is essential to timely identify emerging arboviruses and other novel viruses. Here, a novel isolate of Phasi Charoen-like virus (PCLV Zhanjiang01) was identified from field-captured Aedes aegypti mosquitoes in Zhanjiang by next generation sequencing. Phylogenetic analysis suggested that PCLV Zhanjiang01 belonged to the genus Phasivirus in the family Phenuiviridae. The presence of PCLV in three batches of Aedes aegypti confirmed its high prevalence in nature. Further detection of PCLV in progenies and adult males suggested vertical transmission in mosquitoes. In parallel, PCLV was detected from multiple organs indicating its broad tissue distribution in the infected mosquitoes. To the best of our knowledge, this is the first report of PCLV in China. Our results expanded the global biogeographic distribution of PCLV. Further investigations of PCLV on the arboviral transmission and control strategies are warranted.

Abnormal expression of microRNA (miR) is associated with the occurrence and progression of various types of cancers, including papillary thyroid carcinoma (PTC). In the present study, the aim was to explore miR‑486‑5p expression and its role in PTC, as well as to investigate the biological function of its potential target genes. The expression levels of miR‑486‑5p and its clinicopathological significance were examined in 507 PTC and 59 normal thyroid samples via The Cancer Genome Atlas (TCGA). Subsequently, the results were validated using data from Gene Expression Omnibus (GEO) and ArrayExpress. Receiver operating characteristic and summary receiver operating characteristic curves were used to assess the ability of miR‑486‑5p in distinguishing PTC from normal tissue. Furthermore, potential miR‑486‑5p mRNA targets were identified using 12 prediction tools and enrichment analysis was performed on the encoding genes using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. The expression levels of miR‑486‑5p were consistently downregulated in PTC compared with in normal tissue across datasets from TCGA, GEO (GSE40807, GSE62054 and GSE73182) and ArrayExpress (E‑MTAB‑736). The results also demonstrated that miR‑486‑5p expression was associated with cancer stage (P=0.003), pathologic lymph node (P=0.047), metastasis (P=0.042), neoplasm (P=0.012) and recurrence (P=0.016) in patients with PTC. In addition, low expression of miR‑486‑5p in patients with PTC was associated with a worse overall survival. A total of 80 miR‑486‑5p‑related genes were observed from at least 9 of 12 prediction platforms, and these were involved in 'hsa05200: Pathways in cancer' and 'hsa05206: MicroRNAs in cancer'. Finally, three hub genes, CRK like proto‑oncogene, phosphatase and tensin homolog and tropomyosin 3, were identified as important candidates in tumorigenesis and progression of PTC. In conclusion, it may be hypothesized that miR‑486‑5p contributes towards PTC onset and progression, and may act as a clinical target. However, in vitro and in vivo experiments are required to validate the findings of the present study.

We conducted an investigation of blood management in which blood transfusion recipients underwent molecular biological analysis, to trace the possible source of HIV infection. Epidemiological investigation was carried out among HIV-infected individuals. Blood transfusion recipients infected with HIV were tracked for the date of transfusion, reason for transfusion, hospital where transfusion was received, source of blood, components of transfusion, number of transfusions, and transfusion volume. A total of 285 blood transfusion recipients infected with HIV-1 were detected in Hebei over the study period, with 42.81% (122/285) detected through clinical diagnostic testing. These cases showed a concentrated distribution in southern Hebei, with local outbreak characteristics. A census of the population in Shahe County, which had a high concentration of cases, revealed that recipients of blood transfusions had an HIV infection rate of 15.54% (92/592). Post-transfusion infection frequently occurred among blood transfusion recipients at township medical institutions, with a peak in 1995. Owing to late detection of HIV infection among blood transfusion recipients, the rates of spousal transmission and mother-to-child transmission reached 20.87% and 28.05%, respectively. Around 1995, community medical institutions did not screen for HIV antibodies among paid blood donors, which was an important cause of the outbreak of HIV-1 infection among blood transfusion recipients. Our findings indicate that cases of blood transfusion-related infection decreased rapidly with gradual improvement in the HIV screening system for blood donors that began in 1995, particularly after full implementation of HIV nucleic acid testing of volunteer blood donors was begun in 2015.

From November 2011 to January 2012, a number of clustering cases of HCV infection were reported in Zijin County, Heyuan City, Guangdong, China. Most patients in the clustering cases suspected that they could be infected due to inappropriate medical care in the clinic located at the Xiangshui road. However, the molecular epidemiology of the clustering cases remains unknown.

Mutations in the inositol 5-phosphatase OCRL cause Lowe syndrome and Dent's disease. Although OCRL, a direct clathrin interactor, is recruited to late-stage clathrin-coated pits, clinical manifestations have been primarily attributed to intracellular sorting defects. Here we show that OCRL loss in Lowe syndrome patient fibroblasts impacts clathrin-mediated endocytosis and results in an endocytic defect. These cells exhibit an accumulation of clathrin-coated vesicles and an increase in U-shaped clathrin-coated pits, which may result from sequestration of coat components on uncoated vesicles. Endocytic vesicles that fail to lose their coat nucleate the majority of the numerous actin comets present in patient cells. SNX9, an adaptor that couples late-stage endocytic coated pits to actin polymerization and which we found to bind OCRL directly, remains associated with such vesicles. These results indicate that OCRL acts as an uncoating factor and that defects in clathrin-mediated endocytosis likely contribute to pathology in patients with OCRL mutations.

Vasculogenic mimicry (VM) was related to invasion and metastasis of head and neck squamous cell carcinoma (HNSCC) patients. This study was designed to investigate the role of EphA2 in VM formation of HNSCC.

The freshwater unicellular microalga Haematococcus pluvialis (H. pluvialis) has gained increasing attention because of its high-value metabolite astaxanthin, a super anti-oxidant. For the maximum astaxanthin production, a key problem is how to determine the senescent green vegetative phase of H. pluvialis cells to apply the astaxanthin production inducers. The conventional methods are time-consuming and laborious. In this study, a novel platform based on organic electrochemical transistor (OECT) was produced. A significant channel current change of OECTs caused by settled H. pluvialis cells on the poly(3,4-ethylenedioxythiophene): polystyrene sulfonate (PEDOT: PSS) film was recorded commencing from 75 min and a stationary stage was achieved at 120 min after the combined treatment of blue light irradiation and sodium bicarbonate solution additives, which indicate the onset and maturation of the senescent green vegetative phase, respectively. Therefore, the appropriate time point (120 min after sample loading) to apply astaxanthin production inducers was determined by as-fabricated OECTs. This work may assist to develop a real-time biosensor to indicate the appropriate time to apply inducers for a maximum astaxanthin production of H. pluvialis cells.

Recent studies suggest that the traditional case-control study design does not have sufficient power to discover rare risk variants. Two different methods-collapsing and family data-are suggested as alternatives for discovering these rare variants. Compared with common variants, rare variants have unique characteristics. In this paper, we assess the distribution of rare variants in family data. We notice that a large number of rare variants exist only in one or two families and that the association result is largely shaped by those families. Therefore we explore the possibility of integrating both the collapsing method and the family data method. This combinational approach offers a potential power boost for certain causal genes, including VEGFA, VEGFC, SIRT1, SREBF1, PIK3R3, VLDLR, PLAT, and FLT4, and thus deserves further investigation.