Strategies for integrating models of interdependent subsystems of complex system-of-systems products

2006 Proceeding of the Thirty-Eighth Southeastern Symposium on System Theory© Copyright 2006 IEEEThe Office of Naval Research has established a need for improved design and analysis methods for the next generation of naval surface combatants. The Aerospace Systems Design Lab (ASDL) has initiated the Integrated Reconfigurable Intelligent Systems project to address design issues associated with the future systems. A goal of this program is to define preliminary approaches for developing an integrated modeling and simulation environment for complex systems. Since such systems are heterogeneous, dynamical and interdependent we suggest that a system-of-systems multidisciplinary approach is most appropriate for investigating and executing solutions. An integration methodology employing innovative techniques and a framework of tools that can be used to couple disparate models and simulations is presented. Methods for validating the final product to justify the selected approach and demonstrate a proof of concept for the integrated model are also discussed

An updated checklist and biogeography of the Sardinian large branchiopods, with a focus on Spinicaudata (Crustacea, Branchiopoda)

The large branchiopod fauna of Sardinia is reviewed based both on literature and newly collected data. Based on the available evidence, 13 taxa are present on the island (8 Anostraca, 2 Notostraca, and 3 Spinicaudata). Among them, the finding of the spinicaudatan Leptestheria dahalacensis is new for Sardinia, while the spinicaudatans Cyzicus bucheti and Eulimnadia sp. were overlooked in the most recent synopses on the fauna of the island due to misidentifications. Conversely, Cyzicus tetracerus and Limnadia lenticularis, previously erroneously reported based on misidentifications, must be excluded from the fauna of Sardinia. The finding of Eulimnadia sp. is the first record in Europe and the northernmost record of the genus. The occurrence of Leptestheria dahalacensis in Sardinia is rather unexpected and probably due to its accidental introduction linked with rice cultures. At least four of the 13 Sardinian large branchiopod species are absent from the Italian mainland and Sicily, stressing the uniqueness of its fauna and its significant contribution to the Mediterranean inland water crustacean diversity

Activations in temporal areas using visual and auditory naming stimuli: A language fMRI study in temporal lobe epilepsy

OBJECTIVE: Verbal fluency functional MRI (fMRI) is used for predicting language deficits after anterior temporal lobe resection (ATLR) for temporal lobe epilepsy (TLE), but primarily engages frontal lobe areas. In this observational study we investigated fMRI paradigms using visual and auditory stimuli, which predominately involve language areas resected during ATLR. METHODS: Twenty-three controls and 33 patients (20 left (LTLE), 13 right (RTLE)) were assessed using three fMRI paradigms: verbal fluency, auditory naming with a contrast of auditory reversed speech; picture naming with a contrast of scrambled pictures and blurred faces. RESULTS: Group analysis showed bilateral temporal activations for auditory naming and picture naming. Correcting for auditory and visual input (by subtracting activations resulting from auditory reversed speech and blurred pictures/scrambled faces respectively) resulted in left-lateralised activations for patients and controls, which was more pronounced for LTLE compared to RTLE patients. Individual subject activations at a threshold of T > 2.5, extent >10 voxels, showed that verbal fluency activated predominantly the left inferior frontal gyrus (IFG) in 90% of LTLE, 92% of RTLE, and 65% of controls, compared to right IFG activations in only 15% of LTLE and RTLE and 26% of controls. Middle temporal (MTG) or superior temporal gyrus (STG) activations were seen on the left in 30% of LTLE, 23% of RTLE, and 52% of controls, and on the right in 15% of LTLE, 15% of RTLE, and 35% of controls. Auditory naming activated temporal areas more frequently than did verbal fluency (LTLE: 93%/73%; RTLE: 92%/58%; controls: 82%/70% (left/right)). Controlling for auditory input resulted in predominantly left-sided temporal activations. Picture naming resulted in temporal lobe activations less frequently than did auditory naming (LTLE 65%/55%; RTLE 53%/46%; controls 52%/35% (left/right)). Controlling for visual input had left-lateralising effects. CONCLUSION: Auditory and picture naming activated temporal lobe structures, which are resected during ATLR, more frequently than did verbal fluency. Controlling for auditory and visual input resulted in more left-lateralised activations. We hypothesise that these paradigms may be more predictive of postoperative language decline than verbal fluency fMRI

The impact of SARS-CoV-2 vaccination in Dravet Syndrome: A UK survey

Background: The COVID-19 pandemic led to the urgent need for accelerated vaccine development. Approved vaccines have proved to be safe and well tolerated across millions of people in the general population. Dravet Syndrome (DS) is a severe, early onset, developmental and epileptic encephalopathy. Vaccination is a precipitating factor for seizures. Whilst there is no evidence that vaccine-precipitated seizures lead to adverse outcomes in people with DS, fear surrounding vaccination can remain for caregivers of people with DS, in some cases resulting in rejection of recommended vaccinations, leaving individuals more vulnerable to the relevant infections. A greater understanding of the safety profile of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in this vulnerable group will help provide guidance for caregivers and clinicians when considering vaccination. / Methods: A cross‐sectional survey regarding COVID-19 and SARS-CoV-2 vaccine, in people with DS, was conducted by Dravet Syndrome UK (DSUK). Concomitantly, a review of individuals with DS who had recently received the SARS-CoV-2 vaccine, and who are resident at the Chalfont Centre for Epilepsy (CCE), or attend epilepsy clinics at the National Hospital for Neurology and Neurosurgery (NHNN), was undertaken. / Results: 38 people completed the DSUK survey. 37% of caregivers reported being concerned about someone with DS receiving the SARS-CoV-2 vaccine; with some reporting that they would decline a vaccine when offered. 77% had not received any advice from a health care professional about the SARS-CoV-2 vaccination. 18/38 were eligible for SARS-CoV-2 vaccination, of whom nine had received their first vaccine dose. Combining the results of the DSUK survey and the review of individuals monitored at CCE or NHNN, fifteen people with DS had received their first dose of the SARS-CoV-2 vaccine. 11/15 (73%) reported at least one side effect, the most common being fatigue (6/15; 40%) and fever (6/15; 40%). Three individuals (20%) reported an increase in seizure frequency after the first vaccine dose. No increase in seizure frequency or duration was reported after the second dose. / Conclusion: Overall, these results suggest that SARS-CoV-2 vaccines are safe and well tolerated in individuals with DS, as they are in most people without DS. In most people with DS, SARS-CoV-2 vaccine does not appear to be associated with an increase in the frequency or duration of seizures, even in those who develop fever post-vaccination. Many caregivers are concerned about a person with DS receiving a SARS-CoV-2 vaccine, with some reporting that they would decline a SARS-CoV-2 vaccine when offered. It is crucial that healthcare professionals are proactive in providing accurate information regarding the risks and benefits of vaccination in this population, given the potential for serious outcomes from infection

Decreased MCM2-6 in Drosophila S2 cells does not generate significant DNA damage or cause a marked increase in sensitivity to replication interference.

A reduction in the level of some MCM proteins in human cancer cells (MCM5 in U20S cells or MCM3 in Hela cells) causes a rapid increase in the level of DNA damage under normal conditions of cell proliferation and a loss of viability when the cells are subjected to replication interference. Here we show that Drosophila S2 cells do not appear to show the same degree of sensitivity to MCM2-6 reduction. Under normal cell growth conditions a reduction of >95% in the levels of MCM3, 5, and 6 causes no significant short term alteration in the parameters of DNA replication or increase in DNA damage. MCM depleted cells challenged with HU do show a decrease in the density of replication forks compared to cells with normal levels of MCM proteins, but this produces no consistent change in the levels of DNA damage observed. In contrast a comparable reduction of MCM7 levels has marked effects on viability, replication parameters and DNA damage in the absence of HU treatment

Lipid profile with eslicarbazepine acetate and carbamazepine monotherapy in adult patients with newly diagnosed focal seizures: post hoc analysis of a phase III trial and open-label extension study

BACKGROUND: Antiseizure medications can have negative effects on plasma lipid levels. OBJECTIVES: To evaluate plasma lipid changes in patients with newly diagnosed focal epilepsy treated with eslicarbazepine acetate (ESL) or controlled-release carbamazepine (CBZ-CR) monotherapy during a phase III, randomized, double-blind (DB) trial and 2 years of ESL treatment in an open-label extension (OLE). DESIGN: Post hoc analysis of a phase III trial and OLE study. METHODS": Proportions of patients with elevated levels of total cholesterol and low-density lipoprotein (LDL) cholesterol were assessed at DB baseline, OLE baseline (last visit of DB trial), and end of OLE. RESULTS: A total of 184 patients received ESL monotherapy during the OLE: 96 received ESL monotherapy in the DB trial and 88 patients received CBZ-CR monotherapy. The proportions of patients with elevated total cholesterol and LDL cholesterol increased significantly during the DB trial in those treated with CBZ-CR monotherapy [total cholesterol, +14.9% (p < 0.001); LDL cholesterol, +11.5% (p = 0.012)] but decreased significantly after switching to ESL monotherapy in the OLE [total cholesterol, −15.3% (p = 0.008); LDL cholesterol, −11.1% (p = 0.021)]. No significant changes were observed in those treated with ESL monotherapy during the DB trial and OLE. At the end of the DB trial, between-group differences (ESL–CBZ-CR) in the proportions of patients with elevated total and LDL cholesterol were −13.6% (p = 0.037) and −12.3% (p = 0.061), respectively; at the end of the OLE, these between-group differences were −6.0% (p = 0.360) and −0.6% (p = 1.000), respectively. CONCLUSION:A lower proportion of patients with newly diagnosed focal epilepsy had increased levels of total and LDL cholesterol, compared to baseline, following monotherapy with ESL versus CBZ-CR; after switching from CBZ-CR to ESL, the proportions of patients with increased levels decreased significantly. REGISTRATION: ClinicalTrials.gov NCT01162460/NCT02484001; EudraCT 2009-011135-13/2015-001243-36

Imaging language pathways predicts postoperative naming deficits

Naming difficulties are a well recognised, but difficult to predict, complication of anterior temporal lobe resection (ATLR) for refractory epilepsy. We used MR tractography preoperatively to demonstrate the structural connectivity of language areas in patients undergoing dominant hemisphere ATLR. Greater lateralisation of tracts to the dominant hemisphere was associated with greater decline in naming function. We suggest that this method has the potential to predict language deficits in patients undergoing ATLR

Fission yeast 26S proteasome mutants are multi-drug resistant due to stabilization of the pap1 transcription factor

Here we report the result of a genetic screen for mutants resistant to the microtubule poison methyl benzimidazol-2-yl carbamate (MBC) that were also temperature sensitive for growth. In total the isolated mutants were distributed in ten complementation groups. Cloning experiments revealed that most of the mutants were in essential genes encoding various 26S proteasome subunits. We found that the proteasome mutants are multi-drug resistant due to stabilization of the stress-activated transcription factor Pap1. We show that the ubiquitylation and ultimately the degradation of Pap1 depend on the Rhp6/Ubc2 E2 ubiquitin conjugating enzyme and the Ubr1 E3 ubiquitin-protein ligase. Accordingly, mutants lacking Rhp6 or Ubr1 display drug-resistant phenotypes

Defining Meyer's loop-temporal lobe resections, visual field deficits and diffusion tensor tractography

Anterior temporal lobe resection is often complicated by superior quadrantic visual field deficits (VFDs). In some cases this can be severe enough to prohibit driving, even if a patient is free of seizures. These deficits are caused by damage to Meyer's loop of the optic radiation, which shows considerable heterogeneity in its anterior extent. This structure cannot be distinguished using clinical magnetic resonance imaging sequences. Diffusion tensor tractography is an advanced magnetic resonance imaging technique that enables the parcellation of white matter. Using seed voxels antero-lateral to the lateral geniculate nucleus, we applied this technique to 20 control subjects, and 21 postoperative patients. All patients had visual fields assessed with Goldmann perimetry at least three months after surgery. We measured the distance from the tip of Meyer's loop to the temporal pole and horn in all subjects. In addition, we measured the size of temporal lobe resection using postoperative T1-weighted images, and quantified VFDs. Nine patients suffered VFDs ranging from 22% to 87% of the contralateral superior quadrant. In patients, the range of distance from the tip of Meyer's loop to the temporal pole was 24–43 mm (mean 34 mm), and the range of distance from the tip of Meyer's loop to the temporal horn was –15 to +9 mm (mean 0 mm). In controls the range of distance from the tip of Meyer's loop to the temporal pole was 24–47 mm (mean 35 mm), and the range of distance from the tip of Meyer's loop to the temporal horn was –11 to +9 mm (mean 0 mm). Both quantitative and qualitative results were in accord with recent dissections of cadaveric brains, and analysis of postoperative VFDs and resection volumes. By applying a linear regression analysis we showed that both distance from the tip of Meyer's loop to the temporal pole and the size of resection were significant predictors of the postoperative VFDs. We conclude that there is considerable variation in the anterior extent of Meyer's loop. In view of this, diffusion tensor tractography of the optic radiation is a potentially useful method to assess an individual patient's risk of postoperative VFDs following anterior temporal lobe resection

Motor system hyperconnectivity in juvenile myoclonic epilepsy: a cognitive functional magnetic resonance imaging study

Juvenile myoclonic epilepsy is the most frequent idiopathic generalized epilepsy syndrome. It is characterized by predominant myoclonic jerks of upper limbs, often provoked by cognitive activities, and typically responsive to treatment with sodium valproate. Neurophysiological, neuropsychological and imaging studies in juvenile myoclonic epilepsy have consistently pointed towards subtle abnormalities in the medial frontal lobes. Using functional magnetic resonance imaging with an executive frontal lobe paradigm, we investigated cortical activation patterns and interaction between cortical regions in 30 patients with juvenile myoclonic epilepsy and 26 healthy controls. With increasing cognitive demand, patients showed increasing coactivation of the primary motor cortex and supplementary motor area. This effect was stronger in patients still suffering from seizures, and was not seen in healthy controls. Patients with juvenile myoclonic epilepsy showed increased functional connectivity between the motor system and frontoparietal cognitive networks. Furthermore, we found impaired deactivation of the default mode network during cognitive tasks with persistent activation in medial frontal and central regions in patients. Coactivation in the motor cortex and supplementary motor area with increasing cognitive load and increased functional coupling between the motor system and cognitive networks provide an explanation how cognitive effort can cause myoclonic jerks in juvenile myoclonic epilepsy. The supplementary motor area represents the anatomical link between these two functional systems, and our findings may be the functional correlate of previously described structural abnormalities in the medial frontal lobe in juvenile myoclonic epilepsy