Inherited Cardiomyopathies: From Genotype to Phenotype

The heart undergoes extensive morphological, metabolic, and energetic remodeling in response to inherited, or familial, hypertrophic cardiomyopathies (FHC). Myocyte contractile perturbations downstream of Ca2+, the so-called sarcomere-controlled mechanisms, may represent the earliest indicators of this remodeling. We can now state that the dynamics of cardiac contraction and relaxation during the progression of FHC are governed by downstream mechanisms, particularly the kinetics and energetics of actin and myosin interaction to drive the trajectory of pathological cardiac remodeling. This notion is unambiguously supported by elegant studies above linking inheritable FHC-causing mutations to cardiomyopathies, known to disturb contractile function and alter the energy landscape of the heart. Although studies examining the biophysical properties of cardiac myocytes with FHC-causing mutations have yielded a cellular and molecular understanding of myofilament function, this knowledge has had limited translational success. This is driven by a critical failure in elucidating an integrated and sequential link among the changing energy landscape, myofilament function, and initiated signaling pathways in response to FHC. Similarly, there continues to be a major gap in understanding the cellular and molecular mechanisms contributing to sex differences in FHC development and progression. The primary reason for this gap is a lack of a “unifying” or “central” hypothesis that integrates signaling cascades, energetics, sex and FHC

Multimedia Office System Interface Design using a UIMS

held in Lintz, AustriaInternational audienceno abstrac

Iterative Design of User Interfaces for an Office System using a UIMS

held in Athens, GreeceInternational audienceThe design of the user interface for an office application using a UIMS is described. In particular we report on the iterative development and improvement of the user interface of MUSE, a multimedia document filing system, using ACHILLES, a UIMS designed to produce interfaces for office applications

Fluid type influences acute hydration and muscle performance recovery in human subjects

Abstract Background Exercise and heat trigger dehydration and an increase in extracellular fluid osmolality, leading to deficits in exercise performance and thermoregulation. Evidence from previous studies supports the potential for deep-ocean mineral water to improve recovery of exercise performance post-exercise. We therefore wished to determine whether acute rehydration and muscle strength recovery was enhanced by deep-ocean mineral water following a dehydrating exercise, compared to a sports drink or mountain spring water. We hypothesized that muscle strength would decrease as a result of dehydrating exercise, and that recovery of muscle strength and hydration would depend on the type of rehydrating fluid. Methods Using a counterbalanced, crossover study design, female (n = 8) and male (n = 9) participants performed a dehydrating exercise protocol under heat stress until achieving 3% body mass loss. Participants rehydrated with either deep-ocean mineral water (Deep), mountain spring water (Spring), or a carbohydrate-based sports drink (Sports) at a volume equal to the volume of fluid loss. We measured relative hydration using salivary osmolality (Sosm) and muscle strength using peak torque from a leg extension maneuver. Results Sosm significantly increased (p < 0.0001) with loss of body mass during the dehydrating exercise protocol. Males took less time (90.0 ± 18.3 min; P < 0.0034) to reach 3% body mass loss when compared to females (127.1 ± 20.0 min). We used a mono-exponential model to fit the return of Sosm to baseline values during the rehydrating phase. Whether fitting stimulated or unstimulated Sosm, male and female participants receiving Deep as the hydrating fluid exhibited the most rapid return to baseline Sosm (p < 0.0001) regardless of the fit parameter. Males compared to females generated more peak torque (p = 0.0005) at baseline (308.3 ± 56.7 Nm vs 172.8 ± 40.8 Nm, respectively) and immediately following 3% body mass loss (276.3 ± 39.5 Nm vs 153.5 ± 35.9 Nm). Participants experienced a loss. We also identified a significant effect of rehydrating fluid and sex on post-rehydration peak torque (p < 0.0117). Conclusion We conclude that deep-ocean mineral water positively affected hydration recovery after dehydrating exercise, and that it may also be beneficial for muscle strength recovery, although this, as well as the influence of sex, needs to be further examined by future research. Trial registration clincialtrials.gov PRS, NCT02486224. Registered 08 June 2015

CARARE - D4.1: Live harvesting system for CARARE (Final)

The goal of the project is to harvest content regarding archaeology and architecture (mostly monuments) from a number of content providers, and deliver it to Europeana. The technical architecture has been implemented and supported by the two technical partners of the project: National Technical University of Athens (NTUA) and Digital Curation Unit of the Athena Research Centre (DCU). This deliverable describes in detail the live harvesting system for the CARARE project, which allows content providers to provide their content to the CARARE system using a methodology which will allow for regular automated harvests. There are two main components: a) The CARARE metadata mapping and ingestion system and b) The CARARE repository. Section 3 summarises the main components of the aggregation service. Section 4 summarises the CARARE metadata mapping and ingestion system which was described in full in earlier deliverables (D2.3 and D3.4). The systems went live in April 2011 following testing. Section 5 describes the CARARE repository and the functionality that it offers to CARARE content providers to search for and manage their content, and the OAI-PMH delivery services provided to supply metadata to Europeana. Content ingestion began in April 2011 when the system went live following testing. Section 6 confirms the metadata formats that CARARE will deliver to Europeana. This report presents the CARARE harvesting system and its two main components, the metadata mapping and ingestion tool and the repository service, which both went live during April 2011 to coincide with the delivery of a series of training workshops for content providers. The harvesting of content via the mapping tool to the CARARE repository has now begun

CARARE - D3.1 Tested harvesting and ingestion system (Final)

The goal of the project is to harvest content regarding archaeology and architecture (mostly monuments) from a number of content providers, and deliver it to Europeana. The technical architecture is being implemented and supported by the two technical partners of the project: National Technical University of Athens (NTUA) and Digital Curation Unit of the Athena Research Centre (DCU). The architecture specifies a three stage process, described below. This deliverable describes in detail the testing of the CARARE harvesting and ingestion system. This system is comprised of two main components: a) the mapping tool (NTUA) and b) the CARARE repository (DCU). The first component allows the content providers to upload their metadata (or for it to be harvested by the tool) and map them to the CARARE metadata schema. The metadata is then transformed; the submission packages are created and are streamed to the repository. The points of focus in this deliverable are the following: The harvesting of the content providers’ metadata into the mapping tool The mapping to the CARARE schema The creation of the submission packages and their ingestion to the repositor

Using 4-vinylcyclohexene diepoxide as a model of menopause for cardiovascular disease

There is a sharp rise in cardiovascular disease (CVD) risk and progression with the onset of menopause. The 4-vinylcyclohexene diepoxide (VCD) model of menopause recapitulates the natural, physiological transition through perimenopause to menopause. We hypothesized that menopausal female mice were more susceptible to CVD than pre- or perimenopausal females. Female mice were treated with VCD or vehicle for 20 consecutive days. Premenopausal, perimenopausal, and menopausal mice were administered angiotensin II (ANG II) or subjected to ischemia-reperfusion (I/R). Menopausal females were more susceptible to pathological ANG II-induced cardiac remodeling and cardiac injury from a myocardial infarction (MI), while perimenopausal, like premenopausal, females remained protected. Specifically, ANG II significantly elevated diastolic (130.9 ± 6.0 vs. 114.7 ± 6.2 mmHg) and systolic (156.9 ± 4.8 vs. 141.7 ± 5.0 mmHg) blood pressure and normalized cardiac mass (15.9 ± 1.0 vs. 7.7 ± 1.5%) to a greater extent in menopausal females compared with controls, whereas perimenopausal females demonstrated a similar elevation of diastolic (93.7 ± 2.9 vs. 100.5 ± 4.1 mmHg) and systolic (155.9 ± 7.3 vs. 152.3 ± 6.5 mmHg) blood pressure and normalized cardiac mass (8.3 ± 2.1 vs. 7.5 ± 1.4%) compared with controls. Similarly, menopausal females demonstrated a threefold increase in fibrosis measured by Picrosirus red staining. Finally, hearts of menopausal females (41 ± 5%) showed larger infarct sizes following I/R injury than perimenopausal (18.0 ± 5.6%) and premenopausal (16.2 ± 3.3, 20.1 ± 4.8%) groups. Using the VCD model of menopause, we provide evidence that menopausal females were more susceptible to pathological cardiac remodeling. We suggest that the VCD model of menopause may be critical to better elucidate cellular and molecular mechanisms underlying the transition to CVD susceptibility in menopausal women.NEW & NOTEWORTHY Before menopause, women are protected against cardiovascular disease (CVD) compared with age-matched men; this protection is gradually lost after menopause. We present the first evidence that demonstrates menopausal females are more susceptible to pathological cardiac remodeling while perimenopausal and cycling females are not. The VCD model permits appropriate examination of how increased susceptibility to the pathological process of cardiac remodeling accelerates from pre- to perimenopause to menopause.12 month embargo; published online: 28 May 2020This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Impact of APOE on amyloid and tau accumulation in argyrophilic grain disease and Alzheimer’s disease

Abstract Alzheimer’s disease (AD), characterized by the deposition of amyloid-β (Aβ) in senile plaques and neurofibrillary tangles of phosphorylated tau (pTau), is increasingly recognized as a complex disease with multiple pathologies. AD sometimes pathologically overlaps with age-related tauopathies such as four repeat (4R)-tau predominant argyrophilic grain disease (AGD). While AGD is often detected with AD pathology, the contribution of APOE4 to AGD risk is not clear despite its robust effects on AD pathogenesis. Specifically, how APOE genotype influences Aβ and tau pathology in co-occurring AGD and AD has not been fully understood. Using postmortem brain samples (N = 353) from a neuropathologically defined cohort comprising of cases with AD and/or AGD pathology built to best represent different APOE genotypes, we measured the amounts of major AD-related molecules, including Aβ40, Aβ42, apolipoprotein E (apoE), total tau (tTau), and pTau181, in the temporal cortex. The presence of tau lesions characteristic of AD (AD-tau) was correlated with cognitive decline based on Mini-Mental State Examination (MMSE) scores, while the presence of AGD tau lesions (AGD-tau) was not. Interestingly, while APOE4 increased the risk of AD-tau pathology, it did not increase the risk of AGD-tau pathology. Although APOE4 was significantly associated with higher levels of insoluble Aβ40, Aβ42, apoE, and pTau181, the APOE4 effect was no longer detected in the presence of AGD-tau. We also found that co-occurrence of AGD with AD was associated with lower insoluble Aβ42 and pTau181 levels. Overall, our findings suggest that different patterns of Aβ, tau, and apoE accumulation mediate the development of AD-tau and AGD-tau pathology, which is affected by APOE genotype