Crowellgadegaard0596

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. Our data obtained in two different tumor entities identify suppression of EMT and ciliogenesis as putative synergizing mechanisms of BAG3-driven tumor aggressiveness in therapy-resistant cancers.In the beginning of the COVID pandemic, researchers and bioethicists called for human challenge trials to hasten the development of a vaccine for COVID. However, the fact that we lacked a specific, highly effective treatment for COVID led many to argue that a COVID challenge trial would be unethical and we ought to pursue traditional phase III testing instead. These ethical objections to challenge trials may have slowed the progress of a COVID vaccine, so it is important to evaluate their merit. One common way of doing so is to make an analogy to other social practices that are relevantly similar and which we currently sanction. We submit that non-directed live organ donation (NDLOD) is a promising analogy. After arguing that the risks to volunteers for each activity appear similar, we explore potential disanalogies that would undermine the comparison. We note that there are differences in both the kind and certainty of benefit secured by NDLOD compared to challenge trials. Linrodostat cost We conclude these differences are insufficient to make NDLOD permissible and challenge trials impermissible. Ultimately, if we think the risks associated with NDLOD are ethically permissible, then we should think the same of the risks associated with COVID challenge trials.Sexual satisfaction is the most frequently studied sexual component of human sexuality related to its link with relationship satisfaction and stability (S. Sprecher & R. M. Cate, 2004. The handbook of sexuality in close relationships, pp. 235-256. Mahwah, NJ Taylor & Francis). Previous studies have shown that sexual satisfaction is affected by personal, interpersonal, social and cultural variables, but few studies have considered the associations between these variables. The aim of this study was to evaluate a complex model of sexual satisfaction considering these various levels of variables and their associations. The study was conducted online and comprised 457 individuals in the final sample. The French version of the index of sexual satisfaction evaluated the level of sexual dissatisfaction. Personal, interpersonal, social and cultural variables were assessed with questionnaires and their associations were investigated with the partial least squares-path method. The association between dyadic coping (positive and negative) and sexual dissatisfaction was mediated by relationship satisfaction. The model also showed three sequential mediations through dyadic coping and relationship satisfaction first between intra-individual vulnerability and sexual dissatisfaction, second between intra-individual resources and sexual dissatisfaction, and third between conjugal characteristics and sexual dissatisfaction. The simple and sequential mediations were stronger for positive dyadic coping. The relationship between intra-individual resources and positive dyadic coping was significantly stronger in women, while the relationship between conjugal characteristics and positive dyadic coping was stronger in men. Dyadic coping plays a key role in sexual dissatisfaction. Clinical interventions should reinforce positive self-image (particularly in women), support emotional and physical vulnerabilities, and promote more supportive dyadic coping (particularly in men in a long-term relationship).Maple sap is a rich nutrient matrix collected from Acer trees to produce several food products (i.e., sap, water, extract, syrup, and sugar), of which syrup is the most famous in the food industry for its distinct taste and flavor. Maple syrup is produced from the sap of several species (Acer saccharum, Acer nigrum, and Acer rubrum) of maple. Maple syrup is chiefly produced through the concentration of sap via thermal evaporation (pan evaporation) or membrane separation. Each processing technique affects the quality and characteristics of processed maple products. The chemistry of maple products is dominated by a myriad of other phytoconstituents other than sugar, that is, phenolics, to mediate for its many health benefits. The health-promoting effects of maple products included antioxidant, antimicrobial, antimutagenic, anti-inflammatory, and antiproliferative activities. This review capitalizes on maple food products focusing on their chemistry, processing, and health benefits compared with other sugar sweeocessing techniques and environmental conditions on the phytochemicals profile and biological effects of maple food products should now follow. Application of other omics tools, that is, genomics, proteomics, and metabolomics, to understand maple syrup effects on the human body can help reveal its exact action mechanisms or points for any potential health hazards for certain ailments.Microporous organic networks (MONs) that exhibit good stability and hydrophobicity are promising candidates for performing HPLC separation of small organic compounds. However, their applications in separating large analytes as well as biomolecules are still limited by the microporous nature of MONs. Herein, we demonstrated the fabrication of a MON-functionalized silica (MON@SiO2 ), exhibiting micro and mesopores for the HPLC separations of small drugs as well as large analytes, such as flavones, nonsteroidal anti-inflammatory drugs (NSAIDs), endocrine disrupting chemicals (EDCs), and proteins. MON was successfully modified on SiO2 microspheres to yield the uniform and mono-dispersed MON@SiO2 . The separation mechanisms and performance of the MON@SiO2 packed column were evaluated for a wide range of analytes, including neutral, acidic, basic compounds, drugs, and proteins. Compared with commercial C18 and SiO2 -NH2 packed columns, the proposed MON@SiO2 column afforded superior performance in the separations of flavones, NSAIDs, EDCs, and proteins. Moreover, the MON@SiO2 column also offered good repeatability with intraday RSDs (n = 7) of less then 0.1%, less then 2.0%, less then 2.3%, and less then 0.7% for the retention time, peak height, peak area, and half peak width, respectively, for separating EDCs. This work proved the potential of using MONs in the HPLC separations of drugs and proteins.Myofibrillar protein (MPS) and myosin (MS) from grass carp was irradiated by γ-ray and electron beam (EB) irradiation with different dose (2, 4, 6, 8, and 10 kGy). The changes in the physicochemical properties (solubility, Ca2+ -ATPase activity, total and reactive sulfhydryl content, surface hydrophobicity [S0 -ANS]), and structure of MPS and MS were investigated in the present work. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis revealed that there were degradation and aggregation of MPS and MS caused by irradiation, and the disappearance of myosin heavy chains (MHC) irradiated by EB was earlier than that of irradiated by γ-ray. As compared with MPS, the extracted MS was more easily destroyed. With the increase of irradiation dose, the particle size, solubility, Ca2+ -ATPase activity, and SH content of MPS and MS decreased (p less then .05), while the S0 -ANS first increased and then decreased. Two-way analysis of variance results suggested that the degree of protein denaturation depends on the irradiation mode and dose.