The transcriptional response of Caenorhabditis elegans to ivermectin exposure identifies novel genes involved in the response to reduced food intake

We have examined the transcriptional response of Caenorhabditis elegans following exposure to the anthelmintic drug ivermectin (IVM) using whole genome microarrays and real-time QPCR. Our original aim was to identify candidate molecules involved in IVM metabolism and/or excretion. For this reason the IVM tolerant strain, DA1316, was used to minimise transcriptomic changes related to the phenotype of drug exposure. However, unlike equivalent work with benzimidazole drugs, very few of the induced genes were members of xenobiotic metabolising enzyme families. Instead, the transcriptional response was dominated by genes associated with fat mobilization and fatty acid metabolism including catalase, esterase, and fatty acid CoA synthetase genes. This is consistent with the reduction in pharyngeal pumping, and consequential reduction in food intake, upon exposure of DA1316 worms to IVM. Genes with the highest fold change in response to IVM exposure, cyp-37B1, mtl-1 and scl-2, were comparably up-regulated in response to short–term food withdrawal (4 hr) independent of IVM exposure, and GFP reporter constructs confirm their expression in tissues associated with fat storage (intestine and hypodermis). These experiments have serendipitously identified novel genes involved in an early response of C. elegans to reduced food intake and may provide insight into similar processes in higher organisms

Macroscopic coherent structures in a stochastic neural network: from interface dynamics to coarse-grained bifurcation analysis

We study coarse pattern formation in a cellular automaton modelling a spatially-extended stochastic neural network. The model, originally proposed by Gong and Robinson (Phys Rev E 85(5):055,101(R), 2012), is known to support stationary and travelling bumps of localised activity. We pose the model on a ring and study the existence and stability of these patterns in various limits using a combination of analytical and numerical techniques. In a purely deterministic version of the model, posed on a continuum, we construct bumps and travelling waves analytically using standard interface methods from neural field theory. In a stochastic version with Heaviside firing rate, we construct approximate analytical probability mass functions associated with bumps and travelling waves. In the full stochastic model posed on a discrete lattice, where a coarse analytic description is unavailable, we compute patterns and their linear stability using equation-free methods. The lifting procedure used in the coarse time-stepper is informed by the analysis in the deterministic and stochastic limits. In all settings, we identify the synaptic profile as a mesoscopic variable, and the width of the corresponding activity set as a macroscopic variable. Stationary and travelling bumps have similar meso- and macroscopic profiles, but different microscopic structure, hence we propose lifting operators which use microscopic motifs to disambiguate them. We provide numerical evidence that waves are supported by a combination of high synaptic gain and long refractory times, while meandering bumps are elicited by short refractory times

On the use of the group SO(4,2) in atomic and molecular physics

In this paper the dynamical noninvariance group SO(4,2) for a hydrogen-like atom is derived through two different approaches. The first one is by an established traditional ascent process starting from the symmetry group SO(3). This approach is presented in a mathematically oriented original way with a special emphasis on maximally superintegrable systems, N-dimensional extension and little groups. The second approach is by a new symmetry descent process starting from the noninvariance dynamical group Sp(8,R) for a four-dimensional harmonic oscillator. It is based on the little known concept of a Lie algebra under constraints and corresponds in some sense to a symmetry breaking mechanism. This paper ends with a brief discussion of the interest of SO(4,2) for a new group-theoretical approach to the periodic table of chemical elements. In this connection, a general ongoing programme based on the use of a complete set of commuting operators is briefly described. It is believed that the present paper could be useful not only to the atomic and molecular community but also to people working in theoretical and mathematical physics.Comment: 31 page

A novel RFC1 repeat motif (ACAGG) in two Asia-Pacific CANVAS families

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is a progressive late-onset, neurological disease. Recently, a pentanucleotide expansion in intron 2 of RFC1 was identified as the genetic cause of CANVAS. We screened an Asian-Pacific cohort for CANVAS and identified a novel RFC1 repeat expansion motif, (ACAGG)exp, in three affected individuals. This motif was associated with additional clinical features including fasciculations and elevated serum creatine kinase. These features have not previously been described in individuals with genetically-confirmed CANVAS. Haplotype analysis showed our patients shared the same core haplotype as previously published, supporting the possibility of a single origin of the RFC1 disease allele. We analysed data from >26 000 genetically diverse individuals in gnomAD to show enrichment of (ACAGG) in non-European populations

The dynamics of neural fields on bounded domains: an interface approach for Dirichlet boundary conditions

Continuum neural field equations model the large scale spatio-temporal dynamics of interacting neurons on a cortical surface. They have been extensively studied, both analytically and numerically, on bounded as well as unbounded domains. Neural field models do not require the specification of boundary conditions. Relatively little attention has been paid to the imposition of neural activity on the boundary, or to its role in inducing patterned states. Here we redress this imbalance by studying neural field models of Amari type (posed on one- and two-dimensional bounded domains) with Dirichlet boundary conditions. The Amari model has a Heaviside nonlinearity that allows for a description of localised solutions of the neural field with an interface dynamics. We show how to generalise this reduced but exact description by deriving a normal velocity rule for an interface that encapsulates boundary effects. The linear stability analysis of localised states in the interface dynamics is used to understand how spatially extended patterns may develop in the absence and presence of boundary conditions. Theoretical results for pattern formation are shown to be in excellent agreement with simulations of the full neural field model. Furthermore, a numerical scheme for the interface dynamics is introduced and used to probe the way in which a Dirichlet boundary condition can limit the growth of labyrinthine structures

Helicity within the vortex filament model

Kinetic helicity is one of the invariants of the Euler equations that is associated with the topology of vortex lines within the fluid. In superfluids, the vorticity is concentrated along vortex filaments. In this setting, helicity would be expected to acquire its simplest form. However, the lack of a core structure for vortex filaments appears to result in a helicity that does not retain its key attribute as a quadratic invariant. By defining a spanwise vector to the vortex through the use of a Seifert framing, we are able to introduce twist and henceforth recover the key properties of helicity. We present several examples for calculating internal twist to illustrate why the centreline helicity alone will lead to ambiguous results if a twist contribution is not introduced. Our choice of the spanwise vector can be expressed in terms of the tangential component of velocity along the filament. Since the tangential velocity does not alter the configuration of the vortex at later times, we are able to recover a similar equation for the internal twist angle to that of classical vortex tubes. Our results allow us to explain how a quasi-classical limit of helicity emerges from helicity considerations for individual superfluid vortex filaments

CAV3 mutations causing exercise intolerance, myalgia and rhabdomyolysis: expanding the phenotypic spectrum of caveolinopathies

Rhabdomyolysis is often due to a combination of environmental trigger(s) and genetic predisposition; however, the underlying genetic cause remains elusive in many cases. Mutations in CAV3 lead to various neuromuscular phenotypes with partial overlap, including limb girdle muscular dystrophy type 1C (LGMD1C), rippling muscle disease, distal myopathy and isolated hyperCKemia. Here we present a series of eight patients from seven families presenting with exercise intolerance and rhabdomyolysis caused by mutations in CAV3 diagnosed by next generation sequencing (NGS) (n=6). Symptoms included myalgia (n=7), exercise intolerance (n=6) and episodes of rhabdomyolysis (n=2). Percussion-induced rapid muscle contractions (PIRCs) were seen in five out of six patients examined. A previously reported heterozygous mutation in CAV3 (p.T78M) and three novel variants (p.V14I, p.F41S, p.F54V) were identified. Caveolin-3 immunolabeling in muscle was normal in 3/4 patients however, immunoblotting showed more than 50% reduction of caveolin-3 in five patients compared with controls. This case series demonstrates that exercise intolerance, myalgia and rhabdomyolysis may be caused by CAV3 mutations and broadens the phenotypic spectrum of caveolinopathies. In our series immunoblotting was a more sensitive method to detect reduced caveolin-3 levels than immunohistochemistry in skeletal muscle. Patients presenting with muscle pain, exercise intolerance and rhabdomyolysis should be routinely tested for PIRCs as this may be an important clinical clue for caveolinopathies, even in the absence of other “typical” features. The use of NGS may expand current knowledge concerning inherited diseases, and unexpected/atypical phenotypes may be attributed to well-known human disease genes

Liposomal Co-Entrapment of CD40mAb Induces Enhanced IgG Responses against Bacterial Polysaccharide and Protein

Background Antibody against CD40 is effective in enhancing immune responses to vaccines when chemically conjugated to the vaccine antigen. Unfortunately the requirement for chemical conjugation presents some difficulties in vaccine production and quality control which are compounded when multivalent vaccines are required. We explore here an alternative to chemical conjugation, involving the co-encapsulation of CD40 antibody and antigens in liposomal vehicles. Methodology/Principal Findings Anti-mouse CD40 mAb or isotype control mAb were co-entrapped individually in cationic liposomal vehicles with pneumococcal polysaccharides or diphtheria and tetanus toxoids. Retention of CD40 binding activity upon liposomal entrapment was assessed by ELISA and flow cytometry. After subcutaneous immunization of BALB/c female mice, anti-polysaccharide and DT/TT responses were measured by ELISA. Simple co-encapsulation of CD40 antibody allowed for the retention of CD40 binding on the liposome surface, and also produced vaccines with enhanced imunogenicity. Antibody responses against both co-entrapped protein in the form of tetanus toxoid, and Streptococcus pneumoniae capsular polysaccharide, were enhanced by co-encapsulation with CD40 antibody. Surprisingly, liposomal encapsulation also appeared to decrease the toxicity of high doses of CD40 antibody as assessed by the degree of splenomegaly induced. Conclusions/Significance Liposomal co-encapsulation with CD40 antibody may represent a practical means of producing more immunogenic multivalent vaccines and inducing IgG responses against polysaccharides without the need for conjugation