Multiscale modelling of intestinal crypt organization and carcinogenesis

Colorectal cancers are the third most common type of cancer. They originate from intestinal crypts, glands that descend from the intestinal lumen into the underlying connective tissue. Normal crypts are thought to exist in a dynamic equilibrium where the rate of cell production at the base of a crypt is matched by that of loss at the top. Understanding how genetic alterations accumulate and proceed to disrupt this dynamic equilibrium is fundamental to understanding the origins of colorectal cancer. Colorectal cancer emerges from the interaction of biological processes that span several spatial scales, from mutations that cause inappropriate intracellular responses to changes at the cell/tissue level, such as uncontrolled proliferation and altered motility and adhesion. Multiscale mathematical modelling can provide insight into the spatiotemporal organisation of such a complex, highly regulated and dynamic system. Moreover, the aforementioned challenges are inherent to the multiscale modelling of biological tissue more generally. In this review we describe the mathematical approaches that have been applied to investigate multiscale aspects of crypt behavior, highlighting a number of model predictions that have since been validated experimentally. We also discuss some of the key mathematical and computational challenges associated with the multiscale modelling approach. We conclude by discussing recent efforts to derive coarse-grained descriptions of such models, which may offer one way of reducing the computational cost of simulation by leveraging well-established tools of mathematical analysis to address key problems in multiscale modelling

Exercise training versus angioplasty for stable claudication. Long and medium term results of a prospective, randomised trial

Objectives:To compare percutaneous transluminal angioplsty (PTA) against exercise training in the treatment of stable claudication.Design:Prospective, randomised trial.Materials:Fifty-six patients with unilateral, stable, lower limb claudication assessed prior to randomisation, at 3 monthly intervals for 15 months, and at approximately 6 years follow-up. Thirty-seven patients were available for long term review.Outcome measures:Ankle/brachial pressure index (ABPI), treadmill claudication and maximum walking distances, percentage fall in ankle systolic pressure after exercise.Results:Significant increases were seen in ABPI in the patients treated with PTA at all assessment to 15 months. However in terms of improved walking performance, the most significant changes in claudication and maximum walking distance were seen in the exercise training group. At long term follow-up, there was no significant difference between the groups. Subgroup analysis by angiographic site of disease showed greater functional improvement in those patients with disease confined to the superficial femoral artery treated by exercise training. The overall prognosis for the whole group of patients was benign, with only two (4%) undergoing amputation.Conclusions:Exercise training confers a greater improvement in claudication and maximum walking distance than PTA, especially in patients with disease confined to the superficial femoral artery

Observations of the post shock break-out emission of SN 2011dh with XMM-Newton

After the occurrence of the type cIIb SN 2011dh in the nearby spiral galaxy M 51 numerous observations were performed with different telescopes in various bands ranging from radio to gamma-rays. We analysed the XMM-Newton and Swift observations taken 3 to 30 days after the SN explosion to study the X-ray spectrum of SN 2011dh. We extracted spectra from the XMM-Newton observations, which took place ~7 and 11 days after the SN. In addition, we created integrated Swift/XRT spectra of 3 to 10 days and 11 to 30 days. The spectra are well fitted with a power-law spectrum absorbed with Galactic foreground absorption. In addition, we find a harder spectral component in the first XMM-Newton spectrum taken at t ~ 7 d. This component is also detected in the first Swift spectrum of t = 3 - 10 d. While the persistent power-law component can be explained as inverse Compton emission from radio synchrotron emitting electrons, the harder component is most likely bremsstrahlung emission from the shocked stellar wind. Therefore, the harder X-ray emission that fades away after t ~ 10 d can be interpreted as emission from the shocked circumstellar wind of SN 2011dh.Comment: Accepted for publication as a Research Note in Astronomy and Astrophysic

Current-induced cooling phenomenon in a two-dimensional electron gas under a magnetic field

We investigate the spatial distribution of temperature induced by a dc current in a two-dimensional electron gas (2DEG) subjected to a perpendicular magnetic field. We numerically calculate the distributions of the electrostatic potential phi and the temperature T in a 2DEG enclosed in a square area surrounded by insulated-adiabatic (top and bottom) and isopotential-isothermal (left and right) boundaries (with phi_{left} < phi_{right} and T_{left} =T_{right}), using a pair of nonlinear Poisson equations (for phi and T) that fully take into account thermoelectric and thermomagnetic phenomena, including the Hall, Nernst, Ettingshausen, and Righi-Leduc effects. We find that, in the vicinity of the left-bottom corner, the temperature becomes lower than the fixed boundary temperature, contrary to the naive expectation that the temperature is raised by the prevalent Joule heating effect. The cooling is attributed to the Ettingshausen effect at the bottom adiabatic boundary, which pumps up the heat away from the bottom boundary. In order to keep the adiabatic condition, downward temperature gradient, hence the cooled area, is developed near the boundary, with the resulting thermal diffusion compensating the upward heat current due to the Ettingshausen effect.Comment: 25 pages, 7 figure

Altered myogenesis and premature senescence underlie human TRIM32-related myopathy

TRIM32 is a E3 ubiquitin -ligase containing RING, B-box, coiled-coil and six C-terminal NHL domains. Mutations involving NHL and coiled-coil domains result in a pure myopathy (LGMD2H/STM) while the only described mutation in the B-box domain is associated with a multisystemic disorder without myopathy (Bardet-Biedl syndrome type11), suggesting that these domains are involved in distinct processes. Knock-out (T32KO) and knockin mice carrying the c.1465G > A (p.D489N) involving the NHL domain (T32KI) show alterations in muscle regrowth after atrophy and satellite cells senescence. Here, we present phenotypical description and functional characterization of mutations in the RING, coiled-coil and NHL domains of TRIM32 causing a muscle dystrophy. Reduced levels of TRIM32 protein was observed in all patient muscle studied, regardless of the type of mutation (missense, single amino acid deletion, and frameshift) or the mutated domain. The affected patients presented with variable phenotypes but predominantly proximal weakness. Two patients had symptoms of both muscular dystrophy and Bardet-Biedl syndrome. The muscle magnetic resonance imaging (MRI) pattern is highly variable among patients and families. Primary myoblast culture from these patients demonstrated common findings consistent with reduced proliferation and differentiation, diminished satellite cell pool, accelerated senescence of muscle, and signs of autophagy activation.Health Institute Carlos III PI16-01843 JR15/00042FEDER PI16-01843 JR15/00042Fundación Progreso y Salud, Junta de Andalucía PI-0085-2016Australian National Health and Medical Research Council (NHMRC) APP1122952 APP111751

Altered myogenesis and premature senescence underlie human TRIM32-related myopathy

TRIM32 is a E3 ubiquitin -ligase containing RING, B-box, coiled-coil and six C-terminal NHL domains. Mutations involving NHL and coiled-coil domains result in a pure myopathy (LGMD2H/STM) while the only described mutation in the B-box domain is associated with a multisystemic disorder without myopathy (Bardet-Biedl syndrome type11), suggesting that these domains are involved in distinct processes. Knock-out (T32KO) and knockin mice carrying the c.1465G > A (p.D489N) involving the NHL domain (T32KI) show alterations in muscle regrowth after atrophy and satellite cells senescence. Here, we present phenotypical description and functional characterization of mutations in the RING, coiled-coil and NHL domains of TRIM32 causing a muscle dystrophy. Reduced levels of TRIM32 protein was observed in all patient muscle studied, regardless of the type of mutation (missense, single amino acid deletion, and frameshift) or the mutated domain. The affected patients presented with variable phenotypes but predominantly proximal weakness. Two patients had symptoms of both muscular dystrophy and Bardet-Biedl syndrome. The muscle magnetic resonance imaging (MRI) pattern is highly variable among patients and families. Primary myoblast culture from these patients demonstrated common findings consistent with reduced proliferation and differentiation, diminished satellite cell pool, accelerated senescence of muscle, and signs of autophagy activation.Health Institute Carlos III PI16-01843 JR15/00042FEDER PI16-01843 JR15/00042Fundación Progreso y Salud, Junta de Andalucía PI-0085-2016Australian National Health and Medical Research Council (NHMRC) APP1122952 APP111751

‘O sibling, where art thou?’ – a review of avian sibling recognition with respect to the mammalian literature

Avian literature on sibling recognition is rare compared to that developed by mammalian researchers. We compare avian and mammalian research on sibling recognition to identify why avian work is rare, how approaches differ and what avian and mammalian researchers can learn from each other. Three factors: (1) biological differences between birds and mammals, (2) conceptual biases and (3) practical constraints, appear to influence our current understanding. Avian research focuses on colonial species because sibling recognition is considered adaptive where ‘mixing potential’ of dependent young is high; research on a wider range of species, breeding systems and ecological conditions is now needed. Studies of acoustic recognition cues dominate avian literature; other types of cues (e.g. visual, olfactory) deserve further attention. The effect of gender on avian sibling recognition has yet to be investigated; mammalian work shows that gender can have important influences. Most importantly, many researchers assume that birds recognise siblings through ‘direct familiarisation’ (commonly known as associative learning or familiarity); future experiments should also incorporate tests for ‘indirect familiarisation’ (commonly known as phenotype matching). If direct familiarisation proves crucial, avian research should investigate how periods of separation influence sibling discrimination. Mammalian researchers typically interpret sibling recognition in broad functional terms (nepotism, optimal outbreeding); some avian researchers more successfully identify specific and testable adaptive explanations, with greater relevance to natural contexts. We end by reporting exciting discoveries from recent studies of avian sibling recognition that inspire further interest in this topic

CENTORI: a global toroidal electromagnetic two-fluid plasma turbulence code

A new global two-fluid electromagnetic turbulence code, CENTORI, has been developed for the purpose of studying magnetically-confined fusion plasmas on energy confinement timescales. This code is used to evolve the combined system of electron and ion fluid equations and Maxwell equations in toroidal configurations with axisymmetric equilibria. Uniquely, the equilibrium is co-evolved with the turbulence, and is thus modified by it. CENTORI is applicable to tokamaks of arbitrary aspect ratio and high plasma beta. A predictor-corrector, semi-implicit finite difference scheme is used to compute the time evolution of fluid quantities and fields. Vector operations and the evaluation of flux surface averages are speeded up by choosing the Jacobian of the transformation from laboratory to plasma coordinates to be a function of the equilibrium poloidal magnetic flux. A subroutine, GRASS, is used to co-evolve the plasma equilibrium by computing the steady-state solutions of a diffusion equation with a pseudo-time derivative. The code is written in Fortran 95 and is efficiently parallelized using Message Passing Interface (MPI). Illustrative examples of output from simulations of a tearing mode in a large aspect ratio tokamak plasma and of turbulence in an elongated conventional aspect ratio tokamak plasma are provided.Comment: 9 figure

75th Anniversary of ‘Existence of Electromagnetic-Hydrodynamic Waves’

We have recently passed the 75th anniversary of one of the most important results in solar and space physics: Hannes Alfv\'en's discovery of Alfv\'en waves and the Alfv\'en speed. To celebrate the anniversary, this article recounts some major episodes in the history of MHD waves. Following an initially cool reception, Alfv\'en's ideas were propelled into the spotlight by Fermi's work on cosmic rays, the new mystery of coronal heating and, as scientific perception of interplanetary space shifted dramatically and the space race started, detection of Alfv\'en waves in the solar wind. From then on, interest in MHD waves boomed, laying the foundations for modern remote observations of MHD waves in the Sun, coronal seismology and some of today's leading theories of coronal heating and solar wind acceleration. In 1970, Alfv\'en received the Nobel Prize for his work in MHD, including these discoveries. The article concludes with some reflection about what the history implies about the way we do science, especially the advantages and pitfalls of idealised mathematical models.Comment: 10 pages, accepted by Solar Physic