Biophysical Characterization of the vOTU Proteases from the CCHF and Dugbe Nairoviruses

My research focuses on understanding the substrate specificity of the viral homolog of the ovarian tumor domain protease superfamily (vOTU) from nairoviruses, and the structural reasons for their specificities. The vOTU from the Crimean-Congo Hemorrhagic Fever Virus (CCHFV) has been implicated in the down-regulation of the innate immune response through its ability to cleave post-translational modifications via Ubiquitin (Ub) as well as the Ub-like interferon-stimulated gene 15 (ISG15). vOTU homologs have been found in numerous viruses across several families. Moreover, the effects of these viruses range in severity from mild flu-like symptoms to mortality depending on the species of the infected host. As such, several nairovirus vOTUs including those from the Dugbe Virus (DUGV), Erve Virus (ERVEV), and CCHFV were subjected to enzymological studies to gain insight into substrate specificity. These studies revealed that even vOTUs from the same viral family have differing specificities for Ub and ISG15. Furthermore, these preferences extend to include the different polymeric moieties of Ub. In order to gain insight into any structural reasoning for these substrate predilections, the X-ray crystal structures of the vOTUs from both CCHFV and DUGV were each solved covalently bound with Ub. These structures exposed unique secondary structure elements compared to other members of the OTU superfamily that offer understanding into why certain vOTUs, such as that from CCHFV, can possess robust activity for Ub and ISG15. Likewise, the crystallographic data point to the primary structure of the vOTUs as the main driving force for divergence between nairovirus vOTU specificity

Co-location as a catalyst for service innovation : a study of Scottish health and social care

Academic literature and policy on co-location of local public services focus on the cost benefits. Other benefits and outcomes of co-location, including service innovations benefiting users, are under-conceptualized. This paper suggests a framework for evaluating co-location as a learning environment for innovation, drawing on new case studies of five Community Health Partnerships in Scotland charged with more closely coordinating health and social care. We conclude that partnerships using co-location are benefiting from additional service innovations

Inhibition of Interferon Induction and Action by the Nairovirus Nairobi Sheep Disease Virus/Ganjam Virus

The Nairoviruses are an important group of tick-borne viruses that includes pathogens of man (Crimean Congo hemorrhagic fever virus) and livestock animals (Dugbe virus, Nairobi sheep disease virus (NSDV)). NSDV is found in large parts of East Africa and the Indian subcontinent (where it is known as Ganjam virus). We have investigated the ability of NSDV to antagonise the induction and actions of interferon. Both pathogenic and apathogenic isolates could actively inhibit the induction of type 1 interferon, and also blocked the signalling pathways of both type 1 and type 2 interferons. Using transient expression of viral proteins or sections of viral proteins, these activities all mapped to the ovarian tumour-like protease domain (OTU) found in the viral RNA polymerase. Virus infection, or expression of this OTU domain in transfected cells, led to a great reduction in the incorporation of ubiquitin or ISG15 protein into host cell proteins. Point mutations in the OTU that inhibited the protease activity also prevented it from antagonising interferon induction and action. Interestingly, a mutation at a peripheral site, which had little apparent effect on the ability of the OTU to inhibit ubiquitination and ISG15ylation, removed the ability of the OTU to block the induction of type 1 and the action of type 2 interferons, but had a lesser effect on the ability to block type 1 interferon action, suggesting that targets other than ubiquitin and ISG15 may be involved in the actions of the viral OTU

Play at work, learning and innovation

Suggesting a virtuous triangle constituting public service innovation of new governances, innovation and learning, the paper examines how and why a particular mode of learning occurs: that of play. Having identified an absence of research literature on play as a catalyst for new ideas in public services, the paper argues that the diversified nature of public services and disciplinary intermixing offers fertile ground for playing with new service ideas. Our conception of play avoids functional interpretations, such as Amabile or individualizing the results of play and instead draws upon Vygotsky’s social learning theory to conceptualize play as a group activity from which new ideas emerge and suggest a new framework for understanding purposive play at work and the contribution it can make to public service innovation

“An Exploration in Victorian Ideologies in 1950s and 1960s American literature“

The Victorian Era was a period in England that formally followed the reign of Queen Victoria from 1837 to 1901; however, the era is not so rigidly set. 1960s America experienced similar female oppressions. This analysis of Sylvia Plath\u27s The Bell Jar and Adrienne Rich\u27s Aunt Jennifer\u27s Tigers explores the similarities between the two eras and highlights the detrimental effects of a patriarchal culture

“An Exploration in Victorian Ideologies in 1950s and 1960s American literature“

The Victorian Era was a period in England that formally followed the reign of Queen Victoria from 1837 to 1901; however, the era is not so rigidly set. 1960s America experienced similar female oppressions. This analysis of Sylvia Plath\u27s The Bell Jar and Adrienne Rich\u27s Aunt Jennifer\u27s Tigers explores the similarities between the two eras and highlights the detrimental effects of a patriarchal culture

Trattamento con tetrabenazina in bambini con paralisi cerebrale discinetica: studio longitudinale di coorte

La tetrabenazina (TBZ) è un depletore selettivo e reversibile delle monoamine, prevalentemente dopamina, dei terminali sinaptici. La TBZ è stata approvata dalla USA FDA nel 2008 come un farmaco orfano per il trattamento dei movimenti coreiformi associati alla malattia di Huntington e al momento viene utilizzata off-label nella terapia dei disturbi del movimento. L’utilizzo della TBZ è stato studiato in una varietà di disturbi ipercinetici del movimento, ma esisite una letteratura limitata ed empirica sulla sua potenziale efficacia nei bambini ed in particolare in quelli con paralisi cerebrale infantile discinetica. L’unico trial pubblicato sull’uso della TBZ nella popolazione pediatrica è stato eseguito nel 1974 da Heggarty e Wright. Lo scopo dello studio è stato quello di valutare l’efficacia della TBZ in un campione di bambini con paralisi cerebrale discinetica utilizzando la Movement Disorders- Childhood Rating Scale 4-18 Revised (MD-CRS 4-18 R). Lo studio rappresenta il primo studio omogeneo di coorte in bambini con paralisi cerebrale discinetica seguiti per un periodo di almeno 12 mesi. Lo studio è uno studio multicentrico retrospettivo i cui partecipanti sono stati selezionati dai database di ogni Centro italiano coinvolto, in base a dettagliati criteri di inclusione. I tre Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) coinvolti sono: il Dipartimento di Neuroscienze della Fondazione Stella Maris (Pisa), l’Unità di Neurologia Pediatrica dell’Istituto “C. Besta” (Milano) e l'Unità di Neurologia Pediatrica della Fondazione del Policlinico Universitario “A. Gemelli” (Roma). I criteri di inclusione sono: 1) la presenza di diagnosi di Paralisi Cerebrale Infantile discinetica in base ai criteri europei di “Surveillance of Cerebral Palsy”; 2) una età maggiore o pari a 4 anni; 3) l’uso della TBZ in mono- o poli-terapia ed, in caso di politerapia, con raggiungimento di un dosaggio stabile dell’altro farmaco da almeno 12 mesi; 4) video delle scale MD-CRS raccolti fra Luglio 2007 e Dicembre 2019, nel mese prima di iniziare la TBZ (T0), 6 mesi (T1) e 12 mesi (T2) dopo l’inizio del trattamento e, quando a disposizione, anche un video dopo 2 anni di trattamento (LT). Lo studio è stato condotto in 23 bambini ed adolescenti (19 maschi e 4 femmine, età media 8.28 anni, SD 3,59) con paralisi cerebale infantile discinetica. La coorte ha incluso 4 soggetti con una forma clinica prevalentemente coreoatetosica e 19 con la presenza contemporanea di un pattern misto sia distonico che coreoatetosico. E’ stato usato un modello lineare misto per valutare gli effetti del farmaco nelle differenti tempistiche per ogni Indice della scala MD-CRS 4-18 R (Indice I, Indice II, Indice Globale) aggiungendo l’età ed il tipo di disturbo del movimento come Effetto Random. E’ stato osservato un significativo miglioramento clinico fra T0 e T1, seguito poi da una fase stabile. In particolare è stata rilevata una riduzione degli indici della MD-CRS 4-18 R fra T0-T1 e T0-T2. Questo studio ha dimostrato l’efficacia della TBZ in bambini con paralisi cerebrale discinetica mediante una misura di outcome standardizzata (MD CRS 4-18 R) e ha confermato l’uso della scala MD CRS 4-18 R come uno strumento adatto per rilevare cambiamenti clinici all’interno di trials clinici randomizzati. Tetrabenazine (TBZ) is a selective and reversible depletor of monoamines, preferentially dopamine, from synaptic terminals. TBZ was approved by USA FDA in 2008 as an orphan drug for the treatment of choreiform movements associated with Huntington disease and it is currently being used off-label in the MD therapy. Tetrabenazine (TBZ) has been studied with a variety of hyperkinetic movement disorders, but there is limited and empirical literature on the potential efficacy of TBZ in children with Dyskinetic Cerebral Palsy (DCP). The only published trial on the use of TBZ in paediatric population in CP subjects was performed in 1974 by Heggarty and Wright. The purpose of this study was to evaluate TBZ efficacy in a sample of children with DCP using the Movement Disorders- Childhood Rating Scale 4-18 Revised (MD CRS4-18 R). To our knowledge, this study represents the first homogeneous cohort of children with DCP followed up for a 12 months period. The study is a multicentre retrospective study in which the participants were selected from databases of each Italian Centre involved, according detailed inclusion criteria. The three Research and Clinical Scientific Institutes (IRCCS) designed are: Department of Developmental Neuroscience of Stella Maris Foundation (Pisa), Developmental Neurology Unit Institute “C. Besta” (Milano) and Paediatric Neurology Unit of Foundation Policlinic Universitario “A. Gemelli” (Rome). The inclusion criteria are the following: 1) DCP Diagnosis according to the Surveillance of Cerebral Palsy in Europe criteria; 2) Age ≥ 4 years; 3) use of Tetrabenazine (TBZ), mono- or poly-therapy and in presence of polytherapy a stable dosage of other treatment for at least 12 months must have been reached; 4) Videos of MD-CRS collected between July 2007 and December 2019, in the month before starting the TBZ (T0), and 6 (T1) and 12 (T2) months after the beginning; when available, a MD-CRS video after ≥ 2 years of treatment (LT), was also included. The study was performed on 23 children and adolescents (19 male and 4 females; mean age 8.28 years, SD 3.59) with DCP. The cohort included 4 subjects with a predominant choreoathetosis form and other 19 with a simultaneously presence of dystonic and choreoathetosic pattern. A linear mixed model was used to evaluate the effects of the different timings on each Index (Index I, Index II and Global Index) adding age and type of MD as Random Effect. A significant clinical improvement between the first timing points (T0-T1) has been observed, followed by a stable phase. In particular, a reduction of MD- CRS R Indexes was detected at T0-T1 and T0-T2. This study demonstrates the efficacy of TBZ in DCP children through a standardized outcome measure (MD CRS 4-18 R) and it confirms the use of MD CRS 4-18 R as a suitable tool to detect changes in further randomized clinical trials