Adeno-Associated Viral Vector-Mediated Transgene Expression Is Independent of DNA Methylation in Primate Liver and Skeletal Muscle

Recombinant adeno-associated viral (rAAV) vectors can support long-term transgene expression in quiescent tissues. Intramuscular (IM) administration of a single-stranded AAV vector (ssAAV) in the nonhuman primate (NHP) results in a peak protein level at 2–3 months, followed by a decrease over several months before reaching a steady-state. To investigate transgene expression and vector genome persistence, we previously demonstrated that rAAV vector genomes associate with histones and form a chromatin structure in NHP skeletal muscle more than one year after injection. In the mammalian nucleus, chromatin remodeling via epigenetic modifications plays key role in transcriptional regulation. Among those, CpG hyper-methylation of promoters is a known hallmark of gene silencing. To assess the involvement of DNA methylation on the transgene expression, we injected NHP via the IM or the intravenous (IV) route with a recombinant ssAAV2/1 vector. The expression cassette contains the transgene under the transcriptional control of the constitutive Rous Sarcoma Virus promoter (RSVp). Total DNA isolated from NHP muscle and liver biopsies from 1 to 37 months post-injection was treated with sodium bisulfite and subsequently analyzed by pyrosequencing. No significant CpG methylation of the RSVp was found in rAAV virions or in vector DNA isolated from NHP transduced tissues. Direct de novo DNA methylation appears not to be involved in repressing transgene expression in NHP after gene transfer mediated by ssAAV vectors. The study presented here examines host/vector interactions and the impact on transgene expression in a clinically relevant model

The rehabilitation of face recognition impairments: A critical review and future directions

While much research has investigated the neural and cognitive characteristics of face recognition impairments (prosopagnosia), much less work has examined their rehabilitation. In this paper, we present a critical analysis of the studies that have attempted to improve face-processing skills in acquired and developmental prosopagnosia, and place them in the context of the wider neurorehabilitation literature. First, we examine whether neuroplasticity within the typical face-processing system varies across the lifespan, in order to examine whether timing of intervention may be crucial. Second, we examine reports of interventions in acquired prosopagnosia, where training in compensatory strategies has had some success. Third, we examine reports of interventions in developmental prosopagnosia, where compensatory training in children and remedial training in adults have both been successful. However, the gains are somewhat limited-compensatory strategies have resulted in labored recognition techniques and limited generalization to untrained faces, and remedial techniques require longer periods of training and result in limited maintenance of gains. Critically, intervention suitability and outcome in both forms of the condition likely depends on a complex interaction of factors, including prosopagnosia severity, the precise functional locus of the impairment, and individual differences such as age. Finally, we discuss future directions in the rehabilitation of prosopagnosia, and the possibility of boosting the effects of cognitive training programmes by simultaneous administration of oxytocin or non-invasive brain stimulation. We conclude that future work using more systematic methods and larger participant groups is clearly required, and in the case of developmental prosopagnosia, there is an urgent need to develop early detection and remediation tools for children, in order to optimize intervention outcome. © 2014 Bate and Bennetts

The feeling of me feeling for you: Interoception, alexithymia and empathy in autism.

Following recent evidence for a link between interoception, emotion and empathy, we investigated relationships between these factors in Autism Spectrum Disorder (ASD). 26 adults with ASD and 26 healthy participants completed tasks measuring interoception, alexithymia and empathy. ASD participants with alexithymia demonstrated lower cognitive and affective empathy than ASD participants without alexithymia. ASD participants showed reduced interoceptive sensitivity (IS), and also reduced interoceptive awareness (IA). IA was correlated with empathy and alexithymia, but IS was related to neither. Alexithymia fulfilled a mediating role between IA and empathy. Our findings are suggestive of an alexithymic subgroup in ASD, with distinct interoceptive processing abilities, and have implications for diagnosis and interventions

Association of cardiac infection with SARS-CoV-2 in confirmed COVID-19 autopsy cases

IMPORTANCE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can be documented in various tissues, but the frequency of cardiac involvement as well as possible consequences are unknown. OBJECTIVE: To evaluate the presence of SARS-CoV-2 in the myocardial tissue from autopsy cases and to document a possible cardiac response to that infection. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used data from consecutive autopsy cases from Germany between April 8 and April 18, 2020. All patients had tested positive for SARS-CoV-2 in pharyngeal swab tests. EXPOSURES: Patients who died of coronavirus disease 2019. MAIN OUTCOMES AND MEASURES: Incidence of SARS-CoV-2 positivity in cardiac tissue as well as CD3(+), CD45(+), and CD68(+) cells in the myocardium and gene expression of tumor necrosis growth factor α, interferon γ, chemokine ligand 5, as well as interleukin-6, -8, and -18. RESULTS: Cardiac tissue from 39 consecutive autopsy cases were included. The median (interquartile range) age of patients was 85 (78-89) years, and 23 (59.0%) were women. SARS-CoV-2 could be documented in 24 of 39 patients (61.5%). Viral load above 1000 copies per μg RNA could be documented in 16 of 39 patients (41.0%). A cytokine response panel consisting of 6 proinflammatory genes was increased in those 16 patients compared with 15 patients without any SARS-CoV-2 in the heart. Comparison of 15 patients without cardiac infection with 16 patients with more than 1000 copies revealed no inflammatory cell infiltrates or differences in leukocyte numbers per high power field. CONCLUSIONS AND RELEVANCE: In this analysis of autopsy cases, viral presence within the myocardium could be documented. While a response to this infection could be reported in cases with higher virus load vs no virus infection, this was not associated with an influx of inflammatory cells. Future investigations should focus on evaluating the long-term consequences of this cardiac involvement

Entwicklung neuer fluessigkristalliner Photoleiter

SIGLEAvailable from TIB Hannover: F98B1180+a / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekBundesministerium fuer Bildung, Wissenschaft, Forschung und Technologie, Bonn (Germany)DEGerman

Treating heart failure with preserved ejection fraction: learning from pulmonary fibrosis

Heart failure with preserved ejection fraction (HFpEF) has a poor prognosis, and an effective treatment is currently lacking. Increasing evidence suggests a prevailing pathogenic role of cardiac fibrosis in HFpEF, which generates the possibility of a mechanistic overlap with pulmonary fibrosis. Indeed, cardiac and pulmonary fibrosis share some characteristics and molecular pathways, such as that of transforming growth factor-\u3b2. If pulmonary and cardiac fibrosis share common pathways, we can hypothesize a beneficial effect of anti-fibrotic drugs used in idiopathic pulmonary fibrosis on cardiac outcomes. Of note, pirfenidone has been tested in animal models of cardiac fibrosis and was found to be effective in reducing ventricular remodelling. Yet, no results are hitherto available for humans. In this review article, we discuss the potential benefit of anti-fibrotic treatment in HFpEF. In particular, we propose to reappraise safety data collected in placebo-controlled trials of anti-fibrotic drugs in idiopathic pulmonary fibrosis, to explore the hypothesis that these might reduce cardiac fibrosis