Mediator Complex of the Malaria Parasite Associates with Evolutionarily Novel Subunits.

The eukaryotic Mediator is a large and conserved multisubunit protein complex that directly contacts RNA polymerase II and impinges on multiple aspects of gene expression. The genome of the human malaria parasite has been predicted to encode several Mediator subunits. We provide physical evidence for the presence of a Mediator complex in by using coimmunoprecipitation and mass spectrometry to identify interaction partners of the highly conserved Mediator subunit PfMed31.

Viral Law: Life, Death, Difference, and Indifference from the Spanish Flu to Covid-19.

What is viral law? In order to being my discussion, I note that the last two years have been extremely difficult to understand and that we, meaning those who have lived through the pandemic, have struggled to make sense. Thus, I make the argument that the virus has impacted upon not only the individual's ability to make sense in a world where every day routines have been upended, but also social and political structures that similarly rely on repetition to continue to function. According to this thesis, Covid-19 is more than simply a biological organism, but also a cultural virus that undermines the organisation of social, political, and economic systems and requires new ways of thinking about how we might move forward into a post-Covid world.

Apocalypse Now!: From Freud, Through Lacan, to Stiegler's Psychoanalytic 'Survival Project.

The objective of this article is to explore the value of psychoanalysis in the early twenty-first century through reference to Freud, Lacan, and Stiegler's work on computational madness. In the first section of the article I consider the original objectives of psychoanalysis through reference to what I call Freud's 'normalisation project', before exploring the critique of this discourse concerned with the defence of oedipal law through a discussion of the post-modern 'individualisation project' set out by Deleuze and Guattari and others. Tracking the development of 'the individualisation project' in history, I consider its connections with the cybernetic theories of Wiener and Shannon in the psycho-cyber-utopianism of the 1990s, before moving on to consider the other side of the psychoanalytic-cybernetic interaction through a discussion of Jacques Lacan's rereading of Freud's in the second section of the article.

Psychoanalysing the 21st Century: Introduction.

The purpose of this introduction is to sketch out the value of psychoanalysis for the twenty-first century and in particular the ways in which analysis might enable us to move beyond the crisis of the post-Cold War symbolic order.

A zebrafish hox gene acts before gastrulation to specify the hemangioblast.

Hox genes encode transcription factors that have been implicated in embryonic, adult and disease processes. The earliest developmental program known to be directed by Hox genes is the timing of ingression of presumptive axial mesoderm during gastrulation. We previously used morpholino (MO)-based knockdown to implicate the zebrafish hoxd4a gene in the specification of the hemangioblast, an event occurring at pre-gastrulation stages, well before the earliest known Hox gene function.

Genome-wide analysis in Plasmodium falciparum reveals early and late phases of RNA polymerase II occupancy during the infectious cycle.

Background: Over the course of its intraerythrocytic developmental cycle (IDC), the malaria parasite Plasmodium falciparum tightly orchestrates the rise and fall of transcript levels for hundreds of genes. Considerable debate has focused on the relative importance of transcriptional versus post-transcriptional processes in the regulation of transcript levels. Enzymatically active forms of RNAPII in other organisms have been associated with phosphorylation on the serines at positions 2 and 5 of the heptad repeats within the C-terminal domain (CTD) of RNAPII.

A simple strategy for heritable chromosomal deletions in zebrafish via the combinatorial action of targeting nucleases.

Precise and effective genome-editing tools are essential for functional genomics and gene therapy. Targeting nucleases have been successfully used to edit genomes. However, whole-locus or element-specific deletions abolishing transcript expression have not previously been reported.

Zebrafish hoxd4a acts upstream of meis1.1 to direct vasculogenesis, angiogenesis and hematopoiesis.

Mice lacking the 4th-group paralog Hoxd4 display malformations of the anterior vertebral column, but are viable and fertile. Here, we report that zebrafish embryos having decreased function of the orthologous hoxd4a gene manifest striking perturbations in vasculogenesis, angiogenesis and primitive and definitive hematopoiesis. These defects are preceded by reduced expression of the hemangioblast markers scl1, lmo2 and fli1 within the posterior lateral plate mesoderm (PLM) at 13 hours post fertilization (hpf).

Nuclear accumulation of an uncapped RNA produced by Drosha cleavage of a transcript encoding miR-10b and HOXD4.

Patterning of the animal embryo's antero-posterior (AP) axis is dependent on spatially and temporally regulated Hox gene expression. The murine Hoxd4 gene has been proposed to harbour two promoters, an upstream promoter P2, and a downstream promoter P1, that lie 5.2 and 1.

Linkage of the potent leukemogenic activity of Meis1 to cell-cycle entry and transcriptional regulation of cyclin D3.

MEIS1 is a three-amino acid loop extension class homeodomain-containing homeobox (HOX) cofactor that plays key roles in normal hematopoiesis and leukemogenesis. Expression of Meis1 is rate-limiting in MLL-associated leukemias and potently interacts with Hox and NUP98-HOX genes in leukemic transformation to promote self-renewal and proliferation of hematopoietic progenitors. The oncogenicity of MEIS1 has been linked to its transcriptional activation properties.

Transcriptional activation by MEIS1A in response to protein kinase A signaling requires the transducers of regulated CREB family of CREB co-activators.

The transcription factor encoded by the murine ecotropic integration site 1 gene (MEIS1) is a partner of HOX and PBX proteins. It has been implicated in embryonic patterning and leukemia, and causally linked to restless legs syndrome. The MEIS1A C terminus harbors a transcriptional activation domain that is stimulated by protein kinase A (PKA) in a manner dependent on the co-activator of cAMP response element-binding protein (CREB), CREB-binding protein (CBP).

Stereospecificity and PAX6 function direct Hoxd4 neural enhancer activity along the antero-posterior axis.

The antero-posterior (AP) and dorso-ventral (DV) patterning of the neural tube is controlled in part by HOX and PAX transcription factors, respectively. We have reported on a neural enhancer of Hoxd4 that directs expression in the CNS with the correct anterior border in the hindbrain. Comparison to the orthologous enhancer of zebrafish revealed seven conserved footprints including an obligatory retinoic acid response element (RARE), and adjacent sites D, E and F.

Interplay between chromatin and trans-acting factors regulating the Hoxd4 promoter during neural differentiation.

Correct patterning of the antero-posterior axis of the embryonic trunk is dependent on spatiotemporally restricted Hox gene expression. In this study, we identified components of the Hoxd4 P1 promoter directing expression in neurally differentiating retinoic acid-treated P19 cells. We mapped three nucleosomes that are subsequently remodeled into an open chromatin state upon retinoic acid-induced Hoxd4 transcription.

Molecular dissection of Meis1 reveals 2 domains required for leukemia induction and a key role for Hoxa gene activation.

The Hoxa9 and Meis1 genes represent important oncogenic collaborators activated in a significant proportion of human leukemias with genetic alterations in the MLL gene. In this study, we show that the transforming property of Meis1 is modulated by 3 conserved domains, namely the Pbx interaction motif (PIM), the homeodomain, and the C-terminal region recently described to possess transactivating properties. Meis1 and Pbx1 interaction domain-swapping mutants are dysfunctional separately, but restore the full oncogenic activity of Meis1 when cotransduced in primary cells engineered to overexpress Hoxa9, thus implying a modular nature for PIM in Meis1-accelerated transformation.

MEIS C termini harbor transcriptional activation domains that respond to cell signaling.

MEIS proteins form heteromeric DNA-binding complexes with PBX monomers and PBX.HOX heterodimers. We have shown previously that transcriptional activation by PBX.

Sequential histone modifications at Hoxd4 regulatory regions distinguish anterior from posterior embryonic compartments.

Hox genes are differentially expressed along the embryonic anteroposterior axis. We used chromatin immunoprecipitation to detect chromatin changes at the Hoxd4 locus during neurogenesis in P19 cells and embryonic day 8.0 (E8.

Subcellular localization of multiple PREP2 isoforms is regulated by actin, tubulin, and nuclear export.

The PREP, MEIS, and PBX families are mammalian members of the TALE (three amino acid loop extension) class of homeodomain-containing transcription factors. These factors have been implicated in cooperative DNA binding with the HOX class of homeoproteins, but PREP and MEIS interact with PBX in apparently non-HOX-dependent cooperative DNA binding as well. PREP, MEIS, and PBX have all been reported to reside in the cytoplasm in one or more tissues of the developing vertebrate embryo.

Expression of the Wdr9 gene and protein products during mouse development.

Human WDR9 has been mapped to chromosome 21, within one of the Down syndrome (DS) critical regions. Here, we study the expression pattern of the murine Wdr9 gene and its protein product. We show that Wdr9 is broadly expressed in the mouse embryo by means of in situ hybridization and immunohistochemistry.

Nonmuscle myosin promotes cytoplasmic localization of PBX.

In the absence of MEIS family proteins, two mechanisms are known to restrict the PBX family of homeodomain (HD) transcription factors to the cytoplasm. First, PBX is actively exported from the nucleus via a CRM1-dependent pathway. Second, nuclear localization signals (NLSs) within the PBX HD are masked by intramolecular contacts.

The role of a retinoic acid response element in establishing the anterior neural expression border of Hoxd4 transgenes.

The zebrafish hoxd4a locus was compared to its murine ortholog, Hoxd4. The sequence of regulatory elements, including a DR5 type retinoic acid response element (RARE) required for Hoxd4 neural enhancer activity, are highly conserved. Additionally, zebrafish and mouse neural enhancers function identically in transgenic mouse embryos.

Prep2: cloning and expression of a new prep family member.

We describe Prep2, a new murine homeobox-containing gene closely related to Prep1. The PREP2 protein belongs to the three amino acid loop extension (TALE) superclass of homeodomain-containing proteins and encodes a polypeptide of 462 residues. As for PREP1, PREP2 binds an appropriate site on DNA as a heterodimer with PBX1A.

Coactivators in transcription initiation: here are your orders.

Coactivators are diverse and multifunctional proteins that act downstream of DNA-binding activators to stimulate transcription. Recent studies elucidate the temporal sequence in which coactivators are recruited to target promoters, and how their enzymatic properties and molecular interactions culminate in transcriptional initiation.