Cell cycle regulation of proliferation versus differentiation in the central nervous system

Formation of the central nervous system requires a period of extensive progenitor cell proliferation, accompanied or closely followed by differentiation; the balance between these two processes in various regions of the central nervous system gives rise to differential growth and cellular diversity. The correlation between cell cycle lengthening and differentiation has been reported across several types of cell lineage and from diverse model organisms, both in vivo and in vitro. Furthermore, different cell fates might be determined during different phases of the preceding cell cycle, indicating direct cell cycle influences on both early lineage commitment and terminal cell fate decisions. Significant advances have been made in the last decade and have revealed multi-directional interactions between the molecular machinery regulating the processes of cell proliferation and neuronal differentiation. Here, we first introduce the modes of proliferation in neural progenitor cells and summarise evidence linking cell cycle length and neuronal differentiation. Second, we describe the manner in which components of the cell cycle machinery can have additional and, sometimes, cell-cycle-independent roles in directly regulating neurogenesis. Finally, we discuss the way that differentiation factors, such as proneural bHLH proteins, can promote either progenitor maintenance or differentiation according to the cellular environment. These intricate connections contribute to precise coordination and the ultimate division versus differentiation decision

Bifurcations and chaos in semiconductor superlattices with a tilted magnetic field

We study the effects of dissipation on electron transport in a semiconductor superlattice with an applied bias voltage and a magnetic field that is tilted relative to the superlattice axis.In previous work, we showed that although the applied fields are stationary,they act like a THz plane wave, which strongly couples the Bloch and cyclotron motion of electrons within the lowest miniband. As a consequence,the electrons exhibit a unique type of Hamiltonian chaos, which creates an intricate mesh of conduction channels (a stochastic web) in phase space, leading to a large resonant increase in the current flow at critical values of the applied voltage. This phase-space patterning provides a sensitive mechanism for controlling electrical resistance. In this paper, we investigate the effects of dissipation on the electron dynamics by modifying the semiclassical equations of motion to include a linear damping term. We demonstrate that even in the presence of dissipation,deterministic chaos plays an important role in the electron transport process. We identify mechanisms for the onset of chaos and explore the associated sequence of bifurcations in the electron trajectories. When the Bloch and cyclotron frequencies are commensurate, complex multistability phenomena occur in the system. In particular, for fixed values of the control parameters several distinct stable regimes can coexist, each corresponding to different initial conditions. We show that this multistability has clear, experimentally-observable, signatures in the electron transport characteristics.Comment: 14 pages 11 figure

Combining Realist approaches and Normalization Process Theory to understand implementation: a systematic review

Background: Realist approaches and Normalization Process Theory (NPT) have both gained significant traction in implementation research over the past 10 years. The aim of this study was therefore to explore how the approaches are combined to understand problems of implementation, to determine the degree of complementarity of the two approaches and to provide practical approaches for using them together. Methods: Systematic review of research studies combining Realist and NPT approaches. Realist methodology is concerned with understanding and explaining causation, that is, how and why policies, programmes and interventions achieve their effects. NPT is a theory of implementation that explains how practices become normalised. Databases searched (January 2020) were ASSIA, CINAHL, Health Research Premium Collection via Proquest (Family Health Database, Health & Medical Collection, Health Management Database, MEDLINE, Nursing & Allied Health Database, Psychology Database, Public Health Database) and PsycARTICLES. Studies were included if the author(s) stated they used both approaches: a scientific Realist perspective applying the principles of Pawson and Tilley’s Realist Evaluation or Pawson’s Realist Synthesis and Normalization Process Theory either solely or in addition to other theories. Two authors screened records; discrepancies were reviewed by a third screener. Data was extracted by three members of the team and a narrative synthesis was undertaken. Results: Of 245 total records identified, 223 unique records were screened and 39 full-text papers were reviewed, identifying twelve papers for inclusion in the review. These papers represented eight different studies. Extent and methods of integration of the approaches varied. In most studies (6/8), Realist approaches were the main driver. NPT was mostly used to enhance the explanatory power of Realist analyses, informing development of elements of Contexts, Mechanisms and Outcomes (a common heuristic in realist work). Authors’ reflections on the integration of NPT and Realist approaches were limited. Conclusions: Using Realist and NPT approaches in combination can add explanatory power for understanding the implementation of interventions and programmes. Attention to detailed reporting on methods and analytical process when combining approaches, and appraisal of theoretical and practical utility is advised for advancing knowledge of applying these approaches in research

A Feasibility Study of Quantifying Longitudinal Brain Changes in Herpes Simplex Virus (HSV) Encephalitis Using Magnetic Resonance Imaging (MRI) and Stereology.

OBJECTIVES: To assess whether it is feasible to quantify acute change in temporal lobe volume and total oedema volumes in herpes simplex virus (HSV) encephalitis as a preliminary to a trial of corticosteroid therapy. METHODS: The study analysed serially acquired magnetic resonance images (MRI), of patients with acute HSV encephalitis who had neuroimaging repeated within four weeks of the first scan. We performed volumetric measurements of the left and right temporal lobes and of cerebral oedema visible on T2 weighted Fluid Attenuated Inversion Recovery (FLAIR) images using stereology in conjunction with point counting. RESULTS: Temporal lobe volumes increased on average by 1.6% (standard deviation (SD 11%) in five patients who had not received corticosteroid therapy and decreased in two patients who had received corticosteroids by 8.5%. FLAIR hyperintensity volumes increased by 9% in patients not receiving treatment with corticosteroids and decreased by 29% in the two patients that had received corticosteroids. CONCLUSIONS: This study has shown it is feasible to quantify acute change in temporal lobe and total oedema volumes in HSV encephalitis and suggests a potential resolution of swelling in response to corticosteroid therapy. These techniques could be used as part of a randomized control trial to investigate the efficacy of corticosteroids for treating HSV encephalitis in conjunction with assessing clinical outcomes and could be of potential value in helping to predict the clinical outcomes of patients with HSV encephalitis

A comprehensive assessment of the applicability of available and proposed offshore mooring and foundation technologies and design tools for array applications

PublishedThe function and type of mooring and/or foundation system are determined by a number of factors including: cost, site characteristics, expected environmental loading and environmental or legislative constraints. The design of the device and its mode of operation will also influence the decision making process. It is the role of DTOcean Work Package 4 to produce a decision making tool which has the capability to assess a range of technologies for the design and selection of mooring and foundation systems for marine renewable energy (MRE) device arrays. In this first deliverable report, criteria are introduced which can be used to appraise technologies and approaches relevant to MRE devices. Existing mooring and foundation technologies used in the offshore industry are summarised with examples given of MRE device deployments. A general overview of the design tools which are currently used for mooring and foundation design in the offshore and MRE industries is provided, along with a list of the capabilities of several commercially available software packages.European Commission’s 7th Framework; Grant agreement number: 60859

Follistatin-like 3 (FSTL3) mediated silencing of transforming growth factor (TGF ) signaling is essential for testicular aging and regulating testis size

Follistatin-like 3 (FSTL3) is a glycoprotein that binds and inhibits the action of TGFβ ligands such as activin. The roles played by FSTL3 and activin signaling in organ development and homeostasis are not fully understood. The authors show mice deficient in FSTL3 develop markedly enlarged testes that are also delayed in their age-related regression. These FSTL3 knockout mice exhibit increased Sertoli cell numbers, allowing for increased spermatogenesis but otherwise showing normal testicular function. The data show that FSTL3 deletion leads to increased AKT signaling and SIRT1 expression in the testis. This demonstrates a cross-talk between TGFβ ligand and AKT signaling and leads to a potential mechanism for increased cellular survival and antiaging. The findings identify crucial roles for FSTL3 in limiting testis organ size and promoting age-related testicular regression

Kinome-wide analysis of the effect of statins in colorectal cancer

Background Epidemiological studies and meta-analyses show an association between statin use and a reduced incidence of colorectal cancer (CRC). We have shown that statins act on CRC through bone morphogenetic protein (BMP) signalling, but the exact cellular targets and underlying mechanism of statin action remain elusive. In this study, we set out to assess the influence of statins on global cancer cell signalling by performing an array-based kinase assay using immobilised kinase substrates spanning the entire human kinome. Methods CRC cells with or without Lovastatin treatment were used for kinome analysis. Findings on kinome arrays were further confirmed by immunoblotting with activity-specific antibodies. Experiments in different CRC cell lines using immunoblotting, siRNA-mediated knockdown and treatment with specific BMP inhibitor Noggin were performed. The relevance of in vitro findings was confirmed in xenografts and in CRC patients treated with Simvastatin. Results Kinome analysis can distinguish between non-specific, toxic effects caused by 10 mu M of Lovastatin and specific effects on cell signalling caused by 2 mu M Lovastatin. Statins induce upregulation of PTEN activity leading to downregulation of the PI3K/Akt/mTOR signalling. Treatment of cells with the specific BMP inhibitor Noggin as well as PTEN knockdown and transfection of cells with a constitutively active form of AKT abolishes the effect of Lovastatin on mTOR phosphorylation. Experiments in xenografts and in patients treated with Simvastatin confirm statin-mediated BMP pathway activation, activation of PTEN and downregulation of mTOR signalling. Conclusions Statins induce BMP-specific activation of PTEN and inhibition of PI3K/Akt/mTOR signalling in CRC

Analogue peptides for the immunotherapy of human acute myeloid leukemia

Accepted manuscript. The final publication is available at: http://link.springer.com/article/10.1007%2Fs00262-015-1762-9The use of peptide vaccines, enhanced by adjuvants, has shown some efficacy in clinical trials. However, responses are often short-lived and rarely induce notable memory responses. The reason is that self-antigens have already been presented to the immune system as the tumor develops, leading to tolerance or some degree of host tumor cell destruction. To try to break tolerance against self-antigens, one of the methods employed has been to modify peptides at the anchor residues to enhance their ability to bind major histocompatibility complex molecules, extending their exposure to the T-cell receptor. These modified or analogue peptides have been investigated as stimulators of the immune system in patients with different cancers with variable but sometimes notable success. In this review we describe the background and recent developments in the use of analogue peptides for the immunotherapy of acute myeloid leukemia describing knowledge useful for the application of analogue peptide treatments for other malignancies