Intrinsic host restriction factors of human cytomegalovirus replication and mechanisms of viral escape

Before a pathogen even enters a cell, intrinsic immune defenses are active. This first-line defense is mediated by a variety of constitutively expressed cell proteins collectively termed "restriction factors"(RFs), and they form a vital element of the immune response to virus infections. Over time, however, viruses have evolved in a variety ways so that they are able to overcome these RF defenses via mechanisms that are specific for each virus. This review provides a summary of the universal characteristics of RFs, and goes on to focus on the strategies employed by some of the most important RFs in their attempt to control human cytomegalovirus(HCMV) infection. This is followed by a discussion of the counter-restriction mechanisms evolved by viruses to circumvent the host cell's intrinsic immune defenses. RFs include nuclear proteins IFN-γ inducible protein 16(IFI16)(a Pyrin/HIN domain protein), Sp100, promyelocytic leukemia, and h Daxx; the latter three being the keys elements of nuclear domain 10(ND10). IFI16 inhibits the synthesis of virus DNA by downregulating UL54 transcription- a gene encoding a CMV DNA polymerase; in response, the virus antagonizes IFI16 via a process involving viral proteins UL97 and pp65(p UL83), which results in the mislocalizing of IFI16 into the cytoplasm. In contrast, viral regulatory proteins, including pp71 and IE1, seek to modify or disrupt the ND10 proteins and thus block or reverse their inhibitory effects upon virus replication. All in all, detailed knowledge of these HCMV counter-restriction mechanisms will be fundamental for the future development of new strategies for combating HCMV infection and for identifying novel therapeutic agents.

Three-dimensional automatic artificial intelligence driven augmented-reality selective biopsy during nerve-sparing robot-assisted radical prostatectomy:A feasibility and accuracy study

Objective:To evaluate the accuracy of our new three-dimensional(3D)automatic augmented reality(AAR)system guided by artificial intelligence in the identification of tumour’s location at the level of the preserved neurovascular bundle(NVB)at the end of the extirpative phase of nerve-sparing robot-assisted radical prostatectomy.Methods:In this prospective study,we enrolled patients with prostate cancer(clinical stages cT1ce3,cN0,and cM0)with a positive index lesion at target biopsy,suspicious for capsular contact or extracapsular extension at preoperative multiparametric magnetic resonance imaging.Patients underwent robot-assisted radical prostatectomy at San Luigi Gonzaga Hospital(Orbassano,Turin,Italy),from December 2020 to December 2021.At the end of extirpative phase,thanks to our new AAR artificial intelligence driven system,the virtual prostate 3D model allowed to identify the tumour’s location at the level of the preserved NVB and to perform a selective excisional biopsy,sparing the remaining portion of the bundle.Perioperative and postoperative data were evaluated,especially focusing on the positive surgical margin(PSM)rates,potency,continence recovery,and biochemical recurrence.Results:Thirty-four patients were enrolled.In 15(44.1%)cases,the target lesion was in contact with the prostatic capsule at multiparametric magnetic resonance imaging(Wheeler grade L2)while in 19(55.9%)cases extracapsular extension was detected(Wheeler grade L3).3D AAR guided biopsies were negative in all pathological tumour stage 2(pT2)patients while they revealed the presence of cancer in 14 cases in the pT3 cohort(14/16;87.5%).PSM rates were 0%and 7.1%in the pathological stages pT2 and pT3(<3 mm,Gleason score 3),respectively.Conclusion:With the proposed 3D AAR system,it is possible to correctly identify the lesion’s location on the NVB in 87.5%of pT3 patients and perform a 3D-guided tailored nerve-sparing even in locally advanced diseases,without compromising the oncological safety in terms of PSM rates.

The Doppelgänger phenomenon and death:a peculiar case of homicide by a subject with first-episode psychosis

The Doppelgänger phenomenon refers to the experience of a direct encounter with one’s self,characteriswed by:(i)the perception of a figure with one’s own identical physical features;or(ii)the apprehension that the perceived figure shares the same personality and identity.The Doppelgänger does not only look like the same person,it is his/her double.The perceptual element is usually a hallucination,although occasionally a false perception of an actual figure may be involved.This phenomenon has been described in individuals suffering from overwhelming fear,severe anxiety or intoxication,epilepsy,as well as in the sleep-wakefulness transition.It has also been reported in major psychoses.The fear of imminent death often precedes the Doppelgänger experience.This report presents the case of a 30-year-old man,Mr.Y,who was stabbed to death by Mr.X,his“double”.The aggressor and his victim,although not related,were truly doubles;remarkably,they shared the same name and surname,age,professional activity and place of work.Moreover,they attended the same sports center but barely knew each other.The forensic psychiatric evaluations in Mr.X,subsequent to the crime committed,were suggestive of a psychotic condition.This case is unique in the scientific literature.In the most serious psychotic forms,the issue of the“double”calls into question not only the dissociative processes involved in the etiopathogenesis of the disorder,but also bio-psycho-social elements,as well as personal data in this case,which made the victim and the aggressor“identical”.In the context of psychopathological functioning,the delusional mood(Wahnstimmung)that precedes the development of delirium is a sort of gateway to an impending psychotic illness,involving delusional awareness or mood(atmosphere).In psychosis,splitting is the main issue and this influence is seen as an evil,foreign,apocalyptic and unknown side no longer recognised as belonging to the self even in a physical sense.In such a situation,it is felt that the only way to survive is by suppressing one’s double as a defense against disorganisation of the self.