Stochastic semi-continuous simulation for extreme flood estimation in catchments with combined rainfall–snowmelt flood regimes

Simulation methods for extreme flood estimation represent an important complement to statistical flood frequency analysis because a spectrum of catchment conditions potentially leading to extreme flows can be assessed. In this paper, stochastic, semi-continuous simulation is used to estimate extreme floods in three catchments located in Norway, all of which are characterised by flood regimes in which snowmelt often has a significant role. The simulations are based on SCHADEX, which couples a precipitation probabilistic model with a hydrological simulation such that an exhaustive set of catchment conditions and responses is simulated. The precipitation probabilistic model is conditioned by regional weather patterns, and a bottom–up classification procedure was used to define a set of weather patterns producing extreme precipitation in Norway. SCHADEX estimates for the 1000-year (Q1000) discharge are compared with those of several standard methods, including event-based and long-term simulations which use a single extreme precipitation sequence as input to a hydrological model, statistical flood frequency analysis based on the annual maximum series, and the GRADEX method. The comparison suggests that the combination of a precipitation probabilistic model with a long-term simulation of catchment conditions, including snowmelt, produces estimates for given return periods which are more in line with those based on statistical flood frequency analysis, as compared with the standard simulation methods, in two of the catchments. In the third case, the SCHADEX method gives higher estimates than statistical flood frequency analysis and further suggests that the seasonality of the most likely Q1000 events differs from that of the annual maximum flows. The semi-continuous stochastic simulation method highlights the importance of considering the joint probability of extreme precipitation, snowmelt rates and catchment saturation states when assigning return periods to floods estimated by precipitation-runoff methods. The SCHADEX methodology, as applied here, is dependent on observed discharge data for calibration of a hydrological model, and further study to extend its application to ungauged catchments would significantly enhance its versatility

Retinitis pigmentosa: rapid neurodegeneration is governed by slow cell death mechanisms

For most neurodegenerative diseases the precise duration of an individual cell's death is unknown, which is an obstacle when counteractive measures are being considered. To address this, we used the rd1 mouse model for retinal neurodegeneration, characterized by phosphodiesterase-6 (PDE6) dysfunction and photoreceptor death triggered by high cyclic guanosinemono-phosphate (cGMP) levels. Using cellular data on cGMP accumulation, cell death, and survival, we created mathematical models to simulate the temporal development of the degeneration. We validated model predictions using organotypic retinal explant cultures derived from wild-type animals and exposed to the selective PDE6 inhibitor zaprinast. Together, photoreceptor data and modeling for the first time delineated three major cell death phases in a complex neuronal tissue: (1) initiation, taking up to 36 h, (2) execution, lasting another 40 h, and finally (3) clearance, lasting about 7 h. Surprisingly, photoreceptor neurodegeneration was noticeably slower than necrosis or apoptosis, suggesting a different mechanism of death for these neurons. Cell Death and Disease (2013) 4, e488; doi: 10.1038/cddis.2013.12; published online 7 February 201

Dissection of synaptic pathways through the CSF biomarkers for predicting Alzheimer's disease

OBJECTIVE: To assess the ability of a combination of synaptic CSF biomarkers to separate AD and non-AD disorders and to help in the differential diagnosis between neurocognitive diseases. METHODS: Retrospective cross-sectional monocentric study. All participants explored with CSF assessments for neurocognitive decline were invited to participate. After complete clinical and imaging evaluations, 243 patients were included. CSF synaptic (GAP-43, neurogranin, SNAP-25 total, SNAP-25 aa40, synaptotagmin-1) and AD biomarkers were blindly quantified using ELISA or mass spectrometry. Statistical analysis compared CSF levels between various groups AD dementias n=81, MCI-AD n=30, other MCI n=49, other dementias (OD) n=49, neurological controls n=35) as well as their discriminatory powers. RESULTS: All synaptic biomarkers were significantly increased in MCI-AD and AD -dementias patients compared to other groups. All synaptic biomarkers could efficiently discriminate AD dementias from OD (AUC ≥0.80). All but synaptotagmin were also able to discriminate MCI-AD from controls (AUC ≥0.85) and AD dementias from controls (AUC ≥0.80). Overall, CSF SNAP 25aa40 had the highest discriminative power (AUC=0.93) between AD dementias and controls or OD, and AUC=0.90 between MCI-AD and controls. Higher levels were associated with two alleles of apolipoprotein E (APOE) ε4. CONCLUSION: All synaptic biomarkers tested had a good discriminatory power to distinguish patients with AD abnormal CSF from non-AD disorders. SNAP25aa40 demonstrated the highest power to discriminate AD CSF positive patients from non-AD patients and neurological controls in this cohort. CLASSIFICATION OF EVIDENCE: This retrospective study provides Class II evidence that CSF synaptic biomarkers discriminate patients with AD from non-AD patients

Microscopic Functional Integral Theory of Quantum Fluctuations in Double-Layer Quantum Hall Ferromagnets

We present a microscopic theory of zero-temperature order parameter and pseudospin stiffness reduction due to quantum fluctuations in the ground state of double-layer quantum Hall ferromagnets. Collective excitations in this systems are properly described only when interactions in both direct and exchange particle-hole channels are included. We employ a functional integral approach which is able to account for both, and comment on its relation to diagrammatic perturbation theory. We also discuss its relation to Gaussian fluctuation approximations based on Hubbard-Stratonovich-transformation representations of interactions in ferromagnets and superconductors. We derive remarkably simple analytical expressions for the correlation energy, renormalized order parameter and renormalized pseudospin stiffness.Comment: 15 pages, 5 figure

Full-length and C-terminal neurogranin in Alzheimer's disease cerebrospinal fluid analyzed by novel ultrasensitive immunoassays

Background: Neurogranin (Ng) is a neuron-specific and postsynaptic protein that is abundantly expressed in the brain, particularly in the dendritic spine of the hippocampus and cerebral cortex. The enzymatic cleavage of Ng produces fragments that are released into cerebrospinal (CSF), which have been shown to be elevated in Alzheimer’s disease (AD) patients and predict cognitive decline. Thus, quantification of distinctive cleavage products of Ng could elucidate different features of the disease. Methods: In this study, we developed novel ultrasensitive single molecule array (Simoa) assays for measurement of full-length neurogranin (FL-Ng) and C-terminal neurogranin (CT-Ng) fragments in CSF. The Ng Simoa assays were evaluated in CSF samples from AD patients (N = 23), mild cognitive impairment due to AD (MCI-AD) (N = 18), and from neurological controls (N = 26). Results: The intra-assay repeatability and inter-assay precision of the novel methods had coefficients of variation below 7% and 14%, respectively. CSF FL-Ng and CSF CT-Ng median concentrations were increased in AD patients (6.02 ng/L, P < 0.00001 and 452 ng/L, P = 0.00001, respectively) and in patients with MCI-AD (5.69 ng/L, P < 0.00001 and 566 ng/L, P < 0.00001) compared to neurological controls (0.644 ng/L and 145 ng/L). The median CSF ratio of CT-Ng/FL-Ng were decreased in AD patients (ratio = 101, P = 0.008) and in patients with MCI-AD (ratio = 115, P = 0.016) compared to neurological controls (ratio = 180). CSF of FL-Ng, CT-Ng, and ratio of CT-Ng/FL-Ng could each significantly differentiate AD patients from controls (FL-Ng, AUC = 0.907; CT-Ng, AUC = 0.913; CT-Ng/FL-Ng, AUC = 0.775) and patients with MCI-AD from controls (FL-Ng, AUC = 0.937; CT-Ng, AUC = 0.963; CT-Ng/FL-Ng, AUC = 0.785). Conclusions: Assessments of the FL-Ng and CT-Ng levels in CSF with the novel sensitive immunoassays provide a high separation of AD from controls, even in early phase of the disease. The novel Ng assays are robust and highly sensitive and may be valuable tools to study synaptic alteration in AD, as well as to monitor the effect on synaptic integrity of novel drug candidates in clinical trials

Obsessive passion: a compensatory response to unsatisfied needs

The present research investigated the role of two sources of psychological need satisfaction (inside and outside a passionate activity) as determinants of harmonious (HP) and obsessive (OP) passion. Four studies were carried out with different samples of young and middle-aged adults (e.g., athletes, musicians; total N=648). Different research designs (cross-sectional, mixed, longitudinal) were also used. Results showed that only a rigid engagement in a passionate activity (OP) was predicted by low levels of need satisfaction outside the passionate activity (in an important life context or in life in general), whereas both OP and a more favorable and balanced type of passion, HP were positively predicted by need satisfaction inside the passionate activity. Further, OP led to negative outcomes, and HP predicted positive outcomes. These results suggest that OP may represent a form of compensatory striving for psychological need satisfaction. It appears important to consider two distinct sources of need satisfaction, inside and outside the passionate activity, when investigating determinants of optimal and less optimal forms of activity engagemen