Despite the availability of more than 15 new “antiepileptic drugs”, the proportion of patients with pharmacoresistant epilepsy has remained constant at about 20–30%. Furthermore, no disease-modifying ...treatments shown to prevent the development of epilepsy following an initial precipitating brain injury or to reverse established epilepsy have been identified to date. This is likely in part due to the polyetiologic nature of epilepsy, which in turn requires personalized medicine approaches. Recent advances in imaging, pathology, genetics, and epigenetics have led to new pathophysiological concepts and the identification of monogenic causes of epilepsy. In the context of these advances, the First International Symposium on Personalized Translational Epilepsy Research (1st ISymPTER) was held in Frankfurt on September 8, 2016, to discuss novel approaches and future perspectives for personalized translational research. These included new developments and ideas in a range of experimental and clinical areas such as deep phenotyping, quantitative brain imaging, EEG/MEG-based analysis of network dysfunction, tissue-based translational studies, innate immunity mechanisms, microRNA as treatment targets, functional characterization of genetic variants in human cell models and rodent organotypic slice cultures, personalized treatment approaches for monogenic epilepsies, blood–brain barrier dysfunction, therapeutic focal tissue modification, computational modeling for target and biomarker identification, and cost analysis in (monogenic) disease and its treatment. This report on the meeting proceedings is aimed at stimulating much needed investments of time and resources in personalized translational epilepsy research. This Part II includes the experimental and translational approaches and a discussion of the future perspectives, while the diagnostic methods, EEG network analysis, biomarkers, and personalized treatment approaches were addressed in Part I 1.
•Pharmacological interventions targeting the Zn2+–MTF1–CaV3.2 cascade may provide novel treatment approaches for drug-resistant TLE.•The innate immune system can mediate tissue remodeling, inducing epileptogenesis. This can be studied by cerebral microdialyis in models of TLE.•MiRNA-dependent regulation of synaptic plasticity is a widespread mechanism in epileptogenesis making miRNA suitable epilepsy-biomarkers.•Blood-brain barrier dysfunction may play a relevant role in epileptogenesis and vessel stabilization might be a valuable therapeutic target.•Tissuemodification by focal viral gene transfection or optogenetic interventions may play a role in future personalized epilepsy treatment.
Running Author: Ying‐hui Li et al Ying‐hui Li; Li, Delin; Yong‐qing Jiao ...
Plant biotechnology journal,
02/2020, Letnik:
18, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Landraces often contain genetic diversity that has been lost in modern cultivars, including alleles that confer enhanced local adaptation. To comprehensively identify loci associated with adaptive ...traits in soya bean landraces, for example flowering time, a population of 1938 diverse landraces and 97 accessions of the wild progenitor of cultivated soya bean, Glycine soja was genotyped using tGBS®. Based on 99 085 high‐quality SNPs, landraces were classified into three sub‐populations which exhibit geographical genetic differentiation. Clustering was inferred from STRUCTURE, principal component analyses and neighbour‐joining tree analyses. Using phenotypic data collected at two locations separated by 10 degrees of latitude, 17 trait‐associated SNPs (TASs) for flowering time were identified, including a stable locus Chr12:5914898 and previously undetected candidate QTL/genes for flowering time in the vicinity of the previously cloned flowering genes, E1 and E2. Using passport data associated with the collection sites of the landraces, 27 SNPs associated with adaptation to three bioclimatic variables (temperature, daylength, and precipitation) were identified. A series of candidate flowering genes were detected within linkage disequilibrium (LD) blocks surrounding 12 bioclimatic TASs. Nine of these TASs exhibit significant differences in flowering time between alleles within one or more of the three individual sub‐populations. Signals of selection during domestication and/or subsequent landrace diversification and adaptation were detected at 38 of the 44 flowering and bioclimatic TASs. Hence, this study lays the groundwork to begin breeding for novel environments predicted to arise following global climate change.
Schimke immunoosseous dysplasia (SIOD), which is characterized by prominent spondyloepiphyseal dysplasia, T‐cell deficiency, and focal segmental glomerulosclerosis, is a panethnic autosomal recessive ...multisystem disorder with variable expressivity. Biallelic mutations in switch/sucrose nonfermenting (swi/snf) &!ndash;related, matrix‐associated, actin‐dependent regulator of chromatin, subfamily a‐like 1 (SMARCAL1) are the only identified cause of SIOD. However, among 72 patients from different families, we identified only 38 patients with biallelic mutations in the coding exons and splice junctions of the SMARCAL1 gene. This observation, the variable expressivity, and poor genotype–phenotype correlation led us to test several hypotheses including modifying haplotypes, oligogenic inheritance, or locus heterogeneity in SIOD. Haplotypes associated with the two more common mutations, R820H and E848X, did not correlate with phenotype. Also, contrary to monoallelic SMARCAL1 coding mutations indicating oligogenic inheritance, we found that all these patients did not express RNA and/or protein from the other allele and thus have biallelic SMARCAL1 mutations. We hypothesize therefore that the variable expressivity among patients with biallelic SMARCAL1 mutations arises from environmental, genetic, or epigenetic modifiers. Among patients without detectable SMARCAL1 coding mutations, our analyses of cell lines from four of these patients showed that they expressed normal levels of SMARCAL1 mRNA and protein. This is the first evidence for nonallelic heterogeneity in SIOD. From analysis of the postmortem histopathology from two patients and the clinical data from most patients, we propose the existence of endophenotypes of SIOD. Hum Mutat 28(3), 273–283, 2007. Published 2006, Wiley‐Liss, Inc.
The structure of a catalytic intermediate with important implications for the interpretation of the stereochemical outcome of the palladium complex catalyzed allylic substitution with ...phosphino–oxazoline (PHOX) ligands is determined by liquid state NMR. The complex displays a novel structure that is highly distorted compared with other palladium η2‐olefin complexes known so far. The structure has been determined from nuclear overhauser data (NOE), scalar coupling constants, and long range projection angle restraints derived from dipole dipole cross‐correlated relaxation of multiple quantum coherence. The latter restraints have been implemented into a distance geometry protocol. The projection angle restraints yield a higher precision in the determination of the relative orientation of the two molecular moieties and are essential to provide an exact structural definition of the olefinic part of the catalytic intermediate with respect to the ligand.
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