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E3 ubiquitin ligases are key enzymes within the ubiquitin proteasome system which catalyze the ubiquitination of proteins, targeting them for proteasomal degradation. E3 ligases are gaining importance as targets to small molecules, both for direct inhibition and to be hijacked to induce the degradation of non-native neo-substrates using bivalent compounds known as PROTACs (for ‘proteolysis-targeting chimeras’). We describe Homo-PROTACs as an approach to dimerize an E3 ligase to trigger its suicide-type chemical knockdown inside cells. We provide proof-of-concept of Homo-PROTACs using diverse molecules composed of two instances of a ligand for the von Hippel-Lindau (VHL) E3 ligase. The most active compound, CM11, dimerizes VHL with high avidity in vitro and induces potent, rapid and proteasome-dependent self-degradation of VHL in different cell lines, in a highly isoform-selective fashion and without triggering a hypoxic response. This approach offers a novel chemical probe for selective VHL knockdown, and demonstrates the potential for a new modality of chemical intervention on E3 ligases., Targeting the ubiquitin proteasome system to modulate protein homeostasis using small molecules has promising therapeutic potential. Here the authors describe Homo-PROTACS: small molecules that can induce the homo-dimerization of E3 ubiquitin ligases and cause their proteasome-dependent degradation.

Most of the studies carried out on prisoners have considered male samples or they investigated specific psychiatric disorders. The present study aims to estimate the presence of current and lifetime psychiatric disorders among female inmates. Secondary aims are to evaluate the correlation between a current psychiatric disorder and other variables, and the association with a psycho-pharmacotherapy and a request for a clinical psychological interview. The study included 25 women with a final sentence at the “Casa Circondariale Pagliarelli” from October 2016 to July 2017. The Mini International Neuropsychiatric Interview (MINI) was used to assess the presence of any current or lifetime psychiatric disorder. Exact two-side Fisher test and independent samples Mann-U-Whitney test were used when appropriate to compare characteristics of people with and without a current or lifetime psychiatric history. Eleven inmates presented a psychiatric disorder at the time of the interview, nine of them had a history of past diagnosis. These percentages are higher than that expected in the general population but are lower than those found in previous studies on larger male samples. A major depressive disorder was predicted by a more extended period spent in prison, away from loved one people. Almost the totality of women with a current psychiatric diagnosis asked for psychological support and took medications, especially benzodiazepines alone or in combination with other drugs. The study suggests the need to determine the specific characteristics that differentiate men from women in the adaptation to the custodial regime. Keywords: female detention, prevalence, prison, psychiatric symptoms, Mediterranean Journal of Clinical Psychology, Vol 6, No 2 (2018)