BACKGROUND The narrow host range of Mycobacterium leprae and the fact that it is refractory to growth in culture has limited research on and the biologic understanding of leprosy. Host genetic factors are thought to influence susceptibility to infection as well as disease progression. METHODS We performed a two-stage genomewide association study by genotyping 706 patients and 1225 controls using the Human610-Quad BeadChip (Illumina). We then tested three independent replication sets for an association between the presence of leprosy and 93 single-nucleotide polymorphisms (SNPs) that were most strongly associated with the disease in the genomewide association study. Together, these replication sets comprised 3254 patients and 5955 controls. We also carried out tests of heterogeneity of the associations (or lack thereof) between these 93 SNPs and disease, stratified according to clinical subtype (multibacillary vs. paucibacillary). RESULTS We observed a significant association (P<1.00×10 −10) between SNPs in the genes CCDC122, C13orf31, NOD2, TNFSF15, HLA-DR, and RIPK2 and a trend toward an association (P = 5.10×10 −5) with a SNP in LRRK2. The associations between the SNPs in C13orf31, LRRK2, NOD2, and RIPK2 and multibacillary leprosy were stronger than the associations between these SNPs and paucibacillary leprosy. CONCLUSIONS Variants of genes in the NOD2-mediated signaling pathway (which regulates the innate immune response) are associated with susceptibility to infection with M. leprae.

Sustainable development of nanotechnology requires an understanding of the long term ecotoxicological impact of engineered nanomaterials on the environment. Cerium oxide nanoparticles (CeO₂-NPs) have great potential to accumulate and adversely affect the environment owing to their widespread applications in commercial products. This study documented the chronic phenotypic response of tomato plants to CeO₂-NPs (0.1-10 mg L⁻¹) and determined the effect of CeO₂-NPs on tomato yield. The results indicated that CeO₂-NPs at the concentrations applied in this study had either an inconsequential or a slightly positive effect on plant growth and tomato production. However, elevated cerium content was detected in plant tissues exposed to CeO₂-NPs, suggesting that CeO₂-NPs were taken up by tomato roots and translocated to shoots and edible tissues. In particular, substantially higher Ce concentrations were detected in the fruits exposed to 10 mg L⁻¹ CeO₂-NPs, compared with controls. This study sheds light on the long term impact of CeO₂-NPs on plant health and its implications for our food safety and security.

Reverse genetics systems have been established for all major groups of plant DNA and positive-strand RNA viruses, and our understanding of their infection cycles and pathogenesis has benefitted enormously from use of these approaches. However, technical difficulties have heretofore hampered applications of reverse genetics to plant negative-strand RNA (NSR) viruses. Here, we report recovery of infectious virus from cloned cDNAs of a model plant NSR, Sonchus yellow net rhabdovirus (SYNV). The procedure involves Agrobacterium-mediated transcription of full-length SYNV antigenomic RNA and co-expression of the nucleoprotein (N), phosphoprotein (P), large polymerase core proteins and viral suppressors of RNA silencing in Nicotiana benthamiana plants. Optimization of core protein expression resulted in up to 26% recombinant SYNV (rSYNV) infections of agroinfiltrated plants. A reporter virus, rSYNV-GFP, engineered by inserting a green fluorescence protein (GFP) gene between the N and P genes was able to express GFP during systemic infections and after repeated plant-to-plant mechanical passages. Deletion analyses with rSYNV-GFP demonstrated that SYNV cell-to-cell movement requires the sc4 protein and suggested that uncoiled nucleocapsids are infectious movement entities. Deletion analyses also showed that the glycoprotein is not required for systemic infection, although the glycoprotein mutant was defective in virion morphogenesis. Taken together, we have developed a robust reverse genetics system for SYNV that provides key insights into morphogenesis and movement of an enveloped plant virus. Our study also provides a template for developing analogous systems for reverse genetic analysis of other plant NSR viruses.

IntroductionAngiogenesis, a complex process for new blood vessel formation, involves several important aspects: degradation of the basement membrane by proteases, proliferation, and migration of endothelial cells (ECs), lumen formation, basement membrane resembling, recruitment of pericyte or vascular smooth muscle cells (VSMCs), vascular maturation, and finally blood flow. [1][2][3][4] Many growth factors have been suggested to play pivotal roles in different aspects of this process. For instance, vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) regulate many functions of ECs including proliferation, migration, extracellular proteolysis, and tube formation activity. 5,6 Platelet-derived growth factor (PDGF) induces differentiation of mesenchymal cells toward pericytes and VSMCs and stimulates migration of these cells to the newly formed vessels. [7][8][9][10] Transforming growth factor ␤ (TGF-␤) initiates its signals through heteromeric complexes of type II and type I serine/ threonine kinase receptors. After phosphorylation by type II receptor in the receptor complex, the activated type I receptors, in turn, phosphorylate downstream receptor-regulated Smads (RSmads: Smad2/3 for ALK5 and Smad1/5/8 for ALK1). Then the activated R-Smad proteins bind to Smad4, and together they move into the nucleus and regulate the transcription of target genes. [11][12][13] One of angiogenic factors is TGF-␤. 3,14,15 The importance of TGF-␤ in establishing and maintaining the vascular system has been convincingly documented by genetic studies. Targeted disruption of TGF-␤1 and its receptor genes in mice led to embryonic lethality due to defective vascular development. [16][17][18][19][20] TGF-␤ maintains EC quiescence and induces vessel maturation, promotes basement membrane deposition, and enhances the interactions between ECs and mural cells. 3,14,21 In addition, TGF-␤ regulates angiogenesis by influencing the expression and the activities of other angiogenic factors. For instance, both VEGF and PDGF are the direct target genes of TGF-␤ via Smad proteins. [22][23][24] Monocyte chemoattractant protein-1 (MCP-1), a member of the CC chemokine family, was identified as a potent chemotactic factor for monocytes, macrophages, memory T lymphocytes, and natural killer (NK) cells. 25 MCP-1 is well conserved among humans, mice, and rabbits. 26 It binds to the CC chemokine receptor 2 (CCR2), which is also highly conserved. For example, rabbit CCR2 shares 80% identity to human CCR2b and can bind and respond to mouse MCP-1 and human MCP-1. 27 MCP-1 is expressed in ECs, VSMCs, monocytes, and fibroblasts. 28 Furthermore, MCP-1 is abundantly produced in a variety of inflammatory diseases such as atherosclerosis and rheumatoid arthritis and plays an important role in atherogenesis and in intimal hyperplasia. 25 MCP-1 is highly produced by several tumors and contributes directly to tumor angiogenesis by a mechanism independent of monocyte recruitment. 26 MCP-1 modulates angiogenesis by inducing EC migration and EC sp...

IntroductionErythropoiesis is the complex process during which a fraction of primitive multipotent hematopoietic stem cells become committed to the red cell lineage, undergoing erythroid progenitors (burstforming unit erythroid [BFU-E] and colony-forming unit erythroid [CFU-E]), normoblasts, erythroblasts, reticulocytes, and ultimately differentiating to mature erythrocytes. 1 This process is regulated by various factors such as erythropoietin, testosterone, estrogen, interleukin-3, granulocyte-macrophage colony-stimulating factor, and interleukin-9. 2 Activin, a member of the transforming growth factor-␤ (TGF-␤) superfamily, plays an important role in modulating proliferation and differentiation of erythroid progenitors. [2][3][4] In cooperation with erythropoietin, activin promotes erythroid differentiation by increasing the number of hemoglobin-synthesizing colonies derived from the progenitors CFU-E and enhances the formation of BFU-E. 3,[5][6][7] Activin, like other TGF-␤ superfamily members, signals through 2 types of transmembrane receptors that have intrinsic serine/ threonine kinase activity. 8,9 It binds to type II activin receptor, leading to the recruitment, phosphorylation, and activation of type I activin receptor (ALK4, also known as ActRIB). The activated ALK4 transiently interacts with and then phosphorylates Smad2 and Smad3, which, upon phosphorylation, form a heterocomplex with Co-Smad (Smad4), and the resulting Smad complex is accumulated in the nucleus, binds to the promoter of the target genes, and regulates their expression. 10,11 MicroRNAs (miRNAs) are 21-to 25-nucleotide small regulatory RNAs that modulate gene expression by targeting mRNA for degradation or blocking translation via base-pairing to complementary sites in the 3Ј-untranslated region (3Ј-UTR) of the target mRNAs. 12,13 Hundreds of miRNAs have been identified and they participate in a diverse collection of regulatory events. Investigation of the miRNA expression profile in the course of hematopoietic development suggests their potential regulatory roles in hematopoietic differentiation. 14,15 For example, ectopic expression of miR-181 in hematopoietic progenitor cells increased the proportion of B-lineage cells, whereas miR-142s and miR-223 promote the differentiation to T-lineage but not to B-lineage or myeloid cells. 15 MiR-155 transgenic mice exhibited pre-B cell proliferation and B cell malignancy. 16 Overexpression of miR-150 in hematopoietic stem cells specifically impaired the formation of mature B cells by blocking the transition from the pro-B to the pre-B stage. 17 Although many miRNAs have been implicated in hematopoiesis, few of their targets have been identified. MiR-221 and miR-222, both of which are clustered on the X chromosome and were suggested to inhibit normal erythropoiesis and erythroleukemic cell growth, down-modulated kit receptor expression. 18 In this study, we showed that miR-24 could decrease human ALK4 (hALK4) expression at the mRNA and the protein levels through binding to the 3Ј-untranslated r...

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We conducted a cross-trait meta-analysis of genome-wide association study on schizophrenia (SCZ) (n = 65,967), bipolar disorder (BD) (n = 41,653), autism spectrum disorder (ASD) (n = 46,350), attention deficit hyperactivity disorder (ADHD) (n = 55,374), and depression (DEP) (n = 688,809). After the meta-analysis, the number of genomic loci