<i>Plasmodium </i>Condensin Core Subunits SMC2/SMC4 Mediate Atypical Mitosis and Are Essential for Parasite Proliferation and Transmission

Condensin is a multi-subunit protein complex regulating chromosome condensation and segregation during cell division. In Plasmodium spp., the causative agent of malaria, cell division is atypical and the role of condensin is unclear. Here we examine the role of SMC2 and SMC4, the core subunits of condensin, during endomitosis in schizogony and endoreduplication in male gametogenesis. During early schizogony, SMC2/SMC4 localize to a distinct focus, identified as the centromeres by NDC80 fluorescence and chromatin immunoprecipitation sequencing (ChIP-seq) analyses, but do not form condensin I or II complexes. In mature schizonts and during male gametogenesis, there is a diffuse SMC2/SMC4 distribution on chromosomes and in the nucleus, and both condensin I and condensin II complexes form at these stages. Knockdown of smc2 and smc4 gene expression reveals essential roles in parasite proliferation and transmission. The condensin core subunits (SMC2/SMC4) form different complexes and may have distinct functions at various stages of the parasite life cycle

MMP13 and TIMP1 are functional markers for two different potential modes of action by mesenchymal stem/stromal cells when treating osteoarthritis

Mesenchymal stem cells (MSCs) have been investigated as a potential injectable therapy for the treatment of knee osteoarthritis, with some evidence of success in preliminary human trials. However, optimization and scale‐up of this therapeutic approach depends on the identification of functional markers that are linked to their mechanism of action. One possible mechanism is through their chondrogenic differentiation and direct role in neo‐cartilage synthesis. Alternatively, they could remain undifferentiated and act through the release of trophic factors that stimulate endogenous repair processes within the joint. Here, we show that extensive in vitro aging of bone marrow‐derived human MSCs leads to loss of chondrogenesis but no reduction in trophic repair, thereby separating out the two modes of action. By integrating transcriptomic and proteomic data using Ingenuity Pathway Analysis, we found that reduced chondrogenesis with passage is linked to downregulation of the FOXM1 signaling pathway while maintenance of trophic repair is linked to CXCL12. In an attempt at developing functional markers of MSC potency, we identified loss of mRNA expression for MMP13 as correlating with loss of chondrogenic potential of MSCs and continued secretion of high levels of TIMP1 protein as correlating with the maintenance of trophic repair capacity. Since an allogeneic injectable osteoar therapy would require extensive cell expansion in vitro, we conclude that early passage MMP13+, TIMP1‐secretinghigh MSCs should be used for autologous OA therapies designed to act through engraftment and chondrogenesis, while later passage MMP13−, TIMP1‐secretinghigh MSCs could be exploited for allogeneic OA therapies designed to act through trophic repair

Improving the management of non-ST elevation acute coronary syndromes: systematic evaluation of a quality improvement programme European QUality Improvement Programme for Acute Coronary Syndrome: The EQUIP-ACS project protocol and design

Acute coronary syndromes, including myocardial infarction and unstable angina, are important causes of premature mortality, morbidity and hospital admissions. Acute coronary syndromes consume large amounts of health care resources, and have a major negative economic and social impact through days lost at work, support for disability, and coping with the psychological consequences of illness. Several registries have shown that evidence based treatments are under-utilised in this patient population, particularly in high-risk patients. There is evidence that systematic educational programmes can lead to improvement in the management of these patients. Since application of the results of important clinical trials and expert clinical guidelines into clinical practice leads to improved patient care and outcomes, we propose to test a quality improvement programme in a general group of hospitals in Europe

The Angelina Jolie effect : how high celebrity profile can have a major impact on provision of cancer related services

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Acknowledgements We acknowledge the support of the Genesis Breast Cancer Prevention Appeal and Breast Cancer Campaign, which funds the FH02 study. DGE is a NIHR Senior investigator. FH02 Study Group, Family History Clinics providing data is as follows, Edinburgh: Lynda Luke, Lesley Smart; St Barts, London: Vian Salih, Ilyena Froud; Grantham: Nicky Turner, Natarajan Vaithilingam; Leighton Hospital Crewe: Tracey Hales, Samantha Bennion; LondonDerry: Celia Diver-Hall, Jackie McGee; Nottingham: Douglas MacMillan; Nicky Scott; Bath: Diana Dalgleish, Alison Smith; Coventry: Celia Lewis; Royal Marsden Hospital, London: Janet self, Gerald Gui; Derby: Mark Sibbering, Samantha Crockett; City Hospital, Birmingham: Simerjit Rai, Harriet Goddard; Genesis Prevention Centre, Manchester: Lorraine Roberts, Jayne Beesley. RGC teams are as follows, Nottingham RGC: Gareth Cross; Guys Hospital: Adam Shaw; Manchester RGC: Andrew Wallace.Peer reviewedPublisher PD

Compositional and expression analyses of the glideosome during the Plasmodium life cycle reveal an additional myosin light chain required for maximum motility

Myosin A (MyoA) is a Class XIV myosin implicated in gliding motility and host cell and tissue invasion by malaria parasites. MyoA is part of a membrane-associated protein complex called the glideosome, which is essential for parasite motility and includes the MyoA light chain MTIP, and several glideosome-associated proteins (GAPs). However, most studies of MyoA have focused on single stages of the parasite life cycle. We examined MyoA expression throughout the Plasmodium berghei life cycle in both mammalian and insect hosts. In extracellular ookinetes, sporozoites and merozoites, MyoA was located at the parasite periphery. In the sexual stages, zygote formation and initial ookinete differentiation precede MyoA synthesis and deposition, which occurred only in the developing protuberance. In developing intracellular asexual blood stages, MyoA was synthesized in mature schizonts and was located at the periphery of segmenting merozoites, where it remained throughout maturation, merozoite egress and host cell invasion. Besides the known GAPs in the malaria parasite, the complex included GAP40, an additional myosin light chain designated essential light chain (ELC) and several other candidate components. This ELC bound the MyoA neck region adjacent to the MTIP binding site, and both myosin light chains co-located to the glideosome. Co-expression of MyoA with its two light chains revealed that the presence of both light chains enhances MyoA-dependent actin motility. In conclusion, we have established a system to study the interplay and function of the three glideosome components, enabling the assessment of inhibitors that target this motor complex to block host cell invasion

Plasmodium ARK2 and EB1 drive unconventional spindle dynamics, during chromosome segregation in sexual transmission stages

The Aurora family of kinases orchestrates chromosome segregation and cytokinesis during cell division, with precise spatiotemporal regulation of its catalytic activities by distinct protein scaffolds. Plasmodium spp., the causative agents of malaria, are unicellular eukaryotes with three unique and highly divergent aurora-related kinases (ARK1-3) that are essential for asexual cellular proliferation but lack most canonical scaffolds/activators. Here we investigate the role of ARK2 during sexual proliferation of the rodent malaria Plasmodium berghei, using a combination of super-resolution microscopy, mass spectrometry, and live-cell fluorescence imaging. We find that ARK2 is primarily located at spindle microtubules in the vicinity of kinetochores during both mitosis and meiosis. Interactomic and co-localisation studies reveal several putative ARK2-associated interactors including the microtubule-interacting protein EB1, together with MISFIT and Myosin-K, but no conserved eukaryotic scaffold proteins. Gene function studies indicate that ARK2 and EB1 are complementary in driving endomitotic division and thereby parasite transmission through the mosquito. This discovery underlines the flexibility of molecular networks to rewire and drive unconventional mechanisms of chromosome segregation in the malaria parasite.</p