Chemogenomics identifies acetyl-coenzyme A synthetase as a target for malaria treatment and prevention

We identify the Plasmodium falciparum acetyl-coenzyme A synthetase (PfAcAS) as a druggable target, using genetic and chemical validation. In vitro evolution of resistance with two antiplasmodial drug-like compounds (MMV019721 and MMV084978) selects for mutations in PfAcAS. Metabolic profiling of compound-treated parasites reveals changes in acetyl-CoA levels for both compounds. Genome editing confirms that mutations in PfAcAS are sufficient to confer resistance. Knockdown studies demonstrate that PfAcAS is essential for asexual growth, and partial knockdown induces hypersensitivity to both compounds. In vitro biochemical assays using recombinantly expressed PfAcAS validates that MMV019721 and MMV084978 directly inhibit the enzyme by preventing CoA and acetate binding, respectively. Immunolocalization studies reveal that PfAcAS is primarily localized to the nucleus. Functional studies demonstrate inhibition of histone acetylation in compound-treated wild-type, but not in resistant parasites. Our findings identify and validate PfAcAS as an essential, druggable target involved in the epigenetic regulation of gene expression

Structure–activity Relationships of Amyloid Beta-aggregation Inhibitors Based on Curcumin: Influence of Linker Length and Flexibility

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66293/1/j.1747-0285.2007.00557.x.pd

Denudation of the continental shelf between Britain and France at the glacial-interglacial timescale

The erosional morphology preserved at the sea bed in the eastern English Channel dominantly records denudation of the continental shelf by fluvial processes over multiple glacial-interglacial sea-level cycles rather than by catastrophic flooding through the Straits of Dover during the mid-Quaternary. Here, through the integration of multibeam bathymetry and shallow sub-bottom 2D seismic reflection profiles calibrated with vibrocore records, the first stratigraphic model of erosion and deposition on the eastern English Channel continental shelf is presented. Published Optical Stimulated Luminescence (OSL) and C ages were used to chronometrically constrain the stratigraphy and allow correlation of the continental shelf record with major climatic/sea-level periods. Five major erosion surfaces overlain by discrete sediment packages have been identified. The continental shelf in the eastern English Channel preserves a record of processes operating from Marine Isotope Stage (MIS) 6 to MIS 1. Planar and channelised erosion surfaces were formed by fluvial incision during lowstands or relative sea-level fall. The depth and lateral extent of incision was partly conditioned by underlying geology (rock type and tectonic structure), climatic conditions and changes in water and sediment discharge coupled to ice sheet dynamics and the drainage configuration of major rivers in Northwest Europe. Evidence for major erosion during or prior to MIS 6 is preserved. Fluvial sediments of MIS 2 age were identified within the Northern Palaeovalley, providing insights into the scale of erosion by normal fluvial regimes. Seismic and sedimentary facies indicate that deposition predominantly occurred during transgression when accommodation was created in palaeovalleys to allow discrete sediment bodies to form. Sediment reworking over multiple sea-level cycles (Saalian-Eemian-early Weichselian) by fluvial, coastal and marine processes created a multi-lateral, multi-storey succession of palaeovalley-fills that are preserved as a strath terrace. The data presented here reveal a composite erosional and depositional record that has undergone a high degree of reworking over multiple sea-level cycles leading to the preferential preservation of sediments associated with the most recent glacial-interglacial period

Crosstalk between reactive oxygen species and pro-inflammatory markers in developing various chronic diseases: a review

The inflammation process in the human body plays a central role in the pathogenesis of many chronic diseases. In addition, reactive oxygen species (ROS) exert potentially a decisive role in human body, particularly in physiological and pathological process. The chronic inflammation state could generate several types of diseases such as cancer, atherosclerosis, diabetes mellitus and arthritis, especially if it is concomitant with high levels of pro-inflammatory markers and ROS. The respiratory burst of inflammatory cells during inflammation increases the production and accumulation of ROS. However, ROS regulate various types of kinases and transcription factors such nuclear factor-kappa B which is related to the activation of pro-inflammatory genes. The exact crosstalk between pro-inflammatory markers and ROS in terms of pathogenesis and development of serious diseases is still ambitious. Many studies have been attempting to determine the mechanistic mutual relationship between ROS and pro-inflammatory markers. Therefore hereby, we review the hypothetical relationship between ROS and pro-inflammatory markers in which they have been proposed to initiate cancer, atherosclerosis, diabetes mellitus and arthritis

The impact of workplace stressors on exhaustion and work engagement in policing

This paper uses the challenge-hindrance stressor framework to examine the impact of challenge and hindrance stressors on police officer and staff well-being. Results of two studies conducted in English police forces demonstrate that challenge stressors relate positively to the effort and enthusiasm individuals invest into their work. Findings also indicate that while challenge stressors are positively associated with exhaustion cross-sectionally (Study 1, N = 469), they do not impact exhaustion over time (Study 2, N = 823). Conversely, hindrance stressors cause exhaustion in the long-term and are negatively associated with work engagement cross-sectionally. Implications for theory and practice are discussed

New geomorphological and archaeological evidence for drainage evolution in the Luangwa Valley (Zambia) during the Late Pleistocene

This is the first systematic investigation of two distinctive geomorphological features recorded in the central Luangwa River valley, Zambia. A series of low hills was found to be capped by thin (~1 m) gravel deposits containing stratified Stone Age artefacts. More widespread gravels occur on the margins of the Luangwa River floodplain lacking stratified artefacts. The previously unreported hilltop deposits are interpreted as remnants of a dissected land-surface, and the valley floor gravels as redeposited clasts from c. 20 m of down-cutting. Clast analysis and drainage basin size analysis support a hypothesis of gravel deposition by unconstrained debris flows from the distant Muchinga escarpment, or from an intermediate zone. Excavation of a perched deposit revealed a coarsely stratified Stone Age record indicating periodic emplacement of artefact-bearing gravels over an extended period. Deposition of these perched gravels continued into the Late Pleistocene (~77 ka), based on OSL dating, after which the current dissected landscape formed. We hypothesize further, based on a regional record of landscape instability and core data from Lake Malawi, that fan formation in the valley was linked to periods of extended aridity and reduced vegetation cover followed by episodic erosional events on the return to wetter conditions. We argue that the subsequent dissection of the land-surface is the end state of a sequence of responses to base-level changes and climate change.</p