Stem cell mechanobiology

Stem cells are undifferentiated cells that are capable of proliferation, self-maintenance and differentiation towards specific cell phenotypes. These processes are controlled by a variety of cues including physicochemical factors associated with the specific mechanical environment in which the cells reside. The control of stem cell biology through mechanical factors remains poorly understood and is the focus of the developing field of mechanobiology. This review provides an insight into the current knowledge of the role of mechanical forces in the induction of differentiation of stem cells. While the details associated with individual studies are complex and typically associated with the stem cell type studied and model system adopted, certain key themes emerge. First, the differentiation process affects the mechanical properties of the cells and of specific subcellular components. Secondly, that stem cells are able to detect and respond to alterations in the stiffness of their surrounding microenvironment via induction of lineage-specific differentiation. Finally, the application of external mechanical forces to stem cells, transduced through a variety of mechanisms, can initiate and drive differentiation processes. The coalescence of these three key concepts permit the introduction of a new theory for the maintenance of stem cells and alternatively their differentiation via the concept of a stem cell 'mechano-niche', defined as a specific combination of cell mechanical properties, extracellular matrix stiffness and external mechanical cues conducive to the maintenance of the stem cell population.<br/

Aerospace Laser Ignition/Ablation Variable High Precision Thruster

A laser ignition/ablation propulsion system that captures the advantages of both liquid and solid propulsion. A reel system is used to move a propellant tape containing a plurality of propellant material targets through an ignition chamber. When a propellant target is in the ignition chamber, a laser beam from a laser positioned above the ignition chamber strikes the propellant target, igniting the propellant material and resulting in a thrust impulse. The propellant tape is advanced, carrying another propellant target into the ignition chamber. The propellant tape and ignition chamber are designed to ensure that each ignition event is isolated from the remaining propellant targets. Thrust and specific impulse may by precisely controlled by varying the synchronized propellant tape/laser speed. The laser ignition/ablation propulsion system may be scaled for use in small and large applications

Permutation of Two-Term Local Quadrat Variance Analysis: General Concepts for Interpretation of Peaks

Many ecological studies use Two-Term Local Quadrat Variance Analysis (TTLQV) and its derivatives for spatial pattern analysis. Currently, rules for determining variance peak significance are arbitrary. Variance peaks found at block size 1 and at \u3e 50 % of the transect length are the only peaks whose use is explicitly prohibited. Although the use of variance peaks found at block sizes \u3e 10 % of the transect length have also been warned against, many researchers interpret them regardless. We show in this paper that variance peaks derived from TTLQV are subject to additional ‘rules of thumb’. Through the use of randomization and permutation analyses on real and simulated data of species abundance in contiguous plots along a single transect, we show that variance peaks found at block sizes 1, 2 and 3 occur frequently by chance and thus likely do not indicate biologically meaningful patterns. The use of multiple replicate transects decreases the probability of Type II error

Bright Source of Cold Ions for Surface-Electrode Traps

We produce large numbers of low-energy ions by photoionization of laser-cooled atoms inside a surface-electrode-based Paul trap. The isotope-selective trap loading rate of $4\times10^{5}$ Yb$^{+}$ ions/s exceeds that attained by photoionization (electron impact ionization) of an atomic beam by four (six) orders of magnitude. Traps as shallow as 0.13 eV are easily loaded with this technique. The ions are confined in the same spatial region as the laser-cooled atoms, which will allow the experimental investigation of interactions between cold ions and cold atoms or Bose-Einstein condensates.Comment: Paper submitted to PRL for review on 2/1/0

Changes in dietary patterns and body composition within 12 months of liver transplantation

Background: Cardiometabolic risk factors are increasing in liver transplant recipients (LTR). Influencing dietary factors have not been assessed. The aim of this observational study was to assess changes in weight, metabolic function, dietary intake and eating behaviours in the first year after orthotopic liver transplantation (OLT). Methods: Consecutive recruitment of 17 patients (14 males) awaiting OLT at a single tertiary hospital. Dietary intake, food behaviours and anthropometry were recorded at baseline, and 6 and 12 months posttransplant. Results: By 12 months, patients had gained on average 7.3% of body weight. The prevalence of overweight or obesity increased from baseline 53% to 77% (P=0.001). By 6 months, 65% (n=11/17) of patients had altered glucose metabolism. Dietary intake was consistent with a Western-style dietary pattern with high saturated fat. Over half of the patients (69%, n=11/16) reported low to no depressive feelings and rated their self-esteem as good (53%, n=9/16). The Power of Food Scale increased between pre and post-transplant, indicating a stronger appetitive drive. Conclusions: Weight gain occurs early post-transplant, with significant metabolic dysfunction present within 6 months, however is not associated with significant psychological distress. Early dietary intervention designed to limit weight gain and target cardiometabolic health is recommended for this unique patient population

Changes to DPPC domain structure in the presence of carbon nanoparticles

DPPC (dipalmitoylphosphatidylcholine) is a disaturated lipid capable of forming closely packed monolayers at the air–liquid interface of the lung and allows the surface tension within the alveoli to reduce to almost zero and thus prevent alveolar collapse. Carbon nanoparticles are formed in natural and man-made combustion events, including diesel engines, and are capable of reaching the alveolar epithelium during breathing. In this work, we have used Brewster angle microscopy and neutron reflectivity to study the effect of differing concentrations of carbon nanoparticles on the structure of DPPC monolayer as the monolayer is subject to compression and expansion. The results show that the inclusion of carbon nanoparticles within a DPPC monolayer affects the formation and structure of the lipid domains. The domains lose their circular structure and show a crenated structure as well as a reduction in overall size of the domains. This change in structure is also evident following expansion of the lipid monolayer, suggesting that some carbon nanoparticles may remain associated with the monolayer. This observation could have an important implication regarding the removal of nanosized airborne pollutants from the human lung

A 3-D in vitro co-culture model of mammary gland involution.

Involution is a process whereby the mammary gland undergoes extensive tissue remodelling involving exquisitely coordinated cell death, extracellular matrix degradation and adipose tissue regeneration following the weaning of offspring. These processes are mediated in part through Jak/Stat signalling pathways, which can be deregulated in breast cancer. Synthetic in vitro analogues of the breast could become important tools for studying tumorigenic processes, or as personalized drug discovery platforms and predictors of therapeutic response. Ideally, such models should support 3D neo-tissue formation, so as to recapitulate physiological organ function, and be compatible with high-throughput screening methodologies. We have combined cell lines of epithelial, stromal and immunological origin within engineered porous collagen/hyaluronic acid matrices, demonstrating 3D-specific molecular signatures. Furthermore seeded cells form mammary-like branched tissues, with lobuloalveolar structures that undergo inducible involution phenotypes reminiscent of the native gland under hormonal/cytokine regulation. We confirm that autophagy is mediated within differentiated mammary epithelial cells in a Stat-dependent manner at early time points following the removal of a prolactin stimulus (H/WD). In addition, epithelial cells express markers of an M2 macrophage lineage under H/WD, a process that is attenuated with the introduction of the monocyte/macrophage cell line RAW 264.7. Thus, such 3D models are suitable platforms for studying cell-cell interactions and cell death mechanisms in relation to cancer.This is the accepted manuscript. The final version is available from RSC at http://pubs.rsc.org/en/content/articlehtml/2014/ib/c3ib40257f

Randomised trial of glutamine, selenium, or both, to supplement parenteral nutrition for critically ill patients

Peer reviewedPublisher PD

Clinical effectiveness and cost-effectiveness of open and arthroscopic rotator cuff repair [the UK Rotator Cuff Surgery (UKUFF) randomised trial]

Peer reviewedPublisher PD

Quantification of indirect pathway inhibition by the adenosine A 2a antagonist SYN115 in Parkinson disease

Adenosine A(2a) receptor antagonists reduce symptom severity in Parkinson disease (PD) and animal models. Rodent studies support the hypothesis that A(2a) antagonists produce this benefit by reducing the inhibitory output of the basal ganglia indirect pathway. One way to test this hypothesis in humans is to quantify regional pharmacodynamic responses with cerebral blood flow (CBF) imaging. That approach has also been proposed as a tool to accelerate pharmaceutical dose-finding, but has not yet been applied in humans to drugs in development. We successfully addressed both these aims with a perfusion MRI study of the novel adenosine A(2a) antagonist SYN115. During a randomized, double-blind, placebo-controlled, crossover study in 21 PD patients on levodopa but no agonists, we acquired pulsed arterial spin labeling MRI at the end of each treatment period. SYN115 produced a highly significant decrease in thalamic CBF, consistent with reduced pallidothalamic inhibition via the indirect pathway. Similar decreases occurred in cortical regions whose activity decreases with increased alertness and externally-focused attention, consistent with decreased self-reported sleepiness on SYN115. Remarkably, we also derived quantitative pharmacodynamic parameters from the CBF responses to SYN115. These results suggested that the doses tested were on the low end of the effective dose range, consistent with clinical data reported separately. We conclude that (1) SYN115 enters the brain and exerts dose-dependent regional effects, (2) the most prominent of these effects is consistent with deactivation of the indirect pathway as predicted by preclinical studies; and (3) perfusion MRI can provide rapid, quantitative, clinically relevant dose-finding information for pharmaceutical development