After Recess: Historical Practice, Textual Ambiguity, and Constitutional Adverse Possession

The Supreme Court’s interpretation of the Recess Appointments Clause in NLRB v. Noel Canning stands as one of the Supreme Court’s most significant endorsements of the relevance of “historical gloss” to the interpretation of the separation of powers. This Article uses the decision as a vehicle for examining the relationship between interpretive methodology and historical practice, and between historical practice and textual ambiguity. As the Article explains, Noel Canning exemplifies how the constitutional text, perceptions about clarity or ambiguity, and “extra-textual” considerations such as historical practice operate interactively rather than as separate elements of interpretation. The decision also provides a useful entry point into critically analyzing the concept of constitutional “liquidation,” which the majority in Noel Canning seemed to conflate with historical gloss but which seems more consistent with the approach to historical practice reflected in Justice Scalia’s concurrence in the judgment. Finally, this Article argues that the historical gloss approach, when applied cautiously and with sensitivity to the potential concerns raised by Justice Scalia and others, is not vulnerable to the charge of licensing executive aggrandizement by “adverse possession.

Regulatory interdependence of myeloid transcription factors revealed by Matrix RNAi analysis

The knockdown of 78 transcription factors in differentiating human THP-1 cells using matrix RNAi reveals their interdependenc

RECLU:a pipeline to discover reproducible transcriptional start sites and their alternative regulation using capped analysis of gene expression (CAGE)

BACKGROUND: Next generation sequencing based technologies are being extensively used to study transcriptomes. Among these, cap analysis of gene expression (CAGE) is specialized in detecting the most 5’ ends of RNA molecules. After mapping the sequenced reads back to a reference genome CAGE data highlights the transcriptional start sites (TSSs) and their usage at a single nucleotide resolution. RESULTS: We propose a pipeline to group the single nucleotide TSS into larger reproducible peaks and compare their usage across biological states. Importantly, our pipeline discovers broad peaks as well as the fine structure of individual transcriptional start sites embedded within them. We assess the performance of our approach on a large CAGE datasets including 156 primary cell types and two cell lines with biological replicas. We demonstrate that genes have complicated structures of transcription initiation events. In particular, we discover that narrow peaks embedded in broader regions of transcriptional activity can be differentially used even if the larger region is not. CONCLUSIONS: By examining the reproducible fine scaled organization of TSS we can detect many differentially regulated peaks undetected by previous approaches

The miR-17-5p microRNA is a key regulator of the G1/S phase cell cycle transition

Novel targets of the oncogenic miR-17-92 cluster have been identified and the mechanism of regulation of proliferation at the G1/S phase cell cycle transition via the miR-17-5p microRNA has been elucidated

The FANTOM web resource: from mammalian transcriptional landscape to its dynamic regulation

The genome-scale data collected by the FANTOM4 collaborative research project are presented as an integrated web resource

PhosphoregDB: The tissue and sub-cellular distribution of mammalian protein kinases and phosphatases

BACKGROUND: Protein kinases and protein phosphatases are the fundamental components of phosphorylation dependent protein regulatory systems. We have created a database for the protein kinase-like and phosphatase-like loci of mouse that integrates protein sequence, interaction, classification and pathway information with the results of a systematic screen of their sub-cellular localization and tissue specific expression data mined from the GNF tissue atlas of mouse. RESULTS: The database lets users query where a specific kinase or phosphatase is expressed at both the tissue and sub-cellular levels. Similarly the interface allows the user to query by tissue, pathway or sub-cellular localization, to reveal which components are co-expressed or co-localized. A review of their expression reveals 30% of these components are detected in all tissues tested while 70% show some level of tissue restriction. Hierarchical clustering of the expression data reveals that expression of these genes can be used to separate the samples into tissues of related lineage, including 3 larger clusters of nervous tissue, developing embryo and cells of the immune system. By overlaying the expression, sub-cellular localization and classification data we examine correlations between class, specificity and tissue restriction and show that tyrosine kinases are more generally expressed in fewer tissues than serine/threonine kinases. CONCLUSION: Together these data demonstrate that cell type specific systems exist to regulate protein phosphorylation and that for accurate modelling and for determination of enzyme substrate relationships the co-location of components needs to be considered

FANTOM4 EdgeExpressDB: an integrated database of promoters, genes, microRNAs, expression dynamics and regulatory interactions

EdgeExpressDB is a novel database and set of interfaces for interpreting biological networks and comparing large high-throughput expression datasets

Mesencephalic dopaminergic neurons express a repertoire of olfactory receptors and respond to odorant-like molecules

BACKGROUND: The mesencephalic dopaminergic (mDA) cell system is composed of two major groups of projecting cells in the Substantia Nigra (SN) (A9 neurons) and the Ventral Tegmental Area (VTA) (A10 cells). Selective degeneration of A9 neurons occurs in Parkinson's disease (PD) while abnormal function of A10 cells has been linked to schizophrenia, attention deficit and addiction. The molecular basis that underlies selective vulnerability of A9 and A10 neurons is presently unknown. RESULTS: By taking advantage of transgenic labeling, laser capture microdissection coupled to nano Cap-Analysis of Gene Expression (nanoCAGE) technology on isolated A9 and A10 cells, we found that a subset of Olfactory Receptors (OR)s is expressed in mDA neurons. Gene expression analysis was integrated with the FANTOM5 Helicos CAGE sequencing datasets, showing the presence of these ORs in selected tissues and brain areas outside of the olfactory epithelium. OR expression in the mesencephalon was validated by RT-PCR and in situ hybridization. By screening 16 potential ligands on 5 mDA ORs recombinantly expressed in an heterologous in vitro system, we identified carvone enantiomers as agonists at Olfr287 and able to evoke an intracellular Ca2+ increase in solitary mDA neurons. ORs were found expressed in human SN and down-regulated in PD post mortem brains. CONCLUSIONS: Our study indicates that mDA neurons express ORs and respond to odor-like molecules providing new opportunities for pharmacological intervention in disease

Hierarchical folding and reorganization of chromosomes are linked to transcriptional changes in cellular differentiation

Mammalian chromosomes fold into arrays of megabase‐sized topologically associating domains (TADs), which are arranged into compartments spanning multiple megabases of genomic DNA. TADs have internal substructures that are often cell type specific, but their higher‐order organization remains elusive. Here, we investigate TAD higher‐order interactions with Hi‐C through neuronal differentiation and show that they form a hierarchy of domains‐within‐domains (metaTADs) extending across genomic scales up to the range of entire chromosomes. We find that TAD interactions are well captured by tree‐like, hierarchical structures irrespective of cell type. metaTAD tree structures correlate with genetic, epigenomic and expression features, and structural tree rearrangements during differentiation are linked to transcriptional state changes. Using polymer modelling, we demonstrate that hierarchical folding promotes efficient chromatin packaging without the loss of contact specificity, highlighting a role far beyond the simple need for packing efficiency

MiR-107 and MiR-185 Can Induce Cell Cycle Arrest in Human Non Small Cell Lung Cancer Cell Lines

BACKGROUND: MicroRNAs (miRNAs) are short single stranded noncoding RNAs that suppress gene expression through either translational repression or degradation of target mRNAs. The annealing between messenger RNAs and 5' seed region of miRNAs is believed to be essential for the specific suppression of target gene expression. One miRNA can have several hundred different targets in a cell. Rapidly accumulating evidence suggests that many miRNAs are involved in cell cycle regulation and consequentially play critical roles in carcinogenesis. METHODOLOGY/PRINCIPAL FINDINGS: Introduction of synthetic miR-107 or miR-185 suppressed growth of the human non-small cell lung cancer cell lines. Flow cytometry analysis revealed these miRNAs induce a G1 cell cycle arrest in H1299 cells and the suppression of cell cycle progression is stronger than that by Let-7 miRNA. By the gene expression analyses with oligonucleotide microarrays, we find hundreds of genes are affected by transfection of these miRNAs. Using miRNA-target prediction analyses and the array data, we listed up a set of likely targets of miR-107 and miR-185 for G1 cell cycle arrest and validate a subset of them using real-time RT-PCR and immunoblotting for CDK6. CONCLUSIONS/SIGNIFICANCE: We identified new cell cycle regulating miRNAs, miR-107 and miR-185, localized in frequently altered chromosomal regions in human lung cancers. Especially for miR-107, a large number of down-regulated genes are annotated with the gene ontology term 'cell cycle'. Our results suggest that these miRNAs may contribute to regulate cell cycle in human malignant tumors