Successful development of ultra-sensitive molecular imaging nanoprobes for the detection of targeted biological objects is a challenging task. Although magnetic nanoprobes have the potential to perform such a role, the results from probes that are currently available have been far from optimal. Here we used artificial engineering approaches to develop innovative magnetic nanoprobes, through a process that involved the systematic evaluation of the magnetic spin, size and type of spinel metal ferrites. These magnetism-engineered iron oxide (MEIO) nanoprobes, when conjugated with antibodies, showed enhanced magnetic resonance imaging (MRI) sensitivity for the detection of cancer markers compared with probes currently available. Also, we successfully visualized small tumors implanted in a mouse. Such high-performance, nanotechnology-based molecular probes could enhance the ability to visualize other biological events critical to diagnostics and therapeutics.

Corepressors N-CoR and SMRT participate in diverse repression pathways and exist in large protein complexes including HDAC3, TBL1 and TBLR1. However, the roles of these proteins in SMRT±N-CoR complex function are largely unknown. Here we report the puri®cation and functional characterization of the human N-CoR complex. The puri®ed N-CoR complex contains 10±12 associated proteins, including previously identi®ed components and a novel actinbinding protein IR10. We show that TBL1/TBLR1 associates with N-CoR through two independent interactions: the N-terminal region and the C-terminal WD-40 repeats interact with the N-CoR RD1 and RD4 region, respectively. In vitro, TBL1/TBLR1 bind histones H2B and H4, and, importantly, repression by TBL1/TBLR1 correlates with their interaction with histones. By using speci®c small interference RNAs (siRNAs), we demonstrate that HDAC3 is essential, whereas TBL1 and TBLR1 are functionally redundant but essential for repression by unliganded thyroid hormone receptor. Together, our data reveal the roles of HDAC3 and TBL/TBLR1 and provide evidence for the functional importance of histone interaction in repression mediated by SMRT±N-CoR complexes.

The identification and characterization of molecular mechanisms utilized by cells to mediate transcriptional repression at methylated loci are fundamental to understanding the biological consequences of DNA methylation. Here we demonstrate that Kaiso, a methyl CpG binding protein belonging to the BTB/POZ family of transcription factors, is a component of the human N-CoR complex. In vitro, the Kaiso/N-CoR complex binds specific CpG-rich sequences in a methylation-dependent manner. In vivo, Kaiso targets the N-CoR complex to the MTA2 gene promoter in a methylation-dependent manner. Importantly, we demonstrate that Kaiso is required for transcriptional repression of the methylated MTA2 locus. Furthermore, this repression also requires a functional N-CoR deacetylase complex, which brings about histone hypoacetylation and methylation of H3 lysine 9 to the MTA2 locus. Thus, our data demonstrate a critical role for a methyl CpG binding protein in mediating DNA methylation-dependent repression and reveal the mechanism by which it represses transcription.

Diagnosis and treatment all in one: Multifunctional magneto‐polymeric nanohybrids (MMPNs) have been synthesized using ultrasensitive MnFe2O4 nanocrystals, chemotherapeutic agents, and encapsulating amphiphilic block copolymers for targeted detection by MRI and treatment of breast cancer. See the TEM image (left) of an MMPN and T2‐weighted MR images (top row) and color map (bottom row) of the relaxivity R2 for NIH3T6.7 and MDA‐MB‐231 cells.

Novel hollow silica nanoparticles (HSNPs) for drug delivery vehicles were synthesized using silica-coated magnetic assemblies, which are composed of a number of Fe(3)O(4) nanocrystals, as templates. The core cavity was obtained by removal of Fe(3)O(4) phase with hydrochloric acid and subsequent calcination at a high temperature. HSNPs were modified by amine in order to introduce positive surface charge and further PEGylated for increased solubility in aqueous medium. Doxorubicin as a model drug was loaded into the HSNPs, and notable sustained drug release from HSNPs was demonstrated.

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We have investigated the role of corepressors SMRT (silencing mediator of retinoid and thyroid hormone receptor) and N-CoR (nuclear receptor corepressor) in transcriptional regulation by androgen receptor (AR) in the LNCaP prostate cancer cell line. Using specific small interference RNAs to knock down SMRT and/or N-CoR in LNCaP cells, we found that SMRT and N-CoR not only mediate antagonist-dependent inhibition of AR activation but also have a widespread role in suppressing agonist-dependent activation of several AR target genes we have tested, including PSA (prostate-specific antigen), TSC22 (TSC22 domain family member 1), NKX3-1 (NK3 transcription factor locus 1), and B2M(beta-2-microglobulin). By sequencing analysis followed by analysis of physical association by chromatin immunoprecipitation assay, we mapped the putative androgen response elements in the NKX3-1 and B2M. Consistent with a role in both antagonist- and agonist-regulated transcription by AR, chromatin immunoprecipitation analysis revealed that both SMRT and N-CoR were recruited by AR to these genes in the presence of either flutamide or R1881. Knocking down SMRT and N-CoR enhanced the recruitment of the coactivators steroid receptor coactivator 1 and p300 by agonist-bound AR and led to increased hyperacetylation of histone H3 and H4, suggesting that the corepressors actively compete with coactivators for binding to agonist-bound AR. Taken together, our data indicate that SMRT and N-CoR corepressors are involved in transcriptional regulation by both agonist- and antagonist-bound AR and regulate the magnitude of hormone response, at least in part, by competing with coactivators.

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