H2A.Z Demarcates Intergenic Regions of the Plasmodium falciparum Epigenome That Are Dynamically Marked by H3K9ac and H3K4me3

Epigenetic regulatory mechanisms and their enzymes are promising targets for malaria therapeutic intervention; however, the epigenetic component of gene expression in P. falciparum is poorly understood. Dynamic or stable association of epigenetic marks with genomic features provides important clues about their function and helps to understand how histone variants/modifications are used for indexing the Plasmodium epigenome. We describe a novel, linear amplification method for next-generation sequencing (NGS) that allows unbiased analysis of the extremely AT-rich Plasmodium genome. We used this method for high resolution, genome-wide analysis of a histone H2A variant, H2A.Z and two histone H3 marks throughout parasite intraerythrocytic development. Unlike in other organisms, H2A.Z is a constant, ubiquitous feature of euchromatic intergenic regions throughout the intraerythrocytic cycle. The almost perfect colocalisation of H2A.Z with H3K9ac and H3K4me3 suggests that these marks are preferentially deposited on H2A.Z-containing nucleosomes. By performing RNA-seq on 8 time-points, we show that acetylation of H3K9 at promoter regions correlates very well with the transcriptional status whereas H3K4me3 appears to have stage-specific regulation, being low at early stages, peaking at trophozoite stage, but does not closely follow changes in gene expression. Our improved NGS library preparation procedure provides a foundation to exploit the malaria epigenome in detail. Furthermore, our findings place H2A.Z at the cradle of P. falciparum epigenetic regulation by stably defining intergenic regions and providing a platform for dynamic assembly of epigenetic and other transcription related complexes

Stock-Flow Consistent Dynamic Models: Features, Limitations and Developments

The stock-flow consistent (SFC) approach to macroeconomic dynamic modelling was developed in the 2000s by Godley and Lavoie, (2007a, 2007b), who paved the way for the flourishing of SFC models. These models are based on four accounting principles (flow consistency, stock consistency, stock-flow consistency, and quadruple book-keeping), which allow inferring a set of accounting identities. The latter are then coupled with a set of equations defining the equilibrium conditions. Finally, difference (or differential) stochastic equations are added to define the behaviour of each macro-sector (or agent) of the economy. SFC models’ coefficients can be calibrated to obtain a theoretical baseline scenario and/or estimated through standard econometric techniques. Baseline results are then compared with a variety of ‘possible worlds’ or shocks. This theoretical and analytical flexibility is the reason SFC models are used by economists with different theoretical backgrounds. While SFC models are affected by some limitations, we believe that advantages outdo weaknesse

Proteins, drug targets and the mechanisms they control : the simple truth about complex networks

Realizing the promise of molecularly targeted inhibitors for cancer therapy will require a new level of knowledge about how a drug target is wired into the control circuitry of a complex cellular network. Here we review general homeostatic principles of cellular networks that enable the cell to be resilient in the face of molecular perturbations, while at the same time being sensitive to subtle input signals. Insights into such mechanisms may facilitate the development of combination therapies that take advantage of the cellular control circuitry, with the aim of achieving higher efficacy at a lower drug dosage and with a reduced probability of drug-resistance development

Diverse Synaptic Terminals on Rat Stapedius Motoneurons

Stapedius motoneurons (SMN) mediate the contraction of the stapedius muscle, which protects the inner ear from injury and reduces the masking effects of background noise. A variety of inputs to SMNs are known to exist, but their terminal ultrastructure has not been investigated. We characterized the synaptic terminals on retrogradely labeled SMNs found just ventromedial to the facial motor nucleus. About 80% of the terminals contained round synaptic vesicles. One type (Sm Rnd) had small, round vesicles filling the terminal with occasional dense core vesicles and formed an asymmetric synapse. Sm Rnd terminals were small with lengths of apposition to the SMN less than 3 μm. Partial reconstructions from serial sections demonstrated that these terminals formed up to three synapses per terminal. Another terminal type (Lg Rnd) had large, round vesicles and asymmetric synapses. Most Lg Rnd terminals were small but some were extensive, e.g., abutting the SMN for up to 10 μm. One of these terminals formed at least seven synapses. Another terminal type (Pleo) had pleomorphic vesicles and symmetric active zones that, in some cases, were invaginated by spines from the SMN. A fourth uncommon terminal type (Het Rnd) had round vesicles of heterogeneous sizes and asymmetric synapses. A fifth rare terminal type (Cist) had large, round vesicles and an accompanying subsurface cistern in the SMN. These were generally the same kinds of terminals found on other motoneurons, but the high proportion of round vesicle synapses indicate that SMNs receive mostly excitatory inputs