Huperzine A Provides Robust and Sustained Protection against Induced Seizures in Scn1a Mutant Mice

De novo loss-of-function mutations in the voltage-gated sodium channel (VGSC) SCN1A (encoding Nav1.1) are the main cause of Dravet syndrome (DS), a catastrophic early-life encephalopathy associated with prolonged and recurrent early-life febrile seizures (FSs), refractory afebrile epilepsy, cognitive and behavioral deficits, and a 15–20% mortality rate. SCN1A mutations also lead to genetic epilepsy with febrile seizures plus (GEFS+), which is an inherited disorder characterized by early-life FSs and the development of a range of adult epilepsy subtypes. Current antiepileptic drugs often fail to protect against the severe seizures and behavioral and cognitive deficits found in patients with SCN1A mutations. To address the need for more efficacious treatments for SCN1A-derived epilepsies, we evaluated the therapeutic potential of Huperzine A, a naturally occurring reversible acetylcholinesterase inhibitor. In CF1 mice, Hup A (0.56 or 1 mg/kg) was found to confer protection against 6 Hz-, pentylenetetrazole (PTZ)-, and maximal electroshock (MES)-induced seizures. Robust protection against 6 Hz-, MES-, and hyperthermia-induced seizures was also achieved following Hup A administration in mouse models of DS (Scn1a+/−) and GEFS+ (Scn1aRH/+). Furthermore, Hup A-mediated seizure protection was sustained during 3 weeks of daily injections in Scn1aRH/+ mutants. Finally, we determined that muscarinic and GABAA receptors play a role in Hup A-mediated seizure protection. These findings indicate that Hup A might provide a novel therapeutic strategy for increasing seizure resistance in DS and GEFS+, and more broadly, in other forms of refractory epilepsy

Caring Leadership: A Heideggerian Perspective

This paper develops the idea of caring leadership based on Heidegger’s philosophy of care. From this perspective, caring leadership is grounded in the practices of ‘leaping-in’ and ‘leaping-ahead’ as modes of intervention in the affairs of the world and the efforts of others. This involves gauging and taking responsibility for the ramifications of intervention, balancing the urge for certainty of outcome and visibility of contribution with the desire to encourage and enable others. Our analysis suggests several twists to contemporary leadership debates. We argue that the popular models of transactional and transformational leadership are to be critiqued not for their over-reliance, but rather, their under-reliance on agency. This is a different kind of agency to that of heroic or charismatic models. It involves tolerance of complexity and ambivalence; a rich sense of temporal trajectory; concern for one’s presence in the world; and crucially, the ability to resist the soothing normativity of ‘best practice’. From this position, we argue that the problem with the growing scholarly interest in an ethic of care is that it provides too tempting a recipe to follow. In a Heideggerian view, caring leadership has little to do with compassion, kindness or niceness; it involves and requires a fundamental organization and leadership of self

Models and metaphors: complexity theory and through-life management in the built environment

Complexity thinking may have both modelling and metaphorical applications in the through-life management of the built environment. These two distinct approaches are examined and compared. In the first instance, some of the sources of complexity in the design, construction and maintenance of the built environment are identified. The metaphorical use of complexity in management thinking and its application in the built environment are briefly examined. This is followed by an exploration of modelling techniques relevant to built environment concerns. Non-linear and complex mathematical techniques such as fuzzy logic, cellular automata and attractors, may be applicable to their analysis. Existing software tools are identified and examples of successful built environment applications of complexity modelling are given. Some issues that arise include the definition of phenomena in a mathematically usable way, the functionality of available software and the possibility of going beyond representational modelling. Further questions arising from the application of complexity thinking are discussed, including the possibilities for confusion that arise from the use of metaphor. The metaphor of a 'commentary machine' is suggested as a possible way forward and it is suggested that an appropriate linguistic analysis can in certain situations reduce perceived complexity

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

EMERGENT ORGANIZATIONAL CAPACITY FOR COMPASSION

Our model of emergent organizational capacity for compassion proposes that organizations can develop the capacity for compassion without formal direction. Relying on a framework from complexity science, we describe how the system conditions of agent diversity, interdependent roles, and social interactions enhance the likelihood of self-organizing around an individual response to a pain trigger. When agents then modify their roles to incorporate compassionate responding, their interactions amplify responses, changing the system, and a new order emerges: organizational capacity for compassion. In this new order the organization\u27s structure, culture, routines, and scanning mechanisms incorporate compassionate responding and can influence future responses to pain triggers

Altered function of the SCN1A voltage-gated sodium channel leads to gamma-aminobutyric acid-ergic (GABAergic) interneuron abnormalities.

Voltage-gated sodium channels are required for the initiation and propagation of action potentials. Mutations in the neuronal voltage-gated sodium channel SCN1A are associated with a growing number of disorders including generalized epilepsy with febrile seizures plus (GEFS+),(7) severe myoclonic epilepsy of infancy, and familial hemiplegic migraine. To gain insight into the effect of SCN1A mutations on neuronal excitability, we introduced the human GEFS+ mutation SCN1A-R1648H into the orthologous mouse gene. Scn1a(RH/RH) mice homozygous for the R1648H mutation exhibit spontaneous generalized seizures and premature death between P16 and P26, whereas Scn1a(RH/+) heterozygous mice exhibit infrequent spontaneous generalized seizures, reduced threshold and accelerated propagation of febrile seizures, and decreased threshold to flurothyl-induced seizures. Inhibitory cortical interneurons from P5-P15 Scn1a(RH/+) and Scn1a(RH/RH) mice demonstrated slower recovery from inactivation, greater use-dependent inactivation, and reduced action potential firing compared with wild-type cells. Excitatory cortical pyramidal neurons were mostly unaffected. These results suggest that this SCN1A mutation predominantly impairs sodium channel activity in interneurons, leading to decreased inhibition. Decreased inhibition may be a common mechanism underlying clinically distinct SCN1A-derived disorders

Investigating three explanations of women's relationship aggression

This study investigated explanations of women’s partner aggression in a sample of 358 women. Women completed measures of physical aggression, control, and fear. Three explanations of women’s partner aggression were explored: (a) that its use is associated with fear, (b) that it is reciprocal, and (c) that it is coercive. Each explanation received partial support, with multivariate analysis showing that collectively they explained significant proportions of the variance in women’s self-reported use of physical aggression toward their male partners. These results indicate that women’s physical aggression toward male partners cannot be understood using a unitary explanation. There is a research tradition that assumes that women are only victims of relationship violence and never or rarely perpetrators (e.g., Dobash, Dobash, Cavanagh, &amp; Lewis, 1998). Research on community samples, in particular th