Defining the genetic and molecular basis of inherited eye diseases present in Pakistan

Human Mendelian genetics aims to define the link between the phenotypical manifestations of a disease, and the identity of the gene that when mutated causes disease. Rare ocular genetic disorders are typically difficult to manage due to an incomplete understanding of their genetic causes and clinical outcomes. However, in the last few years rapid advancements in high throughput genomic sequencing techniques has paved the way for the discovery of new genes causing inherited diseases, and provided new insights into the breadth of phenotypical manifestations associated with pathogenic variants in genes already known to be linked with ocular disease. The discovery of new disease-associated genes provides important diagnostic benefits for patients, and also aids scientific understanding of how the biological processes within cells work. In turn, this drives the development of new treatments and therapies. Chapter three documents a comprehensive series of genetic studies leading to the discovery of a novel founder mutation in the CLCC1 gene, associated with an autosomal recessive form of retinitis pigmentosa in families from Pakistan, as well as the characterisation of CLCC1 in zebrafish and mouse retina. Moreover, the chapter details extensive molecular studies to discover the functional role of CLCC1 in the cells. This includes the localisation of CLCC1 within the endoplasmic reticulum, the identification of CLCC1 binding partners, and the exploration of a possible role of CLCC1 in endoplasmic reticulum stress and calcium signalling. This section also describes the generation of a CLCC1 knockout cell line using CRISPR-Cas9, to enable future more extensive studies of CLCC1 molecular function. 3 Chapter four of this thesis entails a comprehensive investigation by way of genetic studies, and literature review, of novel and known genetic variants associated with a wide range of inherited retinal dystrophies in families from Pakistani. This data provides the most comprehensive repository of information available for designing molecular diagnostic testing approaches in the region

The efficacy of transcranial current stimulation techniques to modulate resting-state EEG, to affect vigilance and to promote sleepiness

Transcranial Current Stimulations (tCSs) are non-invasive brain stimulation techniques which modulate cortical excitability and spontaneous brain activity by the application of weak electric currents through the scalp, in a safe, economic, and well-tolerated manner. The direction of the cortical effects mainly depend on the polarity and the waveform of the applied current. The aim of the present work is to provide a broad overview of recent studies in which tCS has been applied to modulate sleepiness, sleep, and vigilance, evaluating the efficacy of different stimulation techniques and protocols. In recent years, there has been renewed interest in these stimulations and their ability to affect arousal and sleep dynamics. Furthermore, we critically review works that, by means of stimulating sleep/vigilance patterns, in the sense of enhancing or disrupting them, intended to ameliorate several clinical conditions. The examined literature shows the efficacy of tCSs in modulating sleep and arousal pattern, likely acting on the top-down pathway of sleep regulation. Finally, we discuss the potential application in clinical settings of this neuromodulatory technique as a therapeutic tool for pathological conditions characterized by alterations in sleep and arousal domains and for sleep disorders per se

VirtuE: a Formal Model of Virtual Enterprises for Information Markets

A vital part of a modern economy is an information market. In this market, information products are being traded in countless ways. Information is bought, modified, integrated, incorporated into other products, and then sold again. Often, the manufacturing of an information product requires the collaboration of several participants. A virtual enterprise is a community of business entities that collaborate on the manufacturing of complex products. This collaboration is often ad hoc, for a specific product only, after which the virtual enterprise may dismantle. The virtual enterprise paradigm is particularly appealing for modeling collaborations for manufacturing information products, and in this paper we present a new model, called VirtuE, for modeling such activities. VirtuE has three principal components. First, it defines a distributed infrastructure with concepts such as members, products, inventories, and production plans. Second, it defines transactions among members, to enable collaborative production of complex products. Finally, it provides means for the instrumentation of enterprises, to measure their performance and to govern their behavior.A vital part of a modern economy is an information market. In this market, information products are being traded in countless ways. Information is bought, modified, integrated, incorporated into other products, and then sold again. Often, the manufacturing of an information product requires the collaboration of several participants. A virtual enterprise is a community of business entities that collaborate on the manufacturing of complex products. This collaboration is often ad hoc, for a specific product only, after which the virtual enterprise may dismantle. The virtual enterprise paradigm is particularly appealing for modeling collaborations for manufacturing information products, and in this paper we present a new model, called VirtuE, for modeling such activities. VirtuE has three principal components. First, it defines a distributed infrastructure with concepts such as members, products, inventories, and production plans. Second, it defines transactions among members, to enable collaborative production of complex products. Finally, it provides means for the instrumentation of enterprises, to measure their performance and to govern their behavior.Non-Refereed Working Papers / of national relevance onl

EEG oscillations during sleep and dream recall. State- or trait-like individual differences?

Dreaming represents a peculiar form of cognitive activity during sleep. On the basis of the well-known relationship between sleep and memory, there has been a growing interest in the predictive role of human brain activity during sleep on dream recall. Neuroimaging studies indicate that rapid eye movement (REM) sleep is characterized by limbic activation and prefrontal cortex deactivation. This pattern could explain the presence of emotional contents in dream reports. Furthermore, the morphoanatomical measures of amygdala and hippocampus predict some features of dream contents (bizarreness, vividness, and emotional load). More relevant for a general view of dreaming mechanisms, empirical data from neuropsychological and electroencephalographic (EEG) studies support the hypothesis that there is a sort of continuity between the neurophysiological mechanisms of encoding and retrieval of episodic memories across sleep and wakefulness. A notable overlap between the electrophysiological mechanisms underlying emotional memory formation and some peculiar EEG features of REM sleep has been suggested. In particular, theta (5–8 Hz) EEG oscillations on frontal regions in the pre-awakening sleep are predictive of dream recall, which parallels the predictive relation during wakefulness between theta activity and successful retrieval of episodic memory. Although some observations support an interpretation more in terms of an intraindividual than interindividual mechanism, the existing empirical evidence still precludes from definitely disentangling if this relation is explained by state- or trait-like differences

Evolving VirtuE

One of the most attractive aspects of virtual enterprises is their agility: the inherent ability to adapt and evolve in response to changing market conditions. Evolving VirtuE is a formal framework within which such agility can be realized. Through the concepts of enterprise time, activity logging, and log mining, the recent behavior and performance of an enterprise may be studied,and corresponding evolutionary steps can be induced. These steps may be intended to benefit the operation of individual enterprise members, as well the enterprise as a whole. In addition, we examine enterprise creation, a period of rapid evolution that concludes when the enterprise reaches stability and begins transacting its business activities.One of the most attractive aspects of virtual enterprises is their agility: the inherent ability to adapt and evolve in response to changing market conditions. Evolving VirtuE is a formal framework within which such agility can be realized. Through the concepts of enterprise time, activity logging, and log mining, the recent behavior and performance of an enterprise may be studied,and corresponding evolutionary steps can be induced. These steps may be intended to benefit the operation of individual enterprise members, as well the enterprise as a whole. In addition, we examine enterprise creation, a period of rapid evolution that concludes when the enterprise reaches stability and begins transacting its business activities.Monograph's chapter

The functional role of dreaming in emotional processes

Dream experience (DE) represents a fascinating condition linked to emotional processes and the human inner world. Although the overlap between REM sleep and dreaming has been overcome, several studies point out that emotional and perceptually vivid contents are more frequent when reported upon awakenings from this sleep stage. Actually, it is well-known that REM sleep plays a pivotal role in the processing of salient and emotional waking-life experiences, strongly contributing to the emotional memory consolidation. In this vein, we highlighted that, to some extent, neuroimaging studies showed that the processes that regulate dreaming and emotional salience in sleep mentation share similar neural substrates of those controlling emotions during wakefulness. Furthermore, the research on EEG correlates of the presence/absence of DE and the results on EEG pattern related to the incorporated memories converged to assign a crucial role of REM theta oscillations in emotional re-processing. In particular, the theta activity is involved in memory processes during REM sleep as well as during the waking state, in line with the continuity hypothesis. Also, the gamma activity seems to be related to emotional processes and dream recall as well as to lucid dreams. Interestingly, similar EEG correlates of DE have been found in clinical samples when nightmares or dreams occur. Research on clinical samples revealed that promoting the rehearsal of frightening contents aimed to change them is a promising method to treat nightmares, and that lucid dreams are associated with an attenuation of nightmares. In this view, DE can defuse emotional traumatic memories when the emotional regulation and the fear extinction mechanisms are compromised by traumatic and frightening events. Finally, dreams could represent a sort of simulation of reality, providing the possibility to create a new scenario with emotional mastery elements to cope with dysphoric items included in nightmares. In addition, it could be hypothesized that the insertion of bizarre items besides traumatic memories might be functional to “impoverish” the negative charge of the experiences

Il Business Model come punto di contatto tra Tecnologia ed Organizzazione

Con la nascita e lo sviluppo della new-economy il concetto di ``Business Model'' si è diffuso sia nella pratica di business che nella ricerca scientifica. Sebbene l'interesse nei confronti di questa tematica, segnalato dalla frequenza della ricorrenza del termine nelle pubblicazioni di carattere scientifico, sia sufficientemente sostenuta, allo stato attuale la ricerca sui Business Model soffre di un problema di frammentazione. I Business Model sono stati analizzati da differenti discipline con obiettivi e finalità diverse. Allo stato attuale manca ancora consenso unanime su una definizione condivisa di Business Model ed emerge la necessità di intensificare la ricerca empirica in questo settore. Recenti lavori di ricerca, nel tentativo di riassumere e considerare tutte le precedenti posizioni, hanno proposto l'adozione di ontologie per la derivazione di una definizione di Business Model condivisa e condivisibile. Il processo di creazione di queste ontologie mette in evidenza come tratti comuni alle esperienze di ricerca in questa area tematica, seppur provenienti da differenti settori scientifici, consistono nel rapporto tra organizzazione, tecnologia e strategia. Alla luce di questo scenario, nel presente paper, dopo una analisi della letteratura esistente sui Business Model, viene presentata l'applicazione della Business Model Ontology al progetto europeo LD- CAST con l'obiettivo di analizzare l'utilità di questo schema concettuale di riferimento, applicandolo ad un caso reale, nell'ambito di un processo di progettazione organizzativa che prende in considerazione una o più tecnologie informatiche e di comunicazione1. 1 Attività di ricerca parzialmente finanziata dal progetto europeo LD-CAST: Local Development Cooperation Action Enabled by Semantic Technology (FP6-2004-IST) -- Sito web del progetto: http://www.ldcastproject.com.Con la nascita e lo sviluppo della new-economy il concetto di ``Business Model'' si è diffuso sia nella pratica di business che nella ricerca scientifica. Sebbene l'interesse nei confronti di questa tematica, segnalato dalla frequenza della ricorrenza del termine nelle pubblicazioni di carattere scientifico, sia sufficientemente sostenuta, allo stato attuale la ricerca sui Business Model soffre di un problema di frammentazione. I Business Model sono stati analizzati da differenti discipline con obiettivi e finalità diverse. Allo stato attuale manca ancora consenso unanime su una definizione condivisa di Business Model ed emerge la necessità di intensificare la ricerca empirica in questo settore. Recenti lavori di ricerca, nel tentativo di riassumere e considerare tutte le precedenti posizioni, hanno proposto l'adozione di ontologie per la derivazione di una definizione di Business Model condivisa e condivisibile. Il processo di creazione di queste ontologie mette in evidenza come tratti comuni alle esperienze di ricerca in questa area tematica, seppur provenienti da differenti settori scientifici, consistono nel rapporto tra organizzazione, tecnologia e strategia. Alla luce di questo scenario, nel presente paper, dopo una analisi della letteratura esistente sui Business Model, viene presentata l'applicazione della Business Model Ontology al progetto europeo LD- CAST con l'obiettivo di analizzare l'utilità di questo schema concettuale di riferimento, applicandolo ad un caso reale, nell'ambito di un processo di progettazione organizzativa che prende in considerazione una o più tecnologie informatiche e di comunicazione1. 1 Attività di ricerca parzialmente finanziata dal progetto europeo LD-CAST: Local Development Cooperation Action Enabled by Semantic Technology (FP6-2004-IST) -- Sito web del progetto: http://www.ldcastproject.com.Uninvited Submission

State- or trait-like individual differences in dream recall. Preliminary findings from a within-subjects study of multiple nap REM sleep awakenings

We examined the question whether the role of EEG oscillations in predicting presence/absence of dream recall (DR) is explained by "state-" or "trait-like" factors. Six healthy subjects were awakened from REM sleep in a within-subjects design with multiple naps, until a recall and a non-recall condition were obtained. Naps were scheduled in the early afternoon and were separated by 1 week. Topographical EEG data of the 5-min of REM sleep preceding each awakening were analyzed by power spectral analysis [Fast Fourier Transform (FFT)] and by a method to detect oscillatory activity [Better OSCillations (BOSC)]. Both analyses show that REC is associated to higher frontal theta activity (5-7 Hz) and theta oscillations (6.06 Hz) compared to NREC condition, but only the second comparison reached significance. Our pilot study provides support to the notion that sleep and wakefulness share similar EEG correlates of encoding in episodic memories, and supports the "state-like hypothesis": DR may depend on the physiological state related to the sleep stage from which the subject is awakened rather than on a stable individual EEG pattern

Oscillatory EEG activity during REM sleep in elderly people predicts subsequent dream recall after awakenings

Several findings underlined that the electrophysiological (EEG) background of the last segment of sleep before awakenings may predict the presence/absence of dream recall (DR) in young subjects. However, little is known about the EEG correlates of DR in elderly people. Only an investigation found differences between recall and non-recall conditions during NREM sleep EEG in older adults, while—surprisingly—no EEG predictor of DR was found for what concerns REMsleep. Considering REMsleep as a privileged scenario to produce mental sleep activity related to cognitive processes, our study aimed to investigate whether specific EEG topography and frequency changes during REM sleep in elderly people may predict a subsequent recall of mental sleep activity. Twenty-one healthy older volunteers (mean age 69.2 ± 6.07 SD) and 20 young adults (mean age 23.4 ± 2.76 SD) were recorded for one night from19 scalp derivations. Dreams were collected upon morning awakenings from REM sleep. EEG signals of the last 5min were analyzed by the Better OSCillation algorithm to detect the peaks of oscillatory activity in both groups. Statistical comparisons revealed that older as well as young individuals recall their dream experience when the last segment of REM sleep is characterized by frontal theta oscillations. No Recall (Recall vs. Non-Recall) × Age (Young vs. Older) interaction was found. This result replicated the previous evidence in healthy young subjects, as shown in within- and between-subjects design. The findings are completely original for older individuals, demonstrating that theta oscillations are crucial for the retrieval of dreaming also in this population. Furthermore, our results did not confirm a greater presence of the theta activity in healthy aging. Conversely, we found a greater amount of rhythmic theta and alpha activity in young than older participants. It is worth noting that the theta oscillations detected are related to cognitive functioning. We emphasize the notion that the oscillatory theta activity should be distinguished from the non-rhythmic theta activity identified in relation to other phenomena such as (a) sleepiness and hypoarousal conditions during the waking state and (b) cortical slowing, considered as an EEG alteration in clinical samples

From Supply Chains to Supply Networks: the Beer Game evolution

The new trends in inter-organisation configurations are challenging the traditional concept of supply chain. Concepts such as Virtual Enterprise have been introduced to describe scenarios in which manufacturers operate as nodes in a network of suppliers, customers, engineers, and other specialised service functions Our aim is to create a simulation based on the rules of the Beer Game which includes the variables of a virtual enterprise, VirtuE in particular, and risk management, in order to understand the strategies underlying the subjects behavior in the face of risk within a means-end chain. This study shows the tests carried out on the original game, the variables that we proposed and the simulation results.The new trends in inter-organisation configurations are challenging the traditional concept of supply chain. Concepts such as Virtual Enterprise have been introduced to describe scenarios in which manufacturers operate as nodes in a network of suppliers, customers, engineers, and other specialised service functions Our aim is to create a simulation based on the rules of the Beer Game which includes the variables of a virtual enterprise, VirtuE in particular, and risk management, in order to understand the strategies underlying the subjects behavior in the face of risk within a means-end chain. This study shows the tests carried out on the original game, the variables that we proposed and the simulation results.Uninvited Submission