Linkage Evidence for a Two-Locus Inheritance of LQT-Associated Seizures in a Multigenerational LQT Family With a Novel KCNQ1 Loss-of-Function Mutation

Mutations in several genes encoding ion channels can cause the long-QT (LQT) syndrome with cardiac arrhythmias, syncope and sudden death. Recently, mutations in some of these genes were also identified to cause epileptic seizures in these patients, and the sudden unexplained death in epilepsy (SUDEP) was considered to be the pathologic overlap between the two clinical conditions. For LQT-associated KCNQ1 mutations, only few investigations reported the coincidence of cardiac dysfunction and epileptic seizures. Clinical, electrophysiological and genetic characterization of a large pedigree (n = 241 family members) with LQT syndrome caused by a 12-base-pair duplication in exon 8 of the KCNQ1 gene duplicating four amino acids in the carboxyterminal KCNQ1 domain (KCNQ1dup12; p.R360_Q361dupQKQR, NM_000218.2, hg19). Electrophysiological recordings revealed no substantial KCNQ1-like currents. The mutation did not exhibit a dominant negative effect on wild-type KCNQ1 channel function. Most likely, the mutant protein was not functionally expressed and thus not incorporated into a heteromeric channel tetramer. Many LQT family members suffered from syncopes or developed sudden death, often after physical activity. Of 26 family members with LQT, seizures were present in 14 (LQTplus seizure trait). Molecular genetic analyses confirmed a causative role of the novel KCNQ1dup12 mutation for the LQT trait and revealed a strong link also with the LQTplus seizure trait. Genome-wide parametric multipoint linkage analyses identified a second strong genetic modifier locus for the LQTplus seizure trait in the chromosomal region 10p14. The linkage results suggest a two-locus inheritance model for the LQTplus seizure trait in which both the KCNQ1dup12 mutation and the 10p14 risk haplotype are necessary for the occurrence of LQT-associated seizures. The data strongly support emerging concepts that KCNQ1 mutations may increase the risk of epilepsy, but additional genetic modifiers are necessary for the clinical manifestation of epileptic seizures

Histone deacetylase inhibition accelerates the early events of stem cell differentiation: transcriptomic and epigenetic analysis

BACKGROUND: Epigenetic mechanisms regulate gene expression patterns affecting cell function and differentiation. In this report, we examine the role of histone acetylation in gene expression regulation in mouse embryonic stem cells employing transcriptomic and epigenetic analysis. RESULTS: Embryonic stem cells treated with the histone deacetylase inhibitor Trichostatin A (TSA), undergo morphological and gene expression changes indicative of differentiation. Gene profiling utilizing Affymetrix microarrays revealed the suppression of important pluripotency factors, including Nanog, a master regulator of stem cell identity, and the activation of differentiation-related genes. Transcriptional and epigenetic changes induced after 6-12 hours of TSA treatment mimic those that appear during embryoid body differentiation. We show here that the early steps of stem cell differentiation are marked by the enhancement of bulk activatory histone modifications. At the individual gene level, we found that transcriptional reprogramming triggered by histone deacetylase inhibition correlates with rapid changes in activating K4 trimethylation and repressive K27 trimethylation of histone H3. The establishment of H3K27 trimethylation is required for stable gene suppression whereas in its absence, genes can be reactivated upon TSA removal. CONCLUSION: Our data suggest that inhibition of histone deacetylases accelerates the early events of differentiation by regulating the expression of pluripotency- and differentiation-associated genes in an opposite manner. This analysis provides information about genes that are important for embryonic stem cell function and the epigenetic mechanisms that regulate their expression

Effect of glenoid concavity loss on shoulder stability- a case report in a professional wrestler

Background Current glenoid defect measurement techniques only quantify bone loss in terms of defect diameter or surface. However, the glenoid depth plays an important role in shoulder stabilization by means of concavity compression. Case presentation We present a case of a professional wrestler who suffered from anterior shoulder instability after sustaining a bony Bankart lesion without loss of glenoid surface area but flattening of the concavity due to medialization of the fragment. The patient’s glenoid concavity was reconstructed arthroscopically by reduction and percutaneous screw fixation of the bony fragment along with a capsulo-ligamentous shift. Changes of the glenoid concavity with according alterations in the Bony Shoulder Stability Ratio (BSSR) were analyzed on pre-op, post-op, and follow-up CT scans. Postoperative CT scans revealed a deepened concavity (3.3 mm) and improved BSSR (46.1 %) compared to pre-op scans (0.7 mm; 11.3 %). Follow-up CT scans showed a slight remodeling of the glenoid concavity (3.2 mm) with steady BSSR (44.7 %). Conclusion This case shows that the passive stabilizing effect of the glenoid can be compromised by loss of concavity despite the absence of loss of articular surface. Therefore, addressing the concavity loss and resulting reduction of the BSSR is recommended in these cases. Bony Bankart repair was successful in restoring the BSSR of the patients shoulder as determined by mathematical calculations based on CT scans

Neural Differentiation of Embryonic Stem Cells In Vitro: A Road Map to Neurogenesis in the Embryo

Background: The in vitro generation of neurons from embryonic stem (ES) cells is a promising approach to produce cells suitable for neural tissue repair and cell-based replacement therapies of the nervous system. Available methods to promote ES cell differentiation towards neural lineages attempt to replicate, in different ways, the multistep process of embryonic neural development. However, to achieve this aim in an efficient and reproducible way, a better knowledge of the cellular and molecular events that are involved in the process, from the initial specification of neuroepithelial progenitors to their terminal differentiation into neurons and glial cells, is required. Methodology/Principal Findings: In this work, we characterize the main stages and transitions that occur when ES cells are driven into a neural fate, using an adherent monolayer culture system. We established improved conditions to routinely produce highly homogeneous cultures of neuroepithelial progenitors, which organize into neural tube-like rosettes when they acquire competence for neuronal production. Within rosettes, neuroepithelial progenitors display morphological and functional characteristics of their embryonic counterparts, namely, apico-basal polarity, active Notch signalling, and proper timing of production of neurons and glia. In order to characterize the global gene activity correlated with each particular stage of neural development, the full transcriptome of different cell populations that arise during the in vitro differentiation protocol was determined by microarray analysis. By using embryo-oriented criteria to cluster the differentially expresse

Настройка моделей при создании систем поддержки принятия стратегических решений

Показана актуальность разработки платформы (программной среды), позволяющей на её основе создавать системы стратегического управления организациями, используя сквозные технологии поддержки принятия решений и универсальные инструментальные средства. Статья посвящена решению одной из задач, возникающей при разработке такой платформы - настройке универсальных моделей поддержки принятия решений под условия принятия решений и особенности предметной области стратегического управления. Разработан механизм настройки моделей, выявлены и представлены параметры настройки

Interaction Network Provides Clues on the Role of BCAR1 in Cellular Response to Changes in Gravity

When culturing cells in space or under altered gravity conditions on Earth to investigate the impact of gravity, their adhesion and organoid formation capabilities change. In search of a target where the alteration of gravity force could have this impact, we investigated p130cas/BCAR1 and its interactions more thoroughly, particularly as its activity is sensitive to applied forces. This protein is well characterized regarding its role in growth stimulation and adhesion processes. To better understand BCAR1′s force-dependent scaffolding of other proteins, we studied its interactions with proteins we had detected by proteome analyses of MCF-7 breast cancer and FTC-133 thyroid cancer cells, which are both sensitive to exposure to microgravity and express BCAR1. Using linked open data resources and our experiments, we collected comprehensive information to establish a semantic knowledgebase and analyzed identified proteins belonging to signaling pathways and their networks. The results show that the force-dependent phosphorylation and scaffolding of BCAR1 influence the structure, function, and degradation of intracellular proteins as well as the growth, adhesion and apoptosis of cells similarly to exposure of whole cells to altered gravity. As BCAR1 evidently plays a significant role in cell responses to gravity changes, this study reveals a clear path to future research performing phosphorylation experiments on BCAR1

Reduced early visual processing of own body images in anorexia nervosa: An event-related potentials study

Introduction. Although body image distortion in anorexia nervosa (AN) has been extensively studied over the past decades, its underlying mechanisms are not yet fully understood. Neuro-imaging studies have identified functional and structural alterations in brain areas involved in visual body perception, but the time course of visual body processing in AN remains mostly unexplored. The current study used event-related brain potentials (ERPs) to investigate single processing steps along the time course, particularly the visual processing of physical body image characteristics (featural processing, P1) and the recognition of a body as such (configural processing, N1). Methods. Twenty in-patients with AN, and 20 healthy women viewed photographs of themselves, of another woman’s body and of their own and another woman’s standardized object (cup) with concurrent EEG recording. Results. Body images elicited an accentuation of the P1 component (105-160 ms), which was absent for the comparison between own-body and own-cup images in the AN group. Results regarding the N1 component suggest alterations in object processing in AN. Conclusions. Our results demonstrate that individuals with AN show reduced featural processing of their own body image, a process which, due to its position early in the visual processing stream, is unlikely to involve higher cognitive stimulus processing. This suggests a possible role of previously undetected pre-conscious mechanisms in body image disturbance