Epileptic high-frequency network activity in a model of non-lesional temporal lobe epilepsy

High-frequency cortical activity, particularly in the 250–600 Hz (fast ripple) band, has been implicated in playing a crucial role in epileptogenesis and seizure generation. Fast ripples are highly specific for the seizure initiation zone. However, evidence for the association of fast ripples with epileptic foci depends on animal models and human cases with substantial lesions in the form of hippocampal sclerosis, which suggests that neuronal loss may be required for fast ripples. In the present work, we tested whether cell loss is a necessary prerequisite for the generation of fast ripples, using a non-lesional model of temporal lobe epilepsy that lacks hippocampal sclerosis. The model is induced by unilateral intrahippocampal injection of tetanus toxin. Recordings from the hippocampi of freely-moving epileptic rats revealed high-frequency activity (4100 Hz), including fast ripples. High-frequency activity was present both during interictal discharges and seizure onset. Interictal fast ripples proved a significantly more reliable marker of the primary epileptogenic zone than the presence of either interictal discharges or ripples (100–250 Hz). These results suggest that fast ripple activity should be considered for its potential value in the pre-surgical workup of non-lesional temporal lobe epilepsy

Determinants of the Settlement Amount in Securities Fraud Class Action Litigation

This article identifies the factors most responsible for determining the settlement amount in securities fraud cases. It also develops a settlement model that incorporates these factors. This article analyzes a sample consisting of 525 securities fraud class action settlements that were reached between 1994 and 2005. It identifies the main drivers of the observed settlement amounts and develop a settlement model that explains more than fifty-six percent of the settlement amounts in terms of these settlement drivers. The settlement model should be useful to counsel or interested parties for gauging a reasonable settlement amount consistent with past experience. It should also be of interest to legal scholars because it identifies a set of factors that affect the settlement amount and quantifies their relative impact on the settlement amount for an important set of class actions. This article\u27s modeling technique could be applied to other types of class action (or other) litigation to estimate similar models to aid in the litigation settlement process

Nitrate enhances skeletal muscle fatty acid oxidation via a nitric oxide-cGMP-PPAR-mediated mechanism.

BACKGROUND: Insulin sensitivity in skeletal muscle is associated with metabolic flexibility, including a high capacity to increase fatty acid (FA) oxidation in response to increased lipid supply. Lipid overload, however, can result in incomplete FA oxidation and accumulation of potentially harmful intermediates where mitochondrial tricarboxylic acid cycle capacity cannot keep pace with rates of β-oxidation. Enhancement of muscle FA oxidation in combination with mitochondrial biogenesis is therefore emerging as a strategy to treat metabolic disease. Dietary inorganic nitrate was recently shown to reverse aspects of the metabolic syndrome in rodents by as yet incompletely defined mechanisms. RESULTS: Herein, we report that nitrate enhances skeletal muscle FA oxidation in rodents in a dose-dependent manner. We show that nitrate induces FA oxidation through a soluble guanylate cyclase (sGC)/cGMP-mediated PPARβ/δ- and PPARα-dependent mechanism. Enhanced PPARβ/δ and PPARα expression and DNA binding induces expression of FA oxidation enzymes, increasing muscle carnitine and lowering tissue malonyl-CoA concentrations, thereby supporting intra-mitochondrial pathways of FA oxidation and enhancing mitochondrial respiration. At higher doses, nitrate induces mitochondrial biogenesis, further increasing FA oxidation and lowering long-chain FA concentrations. Meanwhile, nitrate did not affect mitochondrial FA oxidation in PPARα(-/-) mice. In C2C12 myotubes, nitrate increased expression of the PPARα targets Cpt1b, Acadl, Hadh and Ucp3, and enhanced oxidative phosphorylation rates with palmitoyl-carnitine; however, these changes in gene expression and respiration were prevented by inhibition of either sGC or protein kinase G. Elevation of cGMP, via the inhibition of phosphodiesterase 5 by sildenafil, also increased expression of Cpt1b, Acadl and Ucp3, as well as CPT1B protein levels, and further enhanced the effect of nitrate supplementation. CONCLUSIONS: Nitrate may therefore be effective in the treatment of metabolic disease by inducing FA oxidation in muscle.This work was kindly supported by a British Heart Foundation studentship to TA (FS/09/050). AJMu thanks the Research Councils UK for supporting his academic fellowship. LDR is supported by the Medical Research Council-Human Nutrition Research Elsie Widdowson Fellowship. AJMo thanks the Natural Sciences and Engineering Research Council for supporting her postdoctoral fellowship. MF acknowledges support from the Medical Research Council (G1001536). JLG thanks the Medical Research Council (MC_UP_A090_1006), the Biotechnology and Biological Sciences Research Council (BB/H013539/2) and British Heart Foundation for supporting work in his laboratory

Intraspecific variation in oxidative stress tolerance in a model cnidarian: differences in peroxide sensitivity between and within populations of Nematostella vectensis

Nematostella vectensis is a member of the phylum Cnidaria, a lineage that includes anemones, corals, hydras, and jellyfishes. This estuarine anemone is an excellent model system for investigating the evolution of stress tolerance because it is easy to collect in its natural habitat and to culture in the laboratory, and it has a sequenced genome. Additionally, there is evidence of local adaptation to environmental stress in different N. vectensis populations, and abundant protein-coding polymorphisms have been identified, including polymorphisms in proteins that are implicated in stress responses. N. vectensis can tolerate a wide range of environmental parameters, and has recently been shown to have substantial intraspecific variation in temperature preference. We investigated whether different clonal lines of anemones also exhibit differential tolerance to oxidative stress. N. vectensis populations are continually exposed to reactive oxygen species (ROS) generated during cellular metabolism and by other environmental factors. Fifteen clonal lines of N. vectensis collected from four different estuaries were exposed to hydrogen peroxide. Pronounced differences in survival and regeneration were apparent between clonal lines collected from Meadowlands, NJ, Baruch, SC, and Kingsport, NS, as well as among 12 clonal lines collected from a single Cape Cod marsh. To our knowledge, this is the first example of intraspecific variability in oxidative stress resistance in cnidarians or in any marine animal. As oxidative stress often accompanies heat stress in marine organisms, resistance to oxidative stress could strongly influence survival in warming oceans. For example, while elevated temperatures trigger bleaching in corals, oxidative stress is thought to be the proximal trigger of bleaching at the cellular level.This work was supported National Science Foundation MCB-0920461 (https://www.nsf.gov/awardsearch/showAward?AWD_ID=0924749&HistoricalAwards=false) and National Science Foundation IOS-1354935 (https://www. nst.gov/awardsearch/showAward?AWD_ID=13549358,HistoricalAwards=false). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. (MCB-0920461 - National Science Foundation; IOS-1354935 - National Science Foundation)Published versio

The impact of autotrophic versus heterotrophic nutritional pathways on colony health and wound recovery in corals

For animals that harbor photosynthetic symbionts within their tissues, such as corals, the different relative contributions of autotrophy versus heterotrophy to organismal energetic requirements have direct impacts on fitness. This is especially true for facultatively symbiotic corals, where the balance between host‐caught and symbiont‐produced energy can be altered substantially to meet the variable demands of a shifting environment. In this study, we utilized a temperate coral–algal system (the northern star coral, Astrangia poculata, and its photosynthetic endosymbiont, Symbiodinium psygmophilum) to explore the impacts of nutritional sourcing on the host's health and ability to regenerate experimentally excised polyps. For fed and starved colonies, wound healing and total colony tissue cover were differentially impacted by heterotrophy versus autotrophy. There was an additive impact of positive nutritional and symbiotic states on a coral's ability to initiate healing, but a greater influence of symbiont state on the recovery of lost tissue at the lesion site and complete polyp regeneration. On the other hand, regardless of symbiont state, fed corals maintained a higher overall colony tissue cover, which also enabled more active host behavior (polyp extension) and endosymbiont behavior (photosynthetic ability of Symbiondinium). Overall, we determined that the impact of nutritional state and symbiotic state varied between biological functions, suggesting a diversity in energetic sourcing for each of these processes.PADI Foundation; Cell Signaling Technologies; Boston University Marine Program Warren McLeod Fellowship; New England Aquarium; National Science Foundation, Grant/Award Number: IOS-1354935 (PADI Foundation; Cell Signaling Technologies; Boston University Marine Program Warren McLeod Fellowship; New England Aquarium; IOS-1354935 - National Science Foundation)Published versio

The impact of autotrophic versus heterotrophic nutritional pathways on colony health and wound recovery in corals

For animals that harbor photosynthetic symbionts within their tissues, such as corals, the different relative contributions of autotrophy versus heterotrophy to organismal energetic requirements have direct impacts on fitness. This is especially true for facultatively symbiotic corals, where the balance between host‐caught and symbiont‐produced energy can be altered substantially to meet the variable demands of a shifting environment. In this study, we utilized a temperate coral–algal system (the northern star coral, Astrangia poculata, and its photosynthetic endosymbiont, Symbiodinium psygmophilum) to explore the impacts of nutritional sourcing on the host's health and ability to regenerate experimentally excised polyps. For fed and starved colonies, wound healing and total colony tissue cover were differentially impacted by heterotrophy versus autotrophy. There was an additive impact of positive nutritional and symbiotic states on a coral's ability to initiate healing, but a greater influence of symbiont state on the recovery of lost tissue at the lesion site and complete polyp regeneration. On the other hand, regardless of symbiont state, fed corals maintained a higher overall colony tissue cover, which also enabled more active host behavior (polyp extension) and endosymbiont behavior (photosynthetic ability of Symbiondinium). Overall, we determined that the impact of nutritional state and symbiotic state varied between biological functions, suggesting a diversity in energetic sourcing for each of these processes.PADI Foundation; Cell Signaling Technologies; Boston University Marine Program Warren McLeod Fellowship; New England Aquarium; National Science Foundation, Grant/Award Number: IOS-1354935 (PADI Foundation; Cell Signaling Technologies; Boston University Marine Program Warren McLeod Fellowship; New England Aquarium; IOS-1354935 - National Science Foundation)Published versio

Genomic comparison of the temperate coral Astrangia poculata with tropical corals yields insights into winter quiescence, innate immunity, and sexual reproduction

Facultatively symbiotic corals provide important experimental models to explore the establishment, maintenance, and breakdown of the mutualism between corals and members of the algal family Symbiodiniaceae. The temperate coral Astrangia poculata is one such model as it is not only facultatively symbiotic, but also occurs across a broad temperature and latitudinal gradient. Here, we report the de novo chromosome-scale assembly and annotation of the A. poculata genome. Though widespread segmental/tandem duplications of genomic regions were detected, we did not find strong evidence of a whole genome duplication (WGD) event. Comparison of the gene arrangement between A. poculata and the tropical coral Acropora millepora revealed 56.38% of the orthologous genes were conserved in syntenic blocks despite ~415 million years of divergence. Gene families related to sperm hyperactivation and innate immunity, including lectins, were found to contain more genes in A. millepora relative to A. poculata. Sperm hyperactivation in A. millepora is expected given the extreme requirements of gamete competition during mass spawning events in tropical corals, while lectins are important in the establishment of coral-algal symbiosis. By contrast, gene families involved in sleep promotion, feeding suppression, and circadian sleep/wake cycle processes were expanded in A. poculata. These expanded gene families may play a role in A. poculata’s ability to enter a dormancy-like state (“winter quiescence”) to survive freezing temperatures at the northern edges of the species’ range.IOS-1354935 - National Science FoundationFirst author draf

Pre-Bilaterian Origins of the Hox Cluster and the Hox Code: Evidence from the Sea Anemone, Nematostella vectensis

BACKGROUND: Hox genes were critical to many morphological innovations of bilaterian animals. However, early Hox evolution remains obscure. Phylogenetic, developmental, and genomic analyses on the cnidarian sea anemone Nematostella vectensis challenge recent claims that the Hox code is a bilaterian invention and that no “true” Hox genes exist in the phylum Cnidaria. METHODOLOGY/PRINCIPAL FINDINGS: Phylogenetic analyses of 18 Hox-related genes from Nematostella identify putative Hox1, Hox2, and Hox9+ genes. Statistical comparisons among competing hypotheses bolster these findings, including an explicit consideration of the gene losses implied by alternate topologies. In situ hybridization studies of 20 Hox-related genes reveal that multiple Hox genes are expressed in distinct regions along the primary body axis, supporting the existence of a pre-bilaterian Hox code. Additionally, several Hox genes are expressed in nested domains along the secondary body axis, suggesting a role in “dorsoventral” patterning. CONCLUSIONS/SIGNIFICANCE: A cluster of anterior and posterior Hox genes, as well as ParaHox cluster of genes evolved prior to the cnidarian-bilaterian split. There is evidence to suggest that these clusters were formed from a series of tandem gene duplication events and played a role in patterning both the primary and secondary body axes in a bilaterally symmetrical common ancestor. Cnidarians and bilaterians shared a common ancestor some 570 to 700 million years ago, and as such, are derived from a common body plan. Our work reveals several conserved genetic components that are found in both of these diverse lineages. This finding is consistent with the hypothesis that a set of developmental rules established in the common ancestor of cnidarians and bilaterians is still at work today

Two Alleles of NF-κB in the Sea Anemone Nematostella vectensis Are Widely Dispersed in Nature and Encode Proteins with Distinct Activities

BACKGROUND. NF-κB is an evolutionarily conserved transcription factor that controls the expression of genes involved in many key organismal processes, including innate immunity, development, and stress responses. NF-κB proteins contain a highly conserved DNA-binding/dimerization domain called the Rel homology domain. METHODS/PRINCIPAL FINDINGS. We characterized two NF-κB alleles in the sea anemone Nematostella vectensis that differ at nineteen single-nucleotide polymorphisms (SNPs). Ten of these SNPs result in amino acid substitutions, including six within the Rel homology domain. Both alleles are found in natural populations of Nematostella. The relative abundance of the two NF-κB alleles differs between populations, and departures from Hardy-Weinberg equilibrium within populations indicate that the locus may be under selection. The proteins encoded by the two Nv-NF-κB alleles have different molecular properties, in part due to a Cys/Ser polymorphism at residue 67, which resides within the DNA recognition loop. In nearly all previously characterized NF-κB proteins, the analogous residue is fixed for Cys, and conversion of human RHD proteins from Cys to Ser at this site has been shown to increase DNA-binding ability and increase resistance to inhibition by thiol-reactive compounds. However, the naturally-occurring Nematostella variant with Cys at position 67 binds DNA with a higher affinity than the Ser variant. On the other hand, the Ser variant activates transcription in reporter gene assays more effectively, and it is more resistant to inhibition by a thiol-reactive compound. Reciprocal Cys<->Ser mutations at residue 67 of the native Nv-NF-κB proteins affect DNA binding as in human NF-κB proteins, e.g., a Cys->Ser mutation increases DNA binding of the native Cys variant. CONCLUSIONS/SIGNIFICANCE. These results are the first demonstration of a naturally occurring and functionally significant polymorphism in NF-κB in any species. The functional differences between these alleles and their uneven distribution in the wild suggest that different genotypes could be favored in different environments, perhaps environments that vary in their levels of peroxides or thiol-reactive compounds.National Institutes of Health (CA047763); National Science Foundation (FP-91656101-0); Environmental Protection Agency (F5E11155); Conservation International Marine Management Area Science Program; Boston University (SPRInG grant); Postdoctoral Scholar Program at the Woods Hole Oceanographic Institution; The Beacon Institute for Rivers and Estuaries; the J Seward Johnson Fund; Boston University (5 P42 ES07381