Distinct Functional Connectivity Signatures of Impaired Social Cognition in Multiple Sclerosis

Objective: Multiple sclerosis (MS) is characterized by impairments in basic cognitive functions such as information processing speed as well as in more complex, higher-order domains such as social cognition. However, as these deficits often co-occur, it has remained challenging to determine whether they have a specific pathological basis or are driven by shared biology. Methods: To identify neural signatures of social cognition deficits in MS, data were analyzed from n = 29 patients with relapsing-remitting MS and n = 29 healthy controls matched for age, sex, and education. We used neuropsychological assessments of information processing speed, attention, learning, working memory, and relevant aspects of social cognition (theory of mind, emotion recognition (ER), empathy) and employed neuroimaging of CNS networks using resting-state functional connectivity. Results: MS patients showed significant deficits in verbal learning and memory, as well as implicit ER. Performance in these domains was uncorrelated. Functional connectivity analysis identified a distinct network characterized by significant associations between poorer ER and lower connectivity of the fusiform gyrus (FFG) with the right lateral occipital cortex, which also showed lower connectivity in patients compared to controls. Moreover, while ER was correlated with MS symptoms such as fatigue and motor/sensory functioning on a behavioral level, FFG connectivity signatures of social cognition deficits showed no overlap with these symptoms. Conclusions: Our analyses identify distinct functional connectivity signatures of social cognition deficits in MS, indicating that these alterations may occur independently from those in other neuropsychological functions

YB-1 relocates to the nucleus in adenovirus-infected cells and facilitates viral replication by inducing E2 gene expression through the E2 late promoter

The adenovirus early proteins E1A and E1B-55kDa are key regulators of viral DNA replication, and it was thought that targeting of p53 by E1B-55kDa is essential for this process. Here we have identified a previously unrecognized function of E1B for adenovirus replication. We found that E1B-55kDa is involved in targeting the transcription factor YB-1 to the nuclei of adenovirus type 5-infected cells where it is associated with viral inclusion bodies believed to be sites of viral transcription and replication. We show that YB-1 facilitates E2 gene expression through the E2 late promoter thus controlling E2 gene activity at later stages of infection. The role of YB-1 for adenovirus replication was demonstrated with an E1-minus adenovirus vector containing a YB-1 transgene. In infected cells, AdYB-1 efficiently replicated and produced infectious progeny particles. Thus, adenovirus E1B-55kDa protein and the host cell factor YB-1 act jointly to facilitate adenovirus replication in the late phase of infection

Career development for early career academics: Benefits of networking and the role of professional societies

Whilst effective networking is vitally important for early career academics, understanding and establishing useful networks is challenging. This paper provides an overview of the benefits and challenges of networking in the academic field, particularly for early career academics, and reflects on the role of professional societies in facilitating networkin

Multidrug-resistant cancer cells facilitate E1-independent adenoviral replication: Impact for cancer gene therapy

Resistance to chemotherapy is responsible for a failure of current treatment regimens in cancer patients. We have reported previously that the Y-box protein YB-1 regulates expression of the P-glycoprotein gene mdr1, which plays a major role in the development of a multidrug resistant-tumor phenotype. YB-1 predicts drug resistance and patient outcome in breast cancer. Thus, YB-1 is a promising target for new therapeutic approaches to defeat multidrug resistance. In drug-resistant cancer cells and in adenovirus-infected cells YB-1 is found in the nucleus. Nuclear accumulation of YB-1 in adenovirus-infected cells is a function of the El region, and we have shown that YB-1 facilitates adenovirus replication. Here we report that E1A-deleted or mutant adenovirus vectors, such as Ad312 and Ad520, replicate efficiently in multidrug-resistant (MDR) cancer cells and induce an adenovirus cytopathic effect resulting in host cell lysis. Thus, replication-defective adenoviruses are a previously unrecognized vector system for a selective elimination of MDR cancer cells. Our work forms the basis for the development of novel oncolytic adenovirus vectors for the treatment of MDR malignant diseases in the clinical setting

Adenovirus-based virotherapy enabled by cellular YB-1 expression in vitro and in vivo

This work was supported by grants from BMBF ‘Innovative Therapies of molecular Basis’ to PSH