Cancer-causing HPV E6 oncoproteins are characterized by the presence of a PDZ binding motif (PBM) at their extreme carboxy terminus. It was long thought that this region of E6 had a sole function to confer interaction with a defined set of cellular substrates. However, more recent studies have shown that the E6 PBM has a complex pattern of regulation, whereby phosphorylation within the PBM can regulate interaction with two classes of cellular proteins: those containing PDZ domains and the members of the 14-3-3 family of proteins. In this review, we explore the roles that the PBM and its ligands play in the virus life cycle, and subsequently how these can inadvertently contribute towards the development of malignancy. We also explore how subtle alterations in cellular signal transduction pathways might result in aberrant E6 phosphorylation, which in turn might contribute towards disease progression.

The interplay between the cytokine network and antipsychotic treatment in schizophrenia remains poorly understood. This study aimed to investigate the impact of psychotropic medications on serum levels of IFN-γ, IL-4, TGF-β1, IL-17, and BAFF, and to explore their relationship with psychopathological features. We recruited 63 patients diagnosed with schizophrenia in the acute phase, all of whom were either drug-naïve or had been drug-free for at least three months. Serum levels of IL-4, IFN-γ, TGF-β1, IL-17, and BAFF were measured at baseline and after six months of antipsychotic treatment. The severity of symptoms was assessed using the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Positive Symptoms (SAPS), and the Scale for the Assessment of Negative Symptoms (SANS). Fifty-two patients completed the six-month follow-up for immunoassay analysis. Antipsychotic treatment led to a significant decrease in serum levels of IFN-γ, TGF-β1, and IL-17, alongside a significant increase in BAFF levels. Changes in IFN-γ were positively correlated with SANS scores and negatively correlated with Global Assessment of Functioning (GAF) scores. Changes in TGF-β1 were negatively correlated with GAF scores. Changes in BAFF were negatively correlated with SAPS scores. Multivariable regression models were used to explore the association between cytokine level changes (IL-17, BAFF, IFN-γ, and TGF-β1) and independent variables, including demographic (gender, age), behavioral (tobacco use), clinical (schizophrenia type, disease course, date of onset, prior treatment), and biological (C-reactive protein (CRP), erythrocyte sedimentation rate (ESR)) factors, as well as standardized assessment scores. No significant associations were found, except for a significant negative correlation between TGF-β1 changes and GAF scores, as well as a positive correlation with age. Interestingly, advanced statistical analyses revealed that only changes in IL-17 and BAFF levels were significantly associated with antipsychotic treatment. Our findings suggest that antipsychotic drugs exert both pro- and anti-inflammatory effects on the cytokine network. The observed modulation of IL-17 and BAFF highlights their potential as future therapeutic targets in schizophrenia.

Angelman syndrome (AS) is caused by maternal chromosomal deletions, imprinting defects, paternal uniparental disomy involving chromosome 15 and the ubiquitin-protein ligase UBE3A gene mutations. However the genetic basis remains unclear for several patients. To investigate the involvement of UBE3A gene in AS and identifying new potential genes using exome sequencing. We established a cohort study in 50 patients referred to Farhat Hached University Hospital between 2006 and 2021, with a strong suspicion of AS and absence of chromosomal aberrations. The UBE3A gene was screened for mutation detection. Two unrelated patients issued from consanguineous families were subjected to exome analysis. We describe seven UBE3A variants among them 3 none previously described including intronic variants c.2220+14T>C (intron14), c.2507+43T>A (Exon15) and insertion in Exon7: c.30-47_30-46. The exome sequencing revealed 22 potential genes that could be involved in AS-like syndromes that should be investigated further. Screening for UBE3A mutations in AS patients has been proven to be useful to confirm the diagnosis. Our exome findings could rise to new potential alternative target genes for genetic counseling.