Stabilization of the Yang-Mills chaos in non-Abelian Born-Infeld theory

We investigate dynamics of the homogeneous time-dependent SU(2) Yang-Mills fields governed by the non-Abelian Born-Infeld lagrangian which arises in superstring theory as a result of summation of all orders in the string slope parameter $\alpha'$. It is shown that generically the Born-Infeld dynamics is less chaotic than that in the ordinary Yang-Mills theory, and at high enough field strength the Yang-Mills chaos is stabilized. More generally, a smothering effect of the string non-locality on behavior of classical fields is conjectured.Comment: 7 pages, 5 figure

Primordial fluctuations from nonlinear couplings

We study the spectrum of primordial fluctuations in theories where the inflaton field is coupled to massless fields and/or to itself. Conformally invariant theories generically predict a scale invariant spectrum. Scales entering the theory through infrared divergences cause logarithmic corrections to the spectrum, tiltilng it towards the blue. We discuss in some detail whether these fluctuations are quantum or classical in nature.Comment: 12 pages, Revtex, we added an appendix clarifying our assumptions about the initial conditions at the beggining of inflatio

Dynamics of BPS States in the Dirac-Born-Infeld Theory

The Dirac-Born-Infeld action with transverse scalar fields is considered to study the dynamics of various BPS states. We first describe the characteristic properties of the so-called 1/2 and 1/4 BPS states on the D3 brane, which can be interpreted as F/D-strings ending on a D3-brane in Type IIB string theory picture. We then study the response of the BPS states to low energy excitations of massless fields on the brane, the scalar fields representing the shape fluctuation of the brane and U(1) gauge fields describing the open string excitations on the D-brane. This leads to an identification of interactions between BPS states including the static potentials and the kinetic interactions.Comment: 19 pages, 4 figures References added, Typographical errors are correcte

Non-Linear/Non-Commutative Non-Abelian Monopoles

Using recently proposed non-linearly realized supersymmetry in non-Abelian gauge theory corrected to the order (alpha')^2, we derive the non-linear BPS equations in the background B-field for the U(2) monopoles and instantons. We show that these non-Abelian non-linear BPS equations coincide with the non-commutative anti-self-dual equations via the Seiberg-Witten map.Comment: 9 pages, LaTe

Dyonic BIon black hole in string inspired model

We construct static and spherically symmetric particle-like and black hole solutions with magnetic and/or electric charge in the Einstein-Born-Infeld-dilaton-axion system, which is a generalization of the Einstein-Maxwell-dilaton-axion (EMDA) system and of the Einstein-Born-Infeld (EBI) system. They have remarkable properties which are not seen for the corresponding solutions in the EMDA and the EBI system.Comment: 13 pages, 15 figures, Final version in PR

Dihydropyridine receptor (DHPR, CACNA1S) congenital myopathy

Muscle contraction upon nerve stimulation relies on excitation–contraction coupling (ECC) to promote the rapid and generalized release of calcium within myofibers. In skeletal muscle, ECC is performed by the direct coupling of a voltage-gated L-type Ca2+ channel (dihydropyridine receptor; DHPR) located on the T-tubule with a Ca2+ release channel (ryanodine receptor; RYR1) on the sarcoplasmic reticulum (SR) component of the triad. Here, we characterize a novel class of congenital myopathy at the morphological, molecular, and functional levels. We describe a cohort of 11 patients from 7 families presenting with perinatal hypotonia, severe axial and generalized weakness. Ophthalmoplegia is present in four patients. The analysis of muscle biopsies demonstrated a characteristic intermyofibrillar network due to SR dilatation, internal nuclei, and areas of myofibrillar disorganization in some samples. Exome sequencing revealed ten recessive or dominant mutations in CACNA1S (Cav1.1), the pore-forming subunit of DHPR in skeletal muscle. Both recessive and dominant mutations correlated with a consistent phenotype, a decrease in protein level, and with a major impairment of Ca2+ release induced by depolarization in cultured myotubes. While dominant CACNA1S mutations were previously linked to malignant hyperthermia susceptibility or hypokalemic periodic paralysis, our findings strengthen the importance of DHPR for perinatal muscle function in human. These data also highlight CACNA1S and ECC as therapeutic targets for the development of treatments that may be facilitated by the previous knowledge accumulated on DHPR

Improving genetic diagnosis in Mendelian disease with transcriptome sequencing

Exome and whole-genome sequencing are becoming increasingly routine approaches in Mendelian disease diagnosis. Despite their success, the current diagnostic rate for genomic analyses across a variety of rare diseases is approximately 25 to 50%. We explore the utility of transcriptome sequencing [RNA sequencing (RNA-seq)] as a complementary diagnostic tool in a cohort of 50 patients with genetically undiagnosed rare muscle disorders. We describe an integrated approach to analyze patient muscle RNA-seq, leveraging an analysis framework focused on the detection of transcript-level changes that are unique to the patient compared to more than 180 control skeletal muscle samples. We demonstrate the power of RNA-seq to validate candidate splice-disrupting mutations and to identify splice-altering variants in both exonic and deep intronic regions, yielding an overall diagnosis rate of 35%. We also report the discovery of a highly recurrent de novo intronic mutation in COL6A1 that results in a dominantly acting splice-gain event, disrupting the critical glycine repeat motif of the triple helical domain. We identify this pathogenic variant in a total of 27 genetically unsolved patients in an external collagen VI–like dystrophy cohort, thus explaining approximately 25% of patients clinically suggestive of having collagen VI dystrophy in whom prior genetic analysis is negative. Overall, this study represents a large systematic application of transcriptome sequencing to rare disease diagnosis and highlights its utility for the detection and interpretation of variants missed by current standard diagnostic approaches

PIK3C2B inhibition improves function and prolongs survival in myotubular myopathy animal models

International audienceMyotubular myopathy (MTM) is a devastating pediatric neuromuscular disorder of phosphoinositide (PIP) metabolism resulting from mutations of the PIP phosphatase MTM1 for which there are no treatments. We have previously shown phosphatidylinositol-3-phosphate (PI3P) accumulation in animal models of MTM. Here, we tested the hypothesis that lowering PI3P levels may prevent or reverse the MTM disease process. To test this, we targeted class II and III PI3 kinases (PI3Ks) in an MTM1-deficient mouse model. Muscle-specific ablation of Pik3c2b, but not Pik3c3, resulted in complete prevention of the MTM phenotype, and postsymptomatic targeting promoted a striking rescue of disease. We confirmed this genetic interaction in zebrafish, and additionally showed that certain PI3K inhibitors prevented development of the zebrafish mtm phenotype. Finally, the PI3K inhibitor wortmannin improved motor function and prolonged lifespan of the Mtm1-deficient mice. In all, we have identified Pik3c2b as a genetic modifier of Mtm1 mutation and demonstrated that PIK3C2B inhibition is a potential treatment strategy for MTM. In addition, we set the groundwork for similar reciprocal inhibition approaches for treating other PIP metabolic disorders and highlight the importance of modifier gene pathways as therapeutic targets