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Identifying common genetic variants that confer genetic risk for cluster headache.

We conducted a case-control study in the Dutch Leiden University Cluster headache neuro-Analysis program (LUCA) study population (n=840) and unselected controls from the Netherlands Epidemiology of Obesity Study (NEO; n=1,457). Replication was performed in a Norwegian sample of 144 cases from the Trondheim Cluster headache sample and 1,800 controls from the Nord-Trøndelag Health Survey (HUNT). NRL-1049 Gene set and tissue enrichment analyses, blood cell-derived RNA-sequencing of genes around the risk loci and linkage disequilibrium score regression were part of the downstream analyses.

An association was found with cluster headache for 4 independent loci (r
 < 0.1) with genomewide significance (p < 5 × 10
), rs11579212 (odds ratio [OR]=1.51, 95% confidence interval [CI]=1.33-1.72 near RP11-815 M8.1), rs6541998 (OR=1.53, 95% CI=1.37-1.74 near MERTK), rs10184573 (OR=1.43, 95% CI=1.26-1.61 near AC093590.1), and rs2499799 (OR=0.62, 95% CI=0.54-0.73 near UFL1/FHL5), collectively explaining 7.2% of the variance of cluster headache. SNPs rs11579212, rs10184573, and rs976357, as proxy SNP for rs2499799 (r
=1.0), replicated in the Norwegian sample (p < 0.05). Gene-based mapping yielded ASZ1 as possible fifth locus. RNA-sequencing indicated differential expression of POLR1B and TMEM87B in cluster headache patients.

This genomewide association study (GWAS) identified and replicated genetic risk loci for cluster headache with effect sizes larger than those typically seen in complex genetic disorders. ANN NEUROL 2021;90203-216.
This genomewide association study (GWAS) identified and replicated genetic risk loci for cluster headache with effect sizes larger than those typically seen in complex genetic disorders. ANN NEUROL 2021;90203-216.
Low-level somatic mosaicism in the brain has been shown to be a major genetic cause of intractable focal epilepsy. However, how a relatively few mutation-carrying neurons are able to induce epileptogenesis at the local network level remains poorly understood.

To probe the origin of epileptogenesis, we measured the excitability of neurons with MTOR mutation and nearby nonmutated neurons recorded by whole-cell patch-clamp and array-based electrodes comparing the topographic distribution of mutation. Computational simulation is used to understand neural network-level changes based on electrophysiological properties. To examine the underlying mechanism, we measured inhibitory and excitatory synaptic inputs in mutated neurons and nearby neurons by electrophysiological and histological methods using the mouse model and postoperative human brain tissue for cortical dysplasia. To explain non-cell-autonomous hyperexcitability, an inhibitor of adenosine kinase was injected into mice to enhance adenosine signaling and to mitigate hyperactivity of nearby nonmutated neurons.

We generated mice with a low-level somatic mutation in MTOR presenting spontaneous seizures. The seizure-triggering hyperexcitability originated from nonmutated neurons near mutation-carrying neurons, which proved to be less excitable than nonmutated neurons. Interestingly, the net balance between excitatory and inhibitory synaptic inputs onto mutated neurons remained unchanged. Additionally, we found that inhibition of adenosine kinase, which affects adenosine metabolism and neuronal excitability, reduced the hyperexcitability of nonmutated neurons.

This study shows that neurons carrying somatic mutations in MTOR lead to focal epileptogenesis via non-cell-autonomous hyperexcitability of nearby nonmutated neurons. ANN NEUROL 2021;90285-299.
This study shows that neurons carrying somatic mutations in MTOR lead to focal epileptogenesis via non-cell-autonomous hyperexcitability of nearby nonmutated neurons. ANN NEUROL 2021;90285-299.To determine Borrelia spp. (Spirochaetales Spirochaetaceae) prevalence and species distribution in Northern Germany, Ixodes ticks were sampled from April to October in 2018 and 2019 by the flagging method at three locations each in five regions. Analysis by quantitative real-time PCR of 3150 individual ticks revealed an overall prevalence of 30.6%, without significant differences between tick stages (31.7% positive adults, 28.6% positive nymphs). Significant differences were observed in seasonal infection rates, but not between regions, landscape types or sampling years. Analysis of co-infections with Rickettsiales indicated a negative association between Borrelia and Anaplasma phagocytophilum infection. The most frequent Borrelia species differentiated by Reverse Line Blot were B. afzelii and B. garinii/B. bavariensis, followed by B. valaisiana, B. burgdorferi sensu stricto, B. spielmanii and B. lusitaniae. Furthermore, B. miyamotoi was identified in 12.9% of differentiable samples. No effect of region nor landscape type on species composition was found, but significant variations in the distribution at the different sampling sites within a region were observed. The detected monthly fluctuations in prevalence and the differences in intra-regional Borrelia species distribution underline the importance of long-term and multi-location monitoring of Borrelia spp. in ticks as an essential part of public health assessment.By regulating several hallmarks of cancer, BAG3 exerts oncogenic functions in a wide variety of malignant diseases including glioblastoma (GBM) and triple-negative breast cancer (TNBC). Here we performed global proteomic/phosphoproteomic analyses of CRISPR/Cas9-mediated isogenic BAG3 knockouts of the two GBM lines U343 and U251 in comparison to parental controls. Depletion of BAG3 evoked major effects on proteins involved in ciliogenesis/ciliary function and the activity of the related kinases aurora-kinase A and CDK1. Cilia formation was significantly enhanced in BAG3 KO cells, a finding that could be confirmed in BAG3-deficient versus -proficient BT-549 TNBC cells, thus identifying a completely novel function of BAG3 as a negative regulator of ciliogenesis. Furthermore, we demonstrate that enhanced ciliogenesis and reduced expression of SNAI1 and ZEB1, two key transcription factors regulating epithelial to mesenchymal transition (EMT) are correlated to decreased cell migration, both in the GBM and TNBC BAG3 knockout cells.
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