MicroRNAs (miRNAs) are small regulatory RNAs that participate in posttranscriptional gene regulation in a sequence-specific manner. However, little is understood about the role(s) of miRNAs in Alzheimer's disease (AD). We used miRNA expression microarrays on RNA extracted from human brain tissue from the University of Kentucky Alzheimer's Disease Center Brain Bank with near-optimal clinicopathological correlation. Cases were separated into four groups: elderly nondemented with negligible AD-type pathology, nondemented with incipient AD pathology, mild cognitive impairment (MCI) with moderate AD pathology, and AD. Among the AD-related miRNA expression changes, miR-107 was exceptional because miR-107 levels decreased significantly even in patients with the earliest stages of pathology. In situ hybridization with cross-comparison to neuropathology demonstrated that particular cerebral cortical laminas involved by AD pathology exhibit diminished neuronal miR-107 expression. Computational analysis predicted that the 3Ј-untranslated region (UTR) of ␤-site amyloid precursor protein-cleaving enzyme 1 (BACE1) mRNA is targeted multiply by miR-107. From the same RNA material analyzed on miRNA microarrays, mRNA expression profiling was performed using Affymetrix Exon Array microarrays on nondemented, MCI, and AD patients. BACE1 mRNA levels tended to increase as miR-107 levels decreased in the progression of AD. Cell culture reporter assays performed with a subset of the predicted miR-107 binding sites indicate the presence of at least one physiological miR-107 miRNA recognition sequence in the 3Ј-UTR of BACE1 mRNA. Together, the coordinated application of miRNA profiling, Affymetrix microarrays, new bioinformatics predictions, in situ hybridization, and biochemical validation indicate that miR-107 may be involved in accelerated disease progression through regulation of BACE1.

Glycerol-3-phosphate (G3P) is an important metabolite that contributes to the growth and disease-related physiologies of prokaryotes, plants, animals and humans alike. Here we show that G3P serves as the inducer of an important form of broad-spectrum immunity in plants, termed systemic acquired resistance (SAR). SAR is induced upon primary infection and protects distal tissues from secondary infections. Genetic mutants defective in G3P biosynthesis cannot induce SAR but can be rescued when G3P is supplied exogenously. Radioactive tracer experiments show that a G3P derivative is translocated to distal tissues, and this requires the lipid transfer protein, DIR1. Conversely, G3P is required for the translocation of DIR1 to distal tissues, which occurs through the symplast. These observations, along with the fact that dir1 plants accumulate reduced levels of G3P in their petiole exudates, suggest that the cooperative interaction of DIR1 and G3P orchestrates the induction of SAR in plants.

Significance An experimental system was developed in mice to study the long-term benefits of early exposure to secretory antibodies of the IgA class (SIgA) in breast milk. We found that breast milk-derived SIgA promoted intestinal epithelial barrier function in suckling neonates, preventing systemic infection by potential pathogens. Long-term benefits of early exposure to SIgA included maintenance of a healthy gut microbiota and regulation of gene expression in intestinal epithelial cells. These findings suggest that maternal antibodies provide benefits to the intestinal immune system of the breast-fed infant, which persist into adulthood.

AGAMOUS-Like15 (AGL15) is a MADS domain transcriptional regulator that promotes somatic embryogenesis by binding DNA and regulating gene expression. Chromatin immunoprecipitation (ChIP) analysis previously identified DNA fragments with which AGL15 associates in vivo, and a low-throughput approach revealed a role for AGL15 in gibberellic acid catabolism that is relevant to embryogenesis. However, higher throughput methods are needed to identify targets of AGL15. Here, we mapped AGL15 in vivo binding sites using a ChIP-chip approach and the Affymetrix tiling arrays for Arabidopsis thaliana and found that ;2000 sites represented in three biological replicates of the experiment are annotated to nearby genes. These results were combined with high-throughput measurement of gene expression in response to AGL15 accumulation to discriminate responsive direct targets from those further downstream in the network. LEAFY COTYLE-DON2, FUSCA3, and ABA INSENSITIVE3, which encode B3 domain transcription factors that are key regulators of embryogenesis, were identified and verified as direct target genes of AGL15. Genes identified as targets of the B3 genes are also targets of AGL15, and we found that INDOLEACETIC ACID-INDUCED PROTEIN30 is involved in promotion of somatic embryo development. The data presented here and elsewhere suggest that much cross-regulation occurs in gene regulatory networks underpinning embryogenesis.

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MicroRNA (miRNA) expression was assessed in human cerebral cortical gray matter (GM) and white matter (WM) in order to provide the first insights into the difference between GM and WM miRNA repertoires across a range of Alzheimer's disease (AD) pathology. RNA was isolated separately from GM and WM portions of superior and middle temporal cerebral cortex (N = 10 elderly females, postmortem interval < 4 h). miRNA profiling experiments were performed using state-of-the-art Exiqon © LNA-microarrays. A subset of miRNAs that appeared to be strongly expressed according to the microarrays did not appear to be conventional miRNAs according to Northern blot analyses. Some well-characterized miRNAs were substantially enriched in WM as expected. However, most of the miRNA expression variability that correlated with the presence of early AD-related pathology was seen in GM. We confirm that downregulation of a set of miRNAs in GM (including several miR-15/107 genes and miR-29 paralogs) correlated strongly with the density of diffuse amyloid plaques detected in adjacent tissue. A few miRNAs were differentially expressed in WM, including miR-212 that is downregulated in AD and miR-424 which is upregulated in AD. The expression of certain miRNAs correlates with other miRNAs across different cases, and particular subsets of miRNAs are coordinately expressed in relation to ADrelated pathology. These data support the hypothesis that patterns of miRNA expression in cortical GM may contribute to AD pathogenetically, because the aggregate change in miRNA expression observed early in the disease would be predicted to cause profound changes in gene expression.

Resistance (R) protein–associated pathways are well known to participate in defense against a variety of microbial pathogens. Salicylic acid (SA) and its associated proteinaceous signaling components, including enhanced disease susceptibility 1 (EDS1), non–race-specific disease resistance 1 (NDR1), phytoalexin deficient 4 (PAD4), senescence associated gene 101 (SAG101), and EDS5, have been identified as components of resistance derived from many R proteins. Here, we show that EDS1 and SA fulfill redundant functions in defense signaling mediated by R proteins, which were thought to function independent of EDS1 and/or SA. Simultaneous mutations in EDS1 and the SA–synthesizing enzyme SID2 compromised hypersensitive response and/or resistance mediated by R proteins that contain coiled coil domains at their N-terminal ends. Furthermore, the expression of R genes and the associated defense signaling induced in response to a reduction in the level of oleic acid were also suppressed by compromising SA biosynthesis in the eds1 mutant background. The functional redundancy with SA was specific to EDS1. Results presented here redefine our understanding of the roles of EDS1 and SA in plant defense.

As age increases, so does Breslow thickness, the incidence of ulceration and regression, and the proportion of male patients-all poor prognostic factors. However, the frequency of SLN metastasis declines with increasing age. It is not known whether this represents a decreased sensitivity (higher false-negative rate) of the SLN procedure in older patients or a different biological behavior (hematogenous spread) of melanomas in older patients.