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Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominantly inherited neurodegenerative disorder with preferential affection of Purkinje neurons, which are known as integrators of calcium currents. The expansion of a polyglutamine (polyQ) domain in the RNA-binding protein ataxin-2 (ATXN2) is responsible for this disease, but the causal roles of deficient ATXN2 functions versus aggregation toxicity are still under debate. Here, we studied mouse mutants with Atxn2 knockout (KO) regarding their cerebellar global transcriptome by microarray and RT-qPCR, in comparison with data from Atxn2-CAG42-knock-in (KIN) mouse cerebellum. Global expression downregulations involved lipid and growth signaling pathways in good agreement with previous data. As a novel effect, downregulations of key factors in calcium homeostasis pathways (the transcription factor Rora, transporters Itpr1 and Atp2a2, as well as regulator Inpp5a) were observed in the KO cerebellum, and some of them also occurred subtly early in KIN cerebellum. The ITPR1 protein levels were depleted from soluble fractions of cerebellum in both mutants, but accumulated in its membrane-associated form only in the SCA2 model. Coimmunoprecipitation demonstrated no association of ITPR1 with Q42-expanded or with wild-type ATXN2. These findings provide evidence that the physiological functions and protein interactions of ATXN2 are relevant for calcium-mediated excitation of Purkinje cells as well as for ATXN2-triggered neurotoxicity. These insights may help to understand pathogenesis and tissue specificity in SCA2 and other polyQ ataxias like SCA1, where inositol regulation of calcium flux and RORalpha play a role.
Sexuelle Dysfunktionen bei Frauen mit Posttraumatischer
Belastungsstörung – ein Übersichtsartikel
(2017)
Sexual dysfunctions, clinical as well as subclinical, and other sexual complaints that accompany aversive emotions, cognitions, and sexual risk behavior are very common among women after experiences of sexual violence and are underestimated as a problem. Anyway, among victims of other kinds of traumatic experiences, a high prevalence of sexual distress is found as well. Explanatory approaches concentrate on learning theory as well as the phenomenology of Posttraumatic Stress Disorder (PTSD) itself. Sexuality is an important source of vitality, and the maintenance of sexual dysfunctions can be accompanied by a risk of impairments in quality of life and self-esteem as well as relationship problems. Aside clinical practice, there is also a lack of knowledge in clinical science regarding the association between sexual dysfunctions and traumatic experiences, especially sexual ones. In this article, the phenomenology and diagnostic instruments of female sexual dysfunctions are presented, and consequences of sexual violence on sexuality, also in the context of PTSD, are further explained. Suggestions are being made on how to include suitable interventions into therapy.
Background: Modulation of cortical excitability by transcranial magnetic stimulation (TMS) is used for investigating human brain functions. A common observation is the high variability of long-term depression (LTD)-like changes in human (motor) cortex excitability. This study aimed at analyzing the response subgroup distribution after paired continuous theta burst stimulation (cTBS) as a basis for subject selection.
Methods: The effects of paired cTBS using 80% active motor threshold (AMT) in 31 healthy volunteers were assessed at the primary motor cortex (M1) corresponding to the representation of the first dorsal interosseous (FDI) muscle of the left hand, before and up to 50 min after plasticity induction. The changes in motor evoked potentials (MEPs) were analyzed using machine-learning derived methods implemented as Gaussian mixture modeling (GMM) and computed ABC analysis.
Results: The probability density distribution of the MEP changes from baseline was tri-modal, showing a clear separation at 80.9%. Subjects displaying at least this degree of LTD-like changes were n = 6 responders. By contrast, n = 7 subjects displayed a paradox response with increase in MEP. Reassessment using ABC analysis as alternative approach led to the same n = 6 subjects as a distinct category.
Conclusion: Depressive effects of paired cTBS using 80% AMT endure at least 50 min, however, only in a small subgroup of healthy subjects. Hence, plasticity induction by paired cTBS might not reflect a general mechanism in human motor cortex excitability. A mathematically supported criterion is proposed to select responders for enrolment in assessments of human brain functional networks using virtual brain lesions.
Post-translational modification of proteins with ubiquitin-like SUMO modifiers is a tightly regulated and highly dynamic process. The SENP family of SUMO-specific isopeptidases comprises six cysteine proteases. They are instrumental in counterbalancing SUMO conjugation, but their regulation is not well understood. We demonstrate that in hypoxic cell extracts, the catalytic activity of SENP family members, in particular SENP1 and SENP3, is inhibited in a rapid and fully reversible process. Comparative mass spectrometry from normoxic and hypoxic cells defines a subset of hypoxia-induced SUMO1 targets, including SUMO ligases RanBP2 and PIAS2, glucose transporter 1, and transcriptional regulators. Among the most strongly induced targets, we identified the transcriptional co-repressor BHLHE40, which controls hypoxic gene expression programs. We provide evidence that SUMOylation of BHLHE40 is reversed by SENP1 and contributes to transcriptional repression of the metabolic master regulator gene PGC-1α. We propose a pathway that connects oxygen-controlled SENP activity to hypoxic reprogramming of metabolism.
Choriocarcinoma is the most malignant tumor of gestational trophoblastic disease arising from any gestation. It has a tendency toward relapse as well as metastasis. Here, a case of relapsed high-risk choriocarcinoma (FIGO stage IV, WHO score 12) in a 37-year-old female presenting with vaginal bleedings is described. Relapse developed at the site of the surgical scar from hysterectomy that had been performed 2 years earlier. Although the patient was treated with aggressive chemotherapy, she was in a bad general condition and died from infection and liver insufficiency.
We are pleased to introduce the sixth Journal Club. This edition is focused on several relevant studies published in the last years in the field of Strength and Conditioning, chosen by our Editorial Board members and their colleagues. We hope to stimulate your curiosity in this field and to share with you the passion for sport and exercise seen from a scientific point of view. The Editorial Board members wish you an inspiring read.
Objectives The following study analyses the influence of risk factors among the occupational group of truck drivers on postural control and body mass index (BMI).
Design Observational study.
Setting One motorway station close to several highways in Germany.
Participants 180 truck drivers (177 male/3 female), aged 21–65 years old, took part in this study.
Outcome measures Postural control was examined using a pressure plate. In order to examine the influence of body weight (BMI) and working years on postural control, subjects were divided into samples of five and three groups, respectively. Furthermore, it was evaluated whether the subjects suffered from back pain. For data analysis, the Kruskal-Wallis test was used as the data were not normally distributed. Once the p value of the Kruskal-Wallis test was p≤0.05, the Conover-Iman comparison and afterwards the Bonferroni-Holm correction were used. The significance level was set at α ≤0.05.
Results Regarding the number of working years, a significant increase of frontal (p≤0.04) and sagittal (p≤0.001) sway were observed. The correlation of the five BMI groups with the number of working years demonstrates that an increase of the working years leads to an increase of BMI (p≤0.03). Furthermore, the majority of truck drivers participating in this study suffered from back pain (61.7%).
Conclusions BMI and musculoskeletal impairment are indicators of health risk factors. In this study, it is shown that an increasing number of working years and an increasing BMI lead to a decrease in frontal and sagittal postural sway. In addition, the number of working years correlates with body weight and back pain.
Background: Proteomics of bacterial pathogens is a developing field exploring microbial physiology, gene expression and the complex interactions between bacteria and their hosts. One of the complications in proteomic approach is micro- and macro-heterogeneity of bacterial species, which makes it impossible to build a comprehensive database of bacterial genomes for identification, while most of the existing algorithms rely largely on genomic data.
Results: Here we present a large scale study of identification of single amino acid polymorphisms between bacterial strains. An ad hoc method was developed based on MS/MS spectra comparison without the support of a genomic database. Whole-genome sequencing was used to validate the accuracy of polymorphism detection. Several approaches presented earlier to the proteomics community as useful for polymorphism detection were tested on isolates of Helicobacter pylori, Neisseria gonorrhoeae and Escherichia coli.
Conclusion: The developed method represents a perspective approach in the field of bacterial proteomics allowing to identify hundreds of peptides with novel SAPs from a single proteome.
Gene trap mutagenesis is a powerful tool to create loss-of-function mutations in mice and other model organisms. Modifications of traditional gene trap cassettes, including addition of conditional features in the form of Flip-excision (FlEx) arrays to enable directional gene trap cassette inversions by Cre and Flpe site-specific recombinases, greatly enhanced their experimental potential. By taking advantage of these conditional gene trap cassettes, we developed a generic strategy for generating conditional mutations and validated this strategy in mice carrying a multipurpose allele of the Prdm16 transcription factor gene. We demonstrate that the gene trap insertion creates a null mutation replicating the Pierre Robin sequence-type cleft palate phenotype of other Prdm16 mutant mice. Consecutive breeding to Flpe and Emx1IREScre deleter mice spatially restricted Prdm16 loss to regions of the forebrain expressing the homeobox gene Emx1, demonstrating the utility of the technology for the analysis of tissue-specific gene functions.
Downstream effects of plectin mutations in epidermolysis bullosa simplex with muscular dystrophy
(2016)
Mutations of the human plectin gene (PLEC) on chromosome 8q24 cause autosomal recessive epidermolysis bullosa simplex with muscular dystrophy (EBS-MD). In the present study we analyzed the downstream effects of PLEC mutations on plectin protein expression and localization, the structure of the extrasarcomeric desmin cytoskeleton, protein aggregate formation and mitochondrial distribution in skeletal muscle tissue from three EBS-MD patients.
PLEC gene analysis in a not previously reported 35-year-old EBS-MD patient with additional disease features of cardiomyopathy and malignant arrhythmias revealed novel compound heterozygous (p.(Phe755del) and p.(Lys1040Argfs*139)) mutations resulting in complete abolition of plectin protein expression. In contrast, the other two patients with different homozygous PLEC mutations showed preserved plectin protein expression with one only expressing rodless plectin variants, and the other markedly reduced protein levels. Analysis of skeletal muscle tissue from all three patients revealed severe disruption of the extrasarcomeric intermediate filament cytoskeleton, protein aggregates positive for desmin, syncoilin, and synemin, degenerative myofibrillar changes, and mitochondrial abnormalities comprising respiratory chain dysfunction and an altered organelle distribution and amount.
Our study demonstrates that EBS-MD causing PLEC mutations universally result in a desmin protein aggregate myopathy phenotype despite marked differences in individual plectin protein expression patterns. Since plectin is the key cytolinker protein that regulates the structural and functional organization of desmin filaments, the defective anchorage and spacing of assembled desmin filaments is the key pathogenetic event that triggers the formation of desmin protein aggregates as well as secondary mitochondrial pathology.