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Cardioviruses cause myocarditis and encephalomyelitis in rodents; human cardioviruses have not been ascribed to any disease. We screened 6,854 cerebrospinal fluid and 10 myocardium specimens from children and adults. A genotype 2 cardiovirus was detected from a child who died of sudden infant death syndrome, and 2 untypeable cardioviruses were detected from 2 children with meningitis.

The emotional expression of the face provides an important social signal that allows humans to make inferences about other people's state of mind. However, the underlying brain mechanisms are complex and still not completely understood. Using magnetoencephalography (MEG), we analyzed the spatiotemporal structure of regional electrical brain activity in human adults during a categorization task (faces or hands) and an emotion discrimination task (happy faces or neutral faces). Brain regions that are specifically important for different aspects of processing emotional facial expressions showed interesting hemispheric dominance patterns. The dorsal brain regions showed a right predominance when participants paid attention to facial expressions: The right parietofrontal regions, including the somatosensory, motor/premotor, and inferior frontal cortices showed significantly increased activation in the emotion discrimination task, compared to in the categorization task, in latencies of 350 to 550 ms, while no activation was found in their left hemispheric counterparts. Furthermore, a left predominance of the ventral brain regions was shown for happy faces, compared to neutral faces, in latencies of 350 to 550 ms within the emotion discrimination task. Thus, the present data suggest that the right and left hemispheres play different roles in the recognition of facial expressions depending on cognitive context.

A major challenge in current systems biology is the combination and integrative analysis of large data sets obtained from different high-throughput omics platforms, such as mass spectrometry based Metabolomics and Proteomics or DNA microarray or RNA-seq-based Transcriptomics. Especially in the case of non-targeted Metabolomics experiments, where it is often impossible to unambiguously map ion features from mass spectrometry analysis to metabolites, the integration of more reliable omics technologies is highly desirable. A popular method for the knowledge-based interpretation of single data sets is the (Gene) Set Enrichment Analysis. In order to combine the results from different analyses, we introduce a methodical framework for the meta-analysis of p-values obtained from Pathway Enrichment Analysis (Set Enrichment Analysis based on pathways) of multiple dependent or independent data sets from different omics platforms. For dependent data sets, e.g. obtained from the same biological samples, the framework utilizes a covariance estimation procedure based on the nonsignificant pathways in single data set enrichment analysis. The framework is evaluated and applied in the joint analysis of Metabolomics mass spectrometry and Transcriptomics DNA microarray data in the context of plant wounding. In extensive studies of simulated data set dependence, the introduced correlation could be fully reconstructed by means of the covariance estimation based on pathway enrichment. By restricting the range of p-values of pathways considered in the estimation, the overestimation of correlation, which is introduced by the significant pathways, could be reduced. When applying the proposed methods to the real data sets, the meta-analysis was shown not only to be a powerful tool to investigate the correlation between different data sets and summarize the results of multiple analyses but also to distinguish experiment-specific key pathways.

In pleomorphic adenomas of the salivary glands (PASG) recurrent chromosomal rearrangements affecting either 8q12 or 12q14∼15 lead to an overexpression of the genes of the genuine transcription factor PLAG1 or the architectural transcription factor HMGA2, respectively. Both genes are also affected by recurrent chromosomal rearrangements in benign adipocytic tumors as e. g. lipomas and lipoblastomas. Herein, we observed a strong correlation between the expression of HMGA2 and PLAG1 in 14 benign and 23 malignant thyroid tumors. To address the question if PLAG1 can be activated by HMGA2, the expression of both genes was quantified in 32 uterine leiomyomas 17 of which exhibited an overexpression of HMGA2. All leiomyomas with HMGA2 overexpression also revealed an activation of PLAG1 in the absence of detectable chromosome 8 abnormalities affecting the PLAG1 locus. To further investigate if the overexpression of PLAG1 is inducible by HMGA2 alone, HMGA2 was transiently overexpressed in MCF-7 cells. An increased PLAG1 expression was observed 24 and 48 h after transfection. Likewise, stimulation of HMGA2 by FGF1 in adipose tissue-derived stem cells led to a simultaneous increase of PLAG1 mRNA. Altogether, these data suggest that HMGA2 is an upstream activator of PLAG1. Accordingly, this may explain the formation of tumors as similar as lipomas and lipoblastomas resulting from an activation of either of both genes by chromosomal rearrangements.

Small cell lung carcinomas (SCLCs) represent highly aggressive tumors with an overall five-year survival rate in the range of 5 to 10%. Here, we show that four out of five SCLC cell lines reversibly develop a neuron-like phenotype on extracellular matrix constituents such as fibronectin, laminin or thrombospondin upon staurosporine treatment in an RGD/integrin-mediated manner. Neurite-like processes extend rapidly with an average speed of 10 µm per hour. Depending on the cell line, staurosporine treatment affects either cell cycle arrest in G2/M phase or induction of polyploidy. Neuron-like conversion, although not accompanied by alterations in the expression pattern of a panel of neuroendocrine genes, leads to changes in protein expression as determined by two-dimensional gel electrophoresis. It is likely that SCLC cells already harbour the complete molecular repertoire to convert into a neuron-like phenotype. More extensive studies are needed to evaluate whether the conversion potential of SCLC cells is suitable for therapeutic interventions.

Monozygotic (MZ) twin pair discordance for childhood-onset Type 1 Diabetes (T1D) is ∼50%, implicating roles for genetic and non-genetic factors in the aetiology of this complex autoimmune disease. Although significant progress has been made in elucidating the genetics of T1D in recent years, the non-genetic component has remained poorly defined. We hypothesized that epigenetic variation could underlie some of the non-genetic component of T1D aetiology and, thus, performed an epigenome-wide association study (EWAS) for this disease. We generated genome-wide DNA methylation profiles of purified CD14+ monocytes (an immune effector cell type relevant to T1D pathogenesis) from 15 T1D-discordant MZ twin pairs. This identified 132 different CpG sites at which the direction of the intra-MZ pair DNA methylation difference significantly correlated with the diabetic state, i.e. T1D-associated methylation variable positions (T1D-MVPs). We confirmed these T1D-MVPs display statistically significant intra-MZ pair DNA methylation differences in the expected direction in an independent set of T1D-discordant MZ pairs (P = 0.035). Then, to establish the temporal origins of the T1D-MVPs, we generated two further genome-wide datasets and established that, when compared with controls, T1D-MVPs are enriched in singletons both before (P = 0.001) and at (P = 0.015) disease diagnosis, and also in singletons positive for diabetes-associated autoantibodies but disease-free even after 12 years follow-up (P = 0.0023). Combined, these results suggest that T1D-MVPs arise very early in the etiological process that leads to overt T1D. Our EWAS of T1D represents an important contribution toward understanding the etiological role of epigenetic variation in type 1 diabetes, and it is also the first systematic analysis of the temporal origins of disease-associated epigenetic variation for any human complex disease.

BACKGROUND: Several agents are available to treat osteoporosis while addressing patient-specific medical needs. Individuals' residual risk to severe fracture may require changes in treatment strategy. Data at osseous cellular and microstructural levels due to a therapy switch between agents with different modes of action are rare. Our study on a series of five consecutively taken bone biopsies from an osteoporotic individual over a six-year period analyzes changes in cellular characteristics, bone microstructure and mineralization caused by a therapy switch from an antiresorptive (bisphosphonate) to a dual action bone agent (strontium ranelate). METHODOLOGY/PRINCIPAL FINDINGS: Biopsies were progressively taken from the iliac crest of a female patient. Four biopsies were taken during bisphosphonate therapy and one biopsy was taken after one year of strontium ranelate (SR) treatment. Furthermore, serum bone markers and dual x-ray absorptiometry measurements were acquired. Undecalcified histology was used to assess osteoid parameters and bone turnover. Structural indices and degree of mineralization were determined using microcomputed tomography, quantitative backscattered electron imaging, and combined energy dispersive x-ray/µ-x-ray-fluorescence microanalysis. CONCLUSIONS/SIGNIFICANCE: Microstructural data revealed a notable increase in bone volume fraction after one year of SR treatment compared to the bisphosphonate treatment period. Indices of connectivity density, structure model index and trabecular bone pattern factor were predominantly enhanced indicating that the architectural transformation from trabecular rods to plates was responsible for the bone volume increase and less due to changes in trabecular thickness and number. Administration of SR following bisphosphonates led to a maintained mineralization profile with an uptake of strontium on the bone surface level. Reactivated osteoclasts designed tunneling, hook-like intratrabecular resorption sites. The appearance of tunneling resorption lacunae and the formation of both mini-modeling units and osteon-like structures within increased plate-like cancellous bone mass provides additional information on the mechanisms of strontium ranelate following bisphosphonate treatment, which may deserve special attention when monitoring a treatment switch.

Abstract Background Several lines of research suggest that exposure to cellular material can alter the susceptibility to infection by HIV-1. Because sexual contact often includes exposure to cellular material, we hypothesized that repeated mucosal exposure to heterologous cells would induce an immune response that would alter the susceptibility to mucosal infection. Using the feline immunodeficiency virus (FIV) model of HIV-1 mucosal transmission, the cervicovaginal mucosa was exposed once weekly for 12 weeks to 5,000 heterologous cells or media (control) and then cats were vaginally challenged with cell-associated or cell-free FIV. Results Exposure to heterologous cells decreased the percentage of lymphocytes in the mucosal and systemic lymph nodes (LN) expressing L-selectin as well as the percentage of CD4+ CD25+ T cells. These shifts were associated with enhanced ex-vivo proliferative responses to heterologous cells. Following mucosal challenge with cell-associated, but not cell-free, FIV, proviral burden was reduced by 64% in cats previously exposed to heterologous cells as compared to media exposed controls. Conclusions The pathogenesis and/or the threshold for mucosal infection by infected cells (but not cell-free virus) can be modulated by mucosal exposure to uninfected heterologous cells.

Les troubles du sommeil sont une affection clinique courante dans la population atteinte de polyarthrite rhumatoïde (PR) et sont présentes chez plus de 60 % des patients [1]. Bien que peu d'études longitudinales aient démontré une amélioration sur la qualité du sommeil avec des thérapies avancées [2–5] , aucune d'entre elles n'a décrit de manière intensive la signification clinique de ces changements par des mesures subjectives et objectives ou n'a démontré le maintien de son effet à long terme. L'étude SLEERA vise à étudier l'impact de l'upadacitinib, un inhibiteur sélectif et réversible de JAK, sur la qualité du sommeil dans une population atteinte de PR, en utilisant une auto-évaluation telle que le questionnaire validé Pittsburgh Sleep Quality Index (PSQI) [6] , et une mesure objective basée sur l'actigraphie telle que le traqueur activité ActiGraph GT9x. SLEERA est une sous-étude d'UPHOLD, une étude de cohorte internationale, multicentrique, prospective et observationnelle (NCT04497597), qui évalue la qualité du sommeil dans une population réelle de patients suisses atteints de polyarthrite rhumatoïde, initiant un traitement avec l'upadacitinib conformément à l'autorisation de mise sur le marché et dont la décision de traitement a été prise avant l'inclusion dans l'étude. Cette analyse rapporte les caractéristiques de base sur le sommeil pour les 39 patients suisses ayant effectué leur visite initiale à la date limite du 30 avril 2022. Les données du PSQI lors de la visite initiale et de l'actigraphie durant une période de 2 semaines avant le début du traitement sont présentées de manière descriptive. La plupart des patients étaient des femmes (87 %) et l'âge moyen était de 59,5 ans. Sur les 37 patients ayant rempli le PSQI, 76 % présentaient des troubles du sommeil (défini par un PSQI > 5) avec, en moyenne, un score total de 7,8, une efficacité du sommeil de 78 % et une durée du sommeil de 6,8 heures. Les périodes de sommeil mesurées par l'actigraphie ont pu être analysées pour 36 patients. En moyenne, l'efficacité du sommeil était de 85 %, avec un temps de sommeil total de 6,7 heures, un nombre de réveil de 20 et un temps d'éveil total après l'endormissement de 72 minutes. Selon l'OMS qui recommande un temps de 7 heures ou plus de sommeil par nuit, seulement 36 % ont atteint ce seuil. En plus des caractéristiques du sommeil, 32 patients avaient suffisamment de données sur la mobilité diurne (définie comme > 18 h/jour de temps de port) pour être rapportées. En moyenne, le nombre de pas était de 4 272 et la durée totale d'activité physique modérée à vigoureuse (MVPA) était de 177 minutes. Seuls 3 % respectaient la recommandation d'activité physique de ≥ 10 000 pas/jour et 59 % respectaient la recommandation de l'OMS de ≥ 150 min/jour d'activité modérée à vigoureuse. Dans cette cohorte suisse de PR, une forte proportion de patients présentait des troubles du sommeil, comme le montrent les mesures subjectives et objectives. L'actigraphie du sommeil a démontré des résultats cohérents avec ceux observés avec le questionnaire PSQI. Cette recherche fournit des preuves supplémentaires de troubles du sommeil chez les patients atteints de PR et confirme sa pertinence lors de l'évaluation des objectifs de traitement de la maladie. [ABSTRACT FROM AUTHOR]

An integrated interpretation of seismicity, fault plane solutions and deep seismic reflection data suggests that the NE-SW to NW-SE trending Rhone-Simplon fault zone and the gently S-dipping basal Penninic thrust separate fundamentally different stress regimes in the westernSwiss Alps. North of the Rhone-Simplon fault zone, strike-slip earthquakes on steep-dipping faults within the Helvetic nappes are a consequence of regional NW-SE compression and NE-SW extension. To the south, vertical maximum stress and N-S extension are responsible for normal mechanism earthquakes that occur entirely within the Penninic nappes above the basal Penninic thrust. Such normal faulting likely results from extension associated with southward movements (collapse) of the Penninic nappes and/or continued uplift and relative northward displacements of the underlying Alpine massifs. Geological mapping and fission-track dating suggest that the two distinct stress regimes havecontrolled tectonism in the western Swiss Alps since at least the Neogene. [ABSTRACT FROM AUTHOR]

The activities of glutathione-s-transferase (GST) and cytochrome P-450 1A1 (CYP1A1) enzymes were measured in freshly extracted epidermis of live-biopsied, migrating, southern hemisphere humpback whales (Megaptera novaeangliae). The two quantified enzyme activities did not correlate strongly with each other. Similarly, neither correlated strongly with any of the organochlorine compound groups previously measured in the superficial blubber of the sample biopsy core, likely reflecting the anticipated low levels of typical aryl-hydrocarbon receptor ligands. GST activity did not differ significantly between genders or between northward (early migration) or southward (late migration) migrating cohorts. Indeed, the inter-individual variability in GST measurements was relatively low. This observation raises the possibility that measured activities were basal activities and that GST function was inherently impacted by the fasting state of the sampled animals, as seen in other species. These results do not support the implementation of CYP1A1 or GST as effective biomarkers of organochlorine contaminant burdens in southern hemisphere populations of humpback whales as advocated for other cetacean species. Further investigation of GST activity in feeding versus fasting cohorts may, however, provide some insight into the fasting metabolism of these behaviourally adapted populations. [ABSTRACT FROM AUTHOR]

Examines the oxygen, carbon and strontium isotope patterns in two profiles across the Glarus thrust. Evidence of net mass transport; Indication of vertical mass transport in isotope patterns; Compaction and dehydration of the footwall flysch during thrusting.

In diesem Beitrag wird der Frage nachgegangen, oh es regionaltypische Unterschiede in der Struktur und der Leistungsfähigkeit kleiner und mittlerer Unternehmen gibt. Um diese Frage zu beantworten, wurden die Daten von rund 6 500 Unternehmen ausgewertet, die im Jahr 1981 Investitionsvorhaben durchführten und deren Kreditanträge von der Kreditanstalt für Wiederaufbau bearbeitet wurden. Die Unternehmen wurden danach unterschieden, ob sie in einer Agglomeration oder in der räumlichen Peripherie tätig sind. Diese beiden räumlichen Teilgruppen wurden dann daraußin untersucht, ob sich signifikante Unterschiede im Bezug auf

Abstract: Background: Amyloidosis is a life-threatening protein misfolding disease and affects cardiac tissue, leading to heart failure, myocardial ischemia and arrhythmia. Amyloid deposits result in oxidative stress, inflammation and apoptosis. The purpose of this study was to examine the role of innate defense components, i.e., Deleted in Malignant Brain Tumors 1 (DMBT1) and the complement system, in different types of cardiac amyloidosis. Methods: Expression of DMBT1 and of the complement proteins C1q, C3d and C4d in cardiac specimens of patients with different types of amyloidosis were determined by immunohistochemistry and correlated with amyloid deposits stained by Congo red dye. Results: Strong DMBT1 staining adjacent to amyloid deposits was detected in different amyloidosis types, depending on the extent of the deposits. DMBT1 is localized in the endomysium and perimysium, in the endocardium, in the myocytes and in endothelial cells of affected transmural vessels. C1q, C3d and C4d were detected in the amyloid deposits but also in the endomysium and perimysium, in some myocytes, in endothelial cells, in the endocardium, and around the amyloid deposits. Conclusions: Up-regulated DMBT1 and complement activation in cardiac amyloidosis may be part of the activated pathways induced by protein aggregation and the consecutive inflammatory reaction. [Copyright &y& Elsevier]

Mogler C, Herold-Mende C, Dyckhoff G, Jenetzky E, Beckhove P & Helmke B M (2011) Histopathology , 944-952 Cellular expression of heparanase, a degrading enzyme of the extracellular matrix, is associated with poorer prognosis in several cancers. The present analysis, has studied the role of heparanase in tumour growth and clinical outcome in patients with head and neck squamous cell carcinoma (HNSCC). We analysed the cellular expression of the active form of heparanase in 71 human HNSCCs, using immunohistochemistry. The results were compared with clinicopathological data and, in 65 cases with immunoreactivity for the proliferation marker, MIB1. Cellular heparanase expression was detected in 41 of 71 (57.74%) cases; in particular, UICC IV-stage tumours showed high heparanase levels. Heparanase was localized mainly in the cytoplasm and, to a lesser extent, at the cell membrane. High levels of heparanase were significantly correlated with an almost four-fold decrease in MIB1 labelling ( P = 0.006). Comparison with clinical outcome by multivariate analysis revealed that patients with high-level heparanase expression had prolonged overall survival ( P = 0.029). Although heparanase was mainly found in late-stage HNSCCs, cellular heparanase expression in HNSCCs was associated with prolonged overall survival. We propose that the proliferation-reducing effect of high heparanase levels might outweigh the tumour-promoting effects of heparanase, especially in advanced tumours. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: The prevalence, pathophysiology, and clinical indicators of valvular amyloid deposition have not been clarified yet. Methods: One hundred fifty surgically resected heart valve specimens [67.4±1.0 years; aortic stenosis (AS), n=100; aortic regurgitation, n=19; mitral stenosis, n=7; mitral regurgitation, n=24] were qualitatively, semiquantitatively, and immunohistochemically analyzed and correlated with clinical data. Results: Amyloid was found in 83/150 specimens with highest prevalence in AS (74/100), intermediate prevalence in mitral stenosis (2/7) and regurgitation (7/24), and lowest prevalence in aortic regurgitation (2/19). Severe and polymorphic amyloid deposits were almost exclusively found in AS (35/100). Filamentous cloudy amyloid patterns occurred with the same frequency in AS (29/100). A combination of both was found only in AS (n=7/100). By immunohistochemistry, none of the most common amyloid proteins was identified except for a weak staining by the apolipoprotein AI antibody, but more intense adjacent to amyloid deposits. Amyloid correlated with valvular thickening (P<.05), hyperlipidemia (P=.07), coronary artery disease (P=.084), and obesity (P=.082). Conclusions: Localized valvular amyloid is predominantly found in stenotic aortic valves. It appears to depend on atheroinflammatory conditions and high shear-stress hemodynamics. Further studies are needed to identify the underlying protein. [Copyright &y& Elsevier]

Aims: The prognosis of advanced cardiac light-chain amyloidosis is poor. Heart transplantation might enable causative therapy and ultimately improve prognosis. [ABSTRACT FROM PUBLISHER]

Abstract: The mammalian thioredoxin system, comprising the selenoenzyme thioredoxin reductase (TrxR) and the 12-kDa protein thioredoxin (Trx), is implicated in thiol-mediated antioxidant defense and redox regulatory processes including transcriptional control, DNA synthesis, and apoptosis. Cell proliferation supported by the thioredoxin system can be suppressed by TrxR inhibition. In this study, we assessed the effects of the potent hTrxR inhibitors 4-mercaptopyridine (4′-chloro-2,2′:6′,2ʺ-terpyridine)platinum nitrate (I232N) and 2-mercaptopyridine (4′-chloro-2,2′:6′,2ʺ-terpyridine)platinum nitrate (I252N) on glioblastoma in a rat model. These compounds show no or little cross-resistance with cisplatin and are thus of great clinical interest. Triple intravenous application of 25–35 mg/kg of the compounds led to a significant decrease of tumor growth as determined by magnetic resonance imaging. Metabolic as well as redox parameters in the blood of the animals were not altered. However, TrxR activity was significantly decreased in the tumor tissue, and redox parameters—including glutathione concentrations, total antioxidant status, and the activities of different antioxidant enzymes—showed tissue-specific variations. As indicated by different apoptotic markers, the antitumor activity of I232N is not mediated by the induction of programmed cell death but rather by hTrxR inhibition and DNA intercalation leading to cell cycle arrest. [Copyright &y& Elsevier]

Abstract Background Spontaneous cessation of growth is a frequent finding in uterine fibroids. Increasing evidence suggests an important role of cellular senescence in this growth control. Deciphering the underlying mechanisms of growth control that can be expected not only to shed light on the biology of the tumors but also to identify novel therapeutic targets. Methods We have analyzed uterine leiomyomas and matching normal tissue for the expression of p14Arf and used explants to see if reducing the MDM2 activity using the small-molecule inhibitor nutlin-3 can induce p53 and activate genes involved in senescence and/or apoptosis. For these studies quantitative real-time RT-PCR, Western blots, and immunohistochemistry were used. Statistical analyses were performed using the student's t test. Results An in depth analysis of 52 fibroids along with matching myometrium from 31 patients revealed in almost all cases a higher expression of p14Arf in the tumors than in the matching normal tissue. In tissue explants, treatment with the MDM2 inhibitor nutlin-3 induced apoptosis as well as senescence as revealed by a dose-dependent increase of the expression of BAX as well as of p21, respectively. Simultaneously, the expression of the proliferation marker Ki-67 drastically decreased. Western-blot analysis identified an increase of the p53 level as the most likely reason for the increased activity of its downstream markers BAX and p21. Because as a rule fibroids express much higher levels of p14Arf, a major negative regulator of MDM2, than matching myometrium it was then analyzed if fibroids are more sensitive against nutlin-3 treatment than matching myometrium. We were able to show that in most fibroids analyzed a higher sensibility than that of matching myometrium was noted with a corresponding increase of the p53 immunopositivity of the fibroid samples compared to those from myometrium. Conclusions The results show that uterine fibroids represent a cell population of advanced cellular age compared to matching myometrium. Moreover, the data point to members of the p53-network as to potential novel therapeutic targets for the treatment of uterine fibroids.