609 research outputs found
Regeneration versus scarring in vertebrate appendages and heart
Injuries to complex human organs, such as the limbs and the heart, result in pathological conditions, for which we often lack adequate treatments. While modern regenerative approaches are based on the transplantation of stem cell-derived cells, natural regeneration in lower vertebrates, such as zebrafish and newts, relies predominantly on the intrinsic plasticity of mature tissues. This property involves local activation of the remaining material at the site of injury to promote cell division, cell migration and complete reproduction of the missing structure. It remains an unresolved question why adult mammals are not equally competent to reactivate morphogenetic programmes. Although organ regeneration depends strongly on the proliferative properties of cells in the injured tissue, it is apparent that various organismic factors, such as innervation, vascularization, hormones, metabolism and the immune system, can affect this process. Here, we focus on a correlation between the regenerative capacity and cellular specialization in the context of functional demands, as illustrated by appendages and heart in diverse vertebrates. Elucidation of the differences between homologous regenerative and non-regenerative tissues from various animal models is essential for understanding the applicability of lessons learned from the study of regenerative biology to clinical strategies for the treatment of injured human organs
Matrix theory origins of non-geometric fluxes
We explore the origins of non-geometric fluxes within the context of M theory
described as a matrix model. Building upon compactifications of Matrix theory
on non-commutative tori and twisted tori, we formulate the conditions which
describe compactifications with non-geometric fluxes. These turn out to be
related to certain deformations of tori with non-commutative and
non-associative structures on their phase space. Quantization of flux appears
as a natural consequence of the framework and leads to the resolution of
non-associativity at the level of the unitary operators. The quantum-mechanical
nature of the model bestows an important role on the phase space. In
particular, the geometric and non-geometric fluxes exchange their properties
when going from position space to momentum space thus providing a duality among
the two. Moreover, the operations which connect solutions with different fluxes
are described and their relation to T-duality is discussed. Finally, we provide
some insights on the effective gauge theories obtained from these matrix
compactifications.Comment: 1+31 pages, reference list update
A canine BCAN microdeletion associated with episodic falling syndrome
Episodic falling syndrome (EFS) is a canine paroxysmal hypertonicity disorder found in Cavalier King Charles spaniels. Episodes are triggered by exercise, stress or excitement and characterized by progressive hypertonicity throughout the thoracic and pelvic limbs, resulting in a characteristic 'deer-stalking' position and/or collapse. We used a genome-wide association strategy to map the EFS locus to a 3.48 Mb critical interval on canine chromosome 7. By prioritizing candidate genes on the basis of biological plausibility, we found that a 15.7 kb deletion in BCAN, encoding the brain-specific extracellular matrix proteoglycan brevican, is associated with EFS. This represents a compelling causal mutation for EFS, since brevican has an essential role in the formation of perineuronal nets governing synapse stability and nerve conduction velocity. Mapping of the deletion breakpoint enabled the development of Multiplex PCR and Multiplex Ligation-dependent Probe Amplification (MLPA) genotyping tests that can accurately distinguish normal, carrier and affected animals. Wider testing of a larger population of CKCS dogs without a history of EFS from the USA revealed that carriers are extremely common (12.9%). The development of molecular genetic tests for the EFS microdeletion will allow the implementation of directed breeding programs aimed at minimizing the number of animals with EFS and enable confirmatory diagnosis and pharmacotherapy of affected dogs
Membrane Sigma-Models and Quantization of Non-Geometric Flux Backgrounds
We develop quantization techniques for describing the nonassociative geometry
probed by closed strings in flat non-geometric R-flux backgrounds M. Starting
from a suitable Courant sigma-model on an open membrane with target space M,
regarded as a topological sector of closed string dynamics in R-space, we
derive a twisted Poisson sigma-model on the boundary of the membrane whose
target space is the cotangent bundle T^*M and whose quasi-Poisson structure
coincides with those previously proposed. We argue that from the membrane
perspective the path integral over multivalued closed string fields in Q-space
is equivalent to integrating over open strings in R-space. The corresponding
boundary correlation functions reproduce Kontsevich's deformation quantization
formula for the twisted Poisson manifolds. For constant R-flux, we derive
closed formulas for the corresponding nonassociative star product and its
associator, and compare them with previous proposals for a 3-product of fields
on R-space. We develop various versions of the Seiberg-Witten map which relate
our nonassociative star products to associative ones and add fluctuations to
the R-flux background. We show that the Kontsevich formula coincides with the
star product obtained by quantizing the dual of a Lie 2-algebra via convolution
in an integrating Lie 2-group associated to the T-dual doubled geometry, and
hence clarify the relation to the twisted convolution products for topological
nonassociative torus bundles. We further demonstrate how our approach leads to
a consistent quantization of Nambu-Poisson 3-brackets.Comment: 52 pages; v2: references adde
Asymmetric WIMP dark matter
In existing dark matter models with global symmetries the relic abundance of
dark matter is either equal to that of anti-dark matter (thermal WIMP), or
vastly larger, with essentially no remaining anti-dark matter (asymmetric dark
matter). By exploring the consequences of a primordial asymmetry on the coupled
dark matter and anti-dark matter Boltzmann equations we find large regions of
parameter space that interpolate between these two extremes. Interestingly,
this new asymmetric WIMP framework can accommodate a wide range of dark matter
masses and annihilation cross sections. The present-day dark matter population
is typically asymmetric, but only weakly so, such that indirect signals of dark
matter annihilation are not completely suppressed. We apply our results to
existing models, noting that upcoming direct detection experiments will
constrain a large region of the relevant parameter space.Comment: 32 pages, 6 figures, updated references, updated XENON100 bounds,
typo in figure caption correcte
Planning and monitoring of patients for electrical cardioversion for atrial fibrillation
This study evaluated the waiting list for elective electrical cardioversion (ECV) for persistent atrial fibrillation (AF), focusing on when and why procedures were postponed. We compared the effects of management of the waiting list conducted by physicians versus management by nurse practitioners (NPs) and we evaluated the safety of our anticoagulating policy by means of bleeding or thromboembolic complications during and after ECV. Not all patients selected for ECV receive their treatment at the first planned instance due to a variety of reasons. These reasons are still undocumented. We evaluated 250 consecutive patients with persistent AF admitted to our clinic for elective ECV. Within 5 to 6 weeks, 186 of 242 patients (77%) received ECV. The main reason for postponing an ECV was an inadequate international normalised ratio (INR); other reasons included spontaneous sinus rhythm and switch to rate control. A total of 23 of the 147 patients (16%) managed by the research physician were postponed due to an inadequate INR at admission versus 4 out of 98 patients (4%) managed by NPs (p = 0.005) An inadequate INR is the main reason for postponing an ECV. Management of ECV by NPs is safe and leads to less postponing on admission
Altered splicing of the BIN1 muscle-specific exon in humans and dogs with highly progressive centronuclear myopathy
Amphiphysin 2, encoded by BIN1, is a key factor for membrane sensing and remodelling in different cell types. Homozygous BIN1 mutations in ubiquitously expressed exons are associated with autosomal recessive centronuclear myopathy (CNM), a mildly progressive muscle disorder typically showing abnormal nuclear centralization on biopsies. In addition, misregulation of BIN1 splicing partially accounts for the muscle defects in myotonic dystrophy (DM). However, the muscle-specific function of amphiphysin 2 and its pathogenicity in both muscle disorders are not well understood. In this study we identified and characterized the first mutation affecting the splicing of the muscle-specific BIN1 exon 11 in a consanguineous family with rapidly progressive and ultimately fatal centronuclear myopathy. In parallel, we discovered a mutation in the same BIN1 exon 11 acceptor splice site as the genetic cause of the canine Inherited Myopathy of Great Danes (IMGD). Analysis of RNA from patient muscle demonstrated complete skipping of exon 11 and BIN1 constructs without exon 11 were unable to promote membrane tubulation in differentiated myotubes. Comparative immunofluorescence and ultrastructural analyses of patient and canine biopsies revealed common structural defects, emphasizing the importance of amphiphysin 2 in membrane remodelling and maintenance of the skeletal muscle triad. Our data demonstrate that the alteration of the muscle-specific function of amphiphysin 2 is a common pathomechanism for centronuclear myopathy, myotonic dystrophy, and IMGD. The IMGD dog is the first faithful model for human BIN1-related CNM and represents a mammalian model available for preclinical trials of potential therapies
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