The Arabidopsis thaliana genome encodes 29 AT-HOOK MOTIF CONTAINING NUCLEAR LOCALIZED (AHL) genes, which evolved into two phylogenic clades. The AHL proteins contain one or two AT-hook motif(s) and one plant and prokaryote conserved (PPC)/domain of unknown function #296 (DUF296) domain. Seedlings lacking both SOB3/AHL29 and ESC/AHL27 confer a subtle long-hypocotyl phenotype compared with the WT or either single-null mutant. In contrast, the missense allele sob3-6 confers a dramatic long-hypocotyl phenotype in the light. In this study, we examined the dominant-negative feature of sob3-6 and found that it encodes a protein with a disrupted AT-hook motif that abolishes binding to AT-rich DNA. A loss-of-function approach demonstrated different, yet redundant, contributions of additional AHL genes in suppressing hypocotyl elongation in the light. We showed that AHL proteins interact with each other and themselves via the PPC/DUF296 domain. AHLs also share interactions with other nuclear proteins, such as transcription factors, suggesting that these interactions also contribute to the functional redundancy within this gene family. The coordinated action of AHLs requires an AT-hook motif capable of binding AT-rich DNA, as well as a PPC/DUF296 domain containing a conserved Gly-Arg-Phe-Glu-Ile-Leu region. Alteration of this region abolished SOB3/AHL29's physical interaction with transcription factors and resulted in a dominant-negative allele in planta that was phenotypically similar to sob3-6. We propose a molecular model where AHLs interact with each other and themselves, as well as other nuclear proteins, to form complexes which modulate plant growth and development.enhanceosome | seedling establishment

The Arabidopsis thaliana hypocotyl is a robust system for studying the interplay of light and plant hormones, such as brassinosteroids (BRs), in the regulation of plant growth and development. Since BRs cannot be transported between plant tissues, their cellular levels must be appropriate for given developmental fates. BR homeostasis is maintained in part by transcriptional feedback regulation loops that control the expression of key metabolic enzymes, including the BRinactivating enzymes BAS1 (CYP734A1, formerly CYP72B1) and SOB7 (CYP72C1). Here, we find that the NAC transcription factor (TF) ATAF2 binds the promoters of BAS1 and SOB7 to suppress their expression. ATAF2 restricts the tissue-specific expression of BAS1 and SOB7 in planta. ATAF2 loss-and gain-of-function seedlings have opposite BR-response phenotypes for hypocotyl elongation. ATAF2 modulates hypocotyl growth in a light-dependent manner, with the photoreceptor phytochrome A playing a major role. The photomorphogenic phenotypes of ATAF2 loss-and gain-of-function seedlings are suppressed by treatment with the BR biosynthesis inhibitor brassinazole. Moreover, the disruption of BAS1 and SOB7 abolishes the short-hypocotyl phenotype of ATAF2 loss-offunction seedlings in low fluence rate white light, demonstrating an ATAF2-mediated connection between BR catabolism and photomorphogenesis. ATAF2 expression is suppressed by both BRs and light, which demonstrates the existence of an ATAF2-BAS1/SOB7-BR-ATAF2 feedback regulation loop, as well as a light-ATAF2-BAS1/SOB7-BR-photomorphogenesis pathway. ATAF2 also modulates root growth by regulating BR catabolism. As it is known to regulate plant defense and auxin biosynthesis, ATAF2 therefore acts as a central regulator of plant defense, hormone metabolism and light-mediated seedling development.

Our results suggest that BM-SMPC may be useful in studying SMC differentiation and have high potential for development of cell therapies for the treatment of cardiovascular disease.

Our results suggest that hair follicles may be an easily accessible, autologous, and rich source of functional SMPC for cardiovascular tissue engineering and regenerative medicine.

Autism is a highly heritable neurodevelopmental disorder, and known genetic variants, mostly rare, account only for a small proportion of cases. Here we report a genome-wide association study on autism using two Chinese cohorts as gene discovery (n=2150) and three data sets of European ancestry populations for replication analysis of top association signals. Meta-analysis identified three single-nucleotide polymorphisms, rs936938 (P=4.49 × 10(-8)), non-synonymous rs6537835 (P=3.26 × 10(-8)) and rs1877455 (P=8.70 × 10(-8)), and related haplotypes, AMPD1-NRAS-CSDE1, TRIM33 and TRIM33-BCAS2, associated with autism; all were mapped to a previously reported linkage region (1p13.2) with autism. These genetic associations were further supported by a cis-acting regulatory effect on the gene expressions of CSDE1, NRAS and TRIM33 and by differential expression of CSDE1 and TRIM33 in the human prefrontal cortex of post-mortem brains between subjects with and those without autism. Our study suggests TRIM33 and NRAS-CSDE1 as candidate genes for autism, and may provide a novel insight into the etiology of autism.

We investigated the potential of human hair follicle cells for multilineage differentiation and as a source of functional smooth muscle cells (SMCs). We report that human hair follicle stem cells (HFCs) isolated from individual follicles expressed surface markers that are characteristic of mesenchymal stem cells such as CD44, CD49b, CD73, CD90, and CD105 but lacked hematopoietic markers CD45 and CD34. In addition, HFCs differentiated toward adipocytes, chondrocytes, osteoblasts, or SMCs in the appropriate induction medium. Treatment with basic fibroblast growth factor increased proliferation and prevented myogenic differentiation, suggesting that basic fibroblast growth factor can be used to expand the population of undifferentiated HFCs to the large numbers needed for therapeutic applications. SMCs were isolated from HFCs using tissue-specific promoters and flow cytometry sorting. Cylindrical vascular constructs engineered with HF-SMCs showed remarkable contractility in response to receptor and nonreceptor agonists such KCl, endothelin-1, and the thromboxane mimetic, U46619, as well as superior mechanical properties compared to their counterparts with human vascular SMCs. Our results suggest that HF is a rich source of mesenchymal stem cells with great potential for myogenic differentiation providing functional SMCs for tissue regeneration and cell therapies.

Saikosaponin A (SSA) is a major triterpenoid saponin isolated from Radix bupleuri (RB), a widely used Chinese traditional medicine to treat various inflammation-related diseases. The aim of this study was to investigate the anti-inflammatory activity, as well as the molecular mechanism of SSA in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. In this study, we demonstrated that SSA markedly inhibits the expression of certain immune-related cytotoxic factors, including cyclooxygenase-2 (COX-2) and inducible nitric-oxide synthase (iNOS), as well as pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6. It also significantly upregulates the expression of IL-10, an important anti-inflammatory cytokine, suggesting its anti-inflammatory activity in LPS-stimulated macrophages. We further demonstrated that SSA inhibits the activation of the nuclear factor-κB (NF-κB) signaling pathway by suppressing the phosphorylation of inhibitory NF-κB inhibitor α (IκBα) and thus holding p65 NF-κB in the cytoplasm to prevent its translocation to the nucleus. In addition, SSA also inhibits the mitogen-activated protein kinase (MAPK) signaling pathway by downregulating the phosphorylation of p38 MAPK, c-Jun N-terminal kinase (c-JNK) and extracellular signal-regulated kinase (ERK), the three key components of the MAPK family. In conclusion, our study demonstrates that SSA has an anti-inflammatory effect by regulating inflammatory mediators and suppressing the MAPK and NF-κB signaling pathways in LPS-stimulated RAW 264.7 cells.

No abstract