Gene Transfer of Engineered Calmodulin Alleviates Ventricular Arrhythmias in a Calsequestrin-Associated Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a familial arrhythmogenic syndrome characterized by sudden death. There are several genetic forms of CPVT associated with mutations in genes encoding the cardiac ryanodine receptor (RyR2) and its auxiliary proteins including calsequestrin (CASQ2) and calmodulin (CaM). It has been suggested that impairment of the ability of RyR2 to stay closed (ie, refractory) during diastole may be a common mechanism for these diseases. Here, we explore the possibility of engineering CaM variants that normalize abbreviated RyR2 refractoriness for subsequent viral-mediated delivery to alleviate arrhythmias in non-CaM-related CPVT. METHODS AND RESULTS: To that end, we have designed a CaM protein (GSH-M37Q; dubbed as therapeutic CaM or T-CaM) that exhibited a slowed N-terminal Ca dissociation rate and prolonged RyR2 refractoriness in permeabilized myocytes derived from CPVT mice carrying the CASQ2 mutation R33Q. This T-CaM was introduced to the heart of R33Q mice through recombinant adeno-associated viral vector serotype 9. Eight weeks postinfection, we performed confocal microscopy to assess Ca handling and recorded surface ECGs to assess susceptibility to arrhythmias in vivo. During catecholamine stimulation with isoproterenol, T-CaM reduced isoproterenol-promoted diastolic Ca waves in isolated CPVT cardiomyocytes. Importantly, T-CaM exposure abolished ventricular tachycardia in CPVT mice challenged with catecholamines. CONCLUSIONS: Our results suggest that gene transfer of T-CaM by adeno-associated viral vector serotype 9 improves myocyte Ca handling and alleviates arrhythmias in a calsequestrin-associated CPVT model, thus supporting the potential of a CaM-based antiarrhythmic approach as a therapeutic avenue for genetically distinct forms of CPV

Computer skills and internet use in adults aged 50-74 years: influence of hearing difficulties

BACKGROUND The use of personal computers (PCs) and the Internet to provide health care information and interventions has increased substantially over the past decade. Yet the effectiveness of such an approach is highly dependent upon whether the target population has both access and the skill set required to use this technology. This is particularly relevant in the delivery of hearing health care because most people with hearing loss are over 50 years (average age for initial hearing aid fitting is 74 years). Although PC skill and Internet use by demographic factors have been examined previously, data do not currently exist that examine the effects of hearing difficulties on PC skill or Internet use in older adults. OBJECTIVE To explore the effect that hearing difficulty has on PC skill and Internet use in an opportunistic sample of adults aged 50-74 years. METHODS Postal questionnaires about hearing difficulty, PC skill, and Internet use (n=3629) were distributed to adults aged 50-74 years through three family physician practices in Nottingham, United Kingdom. A subsample of 84 respondents completed a second detailed questionnaire on confidence in using a keyboard, mouse, and track pad. Summed scores were termed the "PC confidence index." The PC confidence index was used to verify the PC skill categories in the postal questionnaire (ie, never used a computer, beginner, and competent). RESULTS The postal questionnaire response rate was 36.78% (1298/3529) and 95.15% (1235/1298) of these contained complete information. There was a significant between-category difference for PC skill by PC confidence index (P<.001), thus verifying the three-category PC skill scale. PC and Internet use was greater in the younger respondents (50-62 years) than in the older respondents (63-74 years). The younger group's PC and Internet use was 81.0% and 60.9%, respectively; the older group's PC and Internet use was 54.0% and 29.8%, respectively. Those with slight hearing difficulties in the older group had significantly greater odds of PC use compared to those with no hearing difficulties (odds ratio [OR]=1.57, 95% confidence interval [CI] 1.06-2.30, P=.02). Those with moderate+ hearing difficulties had lower odds of PC use compared with those with no hearing difficulties, both overall (OR=0.58, 95% CI 0.39-0.87, P=.008) and in the younger group (OR=0.49, 95% CI 0.26-0.86, P=.008). Similar results were demonstrated for Internet use by age group (older: OR=1.57, 95% CI 0.99-2.47, P=.05; younger: OR=0.32, 95% CI 0.16-0.62, P=.001). CONCLUSIONS Hearing health care is of particular relevance to older adults because of the prevalence of age-related hearing loss. Our data show that older adults experiencing slight hearing difficulty have increased odds of greater PC skill and Internet use than those reporting no difficulty. These findings suggest that PC and Internet delivery of hearing screening, information, and intervention is feasible for people between 50-74 years who have hearing loss, but who would not typically present to an audiologist

Explicit attention interferes with selective emotion processing in human extrastriate cortex

BACKGROUND: Brain imaging and event-related potential studies provide strong evidence that emotional stimuli guide selective attention in visual processing. A reflection of the emotional attention capture is the increased Early Posterior Negativity (EPN) for pleasant and unpleasant compared to neutral images (~150–300 ms poststimulus). The present study explored whether this early emotion discrimination reflects an automatic phenomenon or is subject to interference by competing processing demands. Thus, emotional processing was assessed while participants performed a concurrent feature-based attention task varying in processing demands. RESULTS: Participants successfully performed the primary visual attention task as revealed by behavioral performance and selected event-related potential components (Selection Negativity and P3b). Replicating previous results, emotional modulation of the EPN was observed in a task condition with low processing demands. In contrast, pleasant and unpleasant pictures failed to elicit increased EPN amplitudes compared to neutral images in more difficult explicit attention task conditions. Further analyses determined that even the processing of pleasant and unpleasant pictures high in emotional arousal is subject to interference in experimental conditions with high task demand. Taken together, performing demanding feature-based counting tasks interfered with differential emotion processing indexed by the EPN. CONCLUSION: The present findings demonstrate that taxing processing resources by a competing primary visual attention task markedly attenuated the early discrimination of emotional from neutral picture contents. Thus, these results provide further empirical support for an interference account of the emotion-attention interaction under conditions of competition. Previous studies revealed the interference of selective emotion processing when attentional resources were directed to locations of explicitly task-relevant stimuli. The present data suggest that interference of emotion processing by competing task demands is a more general phenomenon extending to the domain of feature-based attention. Furthermore, the results are inconsistent with the notion of effortlessness, i.e., early emotion discrimination despite concurrent task demands. These findings implicate to assess the presumed automatic nature of emotion processing at the level of specific aspects rather than considering automaticity as an all-or-none phenomenon

An Introductory Guide to Aligning Networks Using SANA, the Simulated Annealing Network Aligner.

Sequence alignment has had an enormous impact on our understanding of biology, evolution, and disease. The alignment of biological networks holds similar promise. Biological networks generally model interactions between biomolecules such as proteins, genes, metabolites, or mRNAs. There is strong evidence that the network topology-the "structure" of the network-is correlated with the functions performed, so that network topology can be used to help predict or understand function. However, unlike sequence comparison and alignment-which is an essentially solved problem-network comparison and alignment is an NP-complete problem for which heuristic algorithms must be used.Here we introduce SANA, the Simulated Annealing Network Aligner. SANA is one of many algorithms proposed for the arena of biological network alignment. In the context of global network alignment, SANA stands out for its speed, memory efficiency, ease-of-use, and flexibility in the arena of producing alignments between two or more networks. SANA produces better alignments in minutes on a laptop than most other algorithms can produce in hours or days of CPU time on large server-class machines. We walk the user through how to use SANA for several types of biomolecular networks

Lax pair and first integrals for two of nonlinear coupled oscillators

The system of two nonlinear coupled oscillators is studied. As partial case this system of equation is reduced to the Duffing oscillator which has many applications for describing physical processes. It is well known that the inverse scattering transform is one of the most powerful methods for solving the Cauchy problems of partial differential equations. To solve the Cauchy problem for nonlinear differential equations we can use the Lax pair corresponding to this equation. The Lax pair for ordinary differential or systems or for system ordinary differential equations allows us to find the first integrals, which also allow us to solve the question of integrability for differential equations. In this report we present the Lax pair for the system of coupled oscillators. Using the Lax pair we get two first integrals for the system of equations. The considered system of equations can be also reduced to the fourth-order ordinary differential equation and the Lax pair can be used for the ordinary differential equation of fourth order. Some special cases of the system of equations are considered.Comment: 9 page

Stable hepatitis C virus RNA detection by RT-PCR during four days storage

BACKGROUND: Suboptimal specimen processing and storage conditions of samples which contain hepatitis C virus (HCV) RNA may result in a decline of HCV RNA concentration or false-negative results in the detection of HCV RNA in serum. We evaluated the stability of HCV RNA in serum and clotted blood samples stored at room temperature or at 4°C for 4 days with the aim of optimizing the standard procedures of processing and storage of samples. METHODS: Blood from five HCV RNA positive patients was collected in tubes with and without separator gel, centrifuged 1 or 6 hours after collection. Samples were then left 6, 24, 48, 72 or 96 h at room temperature (21.5 – 25.4°C) or at 4°C before determining their HCV RNA level using the COBAS AMPLICOR HCV MONITOR Test, vs 2.0 (Roche Diagnostic Systems). RESULTS: The logarithm of the HCV RNA level measurements remained within a 0.3 value of the means for 4 days at both temperatures (room temperature or 4°C). CONCLUSIONS: We conclude that blood samples may be collected and aliquoted within 6 h of collection and can be stored at 4°C for 72 hours as proposed by the manufacturer without significant differences in measured HCV RNA level. Our results indicate that lapses in this scheme may still yield reliable results

Interior pathways of the North Atlantic meridional overturning circulation

To understand how our global climate will change in response to natural and anthropogenic forcing, it is essential to determine how quickly and by what pathways climate change signals are transported throughout the global ocean, a vast reservoir for heat and carbon dioxide. Labrador Sea Water (LSW), formed by open ocean convection in the subpolar North Atlantic, is a particularly sensitive indicator of climate change on interannual to decadal timescales. Hydrographic observations made anywhere along the western boundary of the North Atlantic reveal a core of LSW at intermediate depths advected southward within the Deep Western Boundary Current (DWBC). These observations have led to the widely held view that the DWBC is the dominant pathway for the export of LSW from its formation site in the northern North Atlantic towards the Equator. Here we show that most of the recently ventilated LSW entering the subtropics follows interior, not DWBC, pathways. The interior pathways are revealed by trajectories of subsurface RAFOS floats released during the period 2003-2005 that recorded once-daily temperature, pressure and acoustically determined position for two years, and by model-simulated 'e-floats' released in the subpolar DWBC. The evidence points to a few specific locations around the Grand Banks where LSW is most often injected into the interior. These results have implications for deep ocean ventilation and suggest that the interior subtropical gyre should not be ignored when considering the Atlantic meridional overturning circulation.Dissertatio

A Survey on Continuous Time Computations

We provide an overview of theories of continuous time computation. These theories allow us to understand both the hardness of questions related to continuous time dynamical systems and the computational power of continuous time analog models. We survey the existing models, summarizing results, and point to relevant references in the literature