Precision Spectroscopy at Heavy Ion Ring Accelerator SIS300

Unique spectroscopic possibilities open up if a laser beam interacts with relativistic lithium-like ions stored in the heavy ion ring accelerator SIS300 at the future Facility for Antiproton and Ion Research FAIR in Darmstadt, Germany. At a relativistic factor gamma = 36 the 2P 1/2 level can be excited from the 2S 1/2 ground state for any element with frequency doubled dye-lasers in collinear geometry. Precise transition energy measurements can be performed if the fluorescence photons, boosted in forward direction into the X-ray region, are energetically analyzed with a single crystal monochromator. The hyperfine structure can be investigated at the 2P 1/2 - 2S 1/2 transition for all elements and at the 2P 3/2 - 2S 1/2 transition for elements with Z < 50. Isotope shifts and nuclear moments can be measured with unprecedented precision, in principle even for only a few stored radioactive species with known nuclear spin. A superior relative line width in the order of 5E-7 may be feasible after laser cooling, and even polarized external beams may be prepared by optical pumping

4-Aminopyridine is a promising treatment option for patients with gain-of-function KCNA2-encephalopathy

Developmental and epileptic encephalopathies are devastating disorders characterized by epilepsy, intellectual disability, and other neuropsychiatric symptoms, for which available treatments are largely ineffective. Following a precision medicine approach, we show for KCNA2-encephalopathy that the K+ channel blocker 4-aminopyridine can antagonize gain-of-function defects caused by variants in the KV1.2 subunit in vitro, by reducing current amplitudes and negative shifts of steady-state activation and increasing the firing rate of transfected neurons. In n-of-1 trials carried out in nine different centers, 9 of 11 patients carrying such variants benefitted from treatment with 4-aminopyridine. All six patients experiencing daily absence, myoclonic, or atonic seizures became seizure-free (except some remaining provoked seizures). Two of six patients experiencing generalized tonic-clonic seizures showed marked improvement, three showed no effect, and one worsening. Nine patients showed improved gait, ataxia, alertness, cognition, or speech. 4-Aminopyridine was well tolerated up to 2.6 mg/kg per day. We suggest 4-aminopyridine as a promising tailored treatment in KCNA2-(gain-of-function)–encephalopathy and provide an online tool assisting physicians to select patients with gain-of-function mutations suited to this treatment

CSR, co-optation and resistance: the emergence of new agnostic relations between business and civil society

This article examines the theoretical implications of the changing relationships between NGOs and businesses that have emerged as a response to the evolving agenda around CSR and sustainable development. In particular, it focuses upon examining whether greater engagement from non-governmental organisations (NGOs) in this area reflects a process of appropriation and co-optation of protest by the business community. To examine this process, the article considers two forms of appropriation—appropriation of language and appropriation via participation—as a basis for discussion. While co-optation pressures are identified within both areas, the article argues that co-optation is identified almost as an inevitable outcome of engagement without significant consideration of the ability of movements to identify and respond to these processes. In identifying an alternative approach, the article utilises Mouffe’s framework of agonistic pluralism. Mouffe’s framework, it is argued, provides an understanding of the way in which agonistic relationships are emerging between NGOs and businesses while highlighting the continuance of conflict between parties struggling to influence the contested interpretations of responsible business

GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture

Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment

Towards a collaborative research: A case study on linking science to farmers' perceptions and knowledge on Arabica coffee pests and diseases and its management

The scientific community has recognized the importance of integrating farmer's perceptions and knowledge (FPK) for the development of sustainable pest and disease management strategies. However, the knowledge gap between indigenous and scientific knowledge still contributes to misidentification of plant health constraints and poor adoption of management solutions. This is particularly the case in the context of smallholder farming in developing countries. In this paper, we present a case study on coffee production in Uganda, a sector depending mostly on smallholder farming facing a simultaneous and increasing number of socio-ecological pressures. The objectives of this study were (i) to examine and relate FPK on Arabica Coffee Pests and Diseases (CPaD) to altitude and the vegetation structure of the production systems; (ii) to contrast results with perceptions from experts and (iii) to compare results with field observations, in order to identify constraints for improving the information flow between scientists and farmers. Data were acquired by means of interviews and workshops. One hundred and fifty farmer households managing coffee either at sun exposure, under shade trees or inter-cropped with bananas and spread across an altitudinal gradient were selected. Field sampling of the two most important CPaD was conducted on a subset of 34 plots. The study revealed the following findings: (i) Perceptions on CPaD with respect to their distribution across altitudes and perceived impact are partially concordant among farmers, experts and field observations (ii) There are discrepancies among farmers and experts regarding management practices and the development of CPaD issues of the previous years. (iii) Field observations comparing CPaD in different altitudes and production systems indicate ambiguity of the role of shade trees. According to the locality-specific variability in CPaD pressure as well as in FPK, the importance of developing spatially variable and relevant CPaD control practices is proposed. (Résumé d'auteur

Sustainability, epistemology, ecocentric business and marketing strategy:ideology, reality and vision

This conceptual article examines the relationship between marketing and sustainability through the dual lenses of anthropocentric and ecocentric epistemology. Using the current anthropocentric epistemology and its associated dominant social paradigm, corporate ecological sustainability in commercial practice and business school research and teaching is difficult to achieve. However, adopting an ecocentric epistemology enables the development of an alternative business and marketing approach that places equal importance on nature, the planet, and ecological sustainability as the source of human and other species' well-being, as well as the source of all products and services. This article examines ecocentric, transformational business, and marketing strategies epistemologically, conceptually and practically and thereby proposes six ecocentric, transformational, strategic marketing universal premises as part of a vision of and solution to current global un-sustainability. Finally, this article outlines several opportunities for management practice and further research

Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals

Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy