Highlights • Physiological concentrations of Aβ are needed for synaptic function. • Alzheimer’s disease might be due to a dysregulation of Aβ physiological homeostasis. • The increase of Aβ might be ...due to an alteration of the feedback loop between Aβ and α7-nAchRs. • Amyloid Cascade Hypothesis should be revisited.
•A method for characterising system uncertainty in the modal space of linear systems.•It reduces the number of uncertain parameters and the size of the dynamic problem.•Model parameters can be ...calibrated based on information from the geometrical space.•A high-order perturbation technique for the multi-fidelity response quantification.•Demonstrated on the dynamic analysis of a multi-storey steel frame and a bridge.
A novel method for characterising and propagating system uncertainty in structures subjected to dynamic actions is proposed, whereby modal shapes, frequencies and damping ratios constitute the random quantities. The latter, defined in the modal subspace rather than the full geometrical space, reduce the number of the random variables and the size of the dynamic problem. A numerical procedure is presented for their identification by calibrating their probabilistic definition in line with the geometrical space. A high-order perturbation technique is proposed for the multi-fidelity response quantification by means of an ad hoc extension of the conventional perturbation method. The approach involves a set of auxiliary deterministic differential equations to be adaptively solved with the piecewise exact method, and moment-cumulant relationships are employed to approximate high-order moments. Finally, a polynomial chaos expansion approach is adopted to complement the second-moment analysis for spectral quantification with the modal subspace reduction. Demonstrated on a multi-storey steel frame with semi-rigid connections and a simply supported bridge subjected to a moving load, the proposed variants exhibit improved performance with respect to the conventional second-order and improved perturbation, as well as increased flexibility, enabling the analyst to decide, on-demand, the level of fidelity, balancing accuracy and computational effort.
Multiple Tuned Mass Dampers (MTMD) is one of the simplest and most reliable solution to control the vibrations of a structure, e.g. allowing to deal with a wide distribution of structural natural ...frequencies and usually showing inherent stability. Nevertheless, uncertainties in the behavior of structures under random dynamic input may induce implications on the MTMD effectiveness, e.g. detuning or amplifications. Typically, uncertainties in the input are exclusively considered, while uncertainties affect as much also the mechanical parameters.
This paper proposes a robust optimum design of the MTMD, considering uncertainties both in the structural parameters and in the earthquake input. At this aim, a random vibration analysis of the response is adopted, and a direct linear perturbation method is applied on the uncertain parameters. Results show that a deterministic optimization is inappropriate for sensible systems as TMDs, while a robust optimization aims to better control the response with low computational efforts. Furthermore, the selection of the objective functions significantly affects the optimal design parameters, as the number of TMDs influences the robust designs.
Non-fibrillar soluble oligomeric forms of amyloid-β peptide (oAβ) and tau proteins are likely to play a major role in Alzheimer's disease (AD). The prevailing hypothesis on the disease ...etiopathogenesis is that oAβ initiates tau pathology that slowly spreads throughout the medial temporal cortex and neocortices independently of Aβ, eventually leading to memory loss. Here we show that a brief exposure to extracellular recombinant human tau oligomers (oTau), but not monomers, produces an impairment of long-term potentiation (LTP) and memory, independent of the presence of high oAβ levels. The impairment is immediate as it raises as soon as 20 min after exposure to the oligomers. These effects are reproduced either by oTau extracted from AD human specimens, or naturally produced in mice overexpressing human tau. Finally, we found that oTau could also act in combination with oAβ to produce these effects, as sub-toxic doses of the two peptides combined lead to LTP and memory impairment. These findings provide a novel view of the effects of tau and Aβ on memory loss, offering new therapeutic opportunities in the therapy of AD and other neurodegenerative diseases associated with Aβ and tau pathology.
The second messengers cGMP and cAMP have a vital role in synaptic plasticity and memory processes. As such, phosphodiesterases inhibitors (PDE-Is), which prevent the breakdown of these cyclic ...nucleotides, represent a potential treatment strategy in memory decline. Recently it has been demonstrated that cGMP and cAMP signaling act in sequence during memory consolidation, with early cGMP signaling requiring subsequent cAMP signaling. Here, we sought to confirm this relationship, and to evaluate its therapeutic implications. Combining sub-efficacious doses of the cGMP-specific PDE type 5 inhibitor vardenafil (0.1 mg/kg) and cAMP-specific PDE type 4 inhibitor rolipram (0.01 mg/kg) during the early and late memory consolidation phase, respectively, led to improved memory performance in a 24 h interval object recognition task. Similarly, such a sub-efficacious combination treatment enhanced the transition of early-phase long-term potentiation (LTP) to late-phase LTP in hippocampal slices. In addition, both object memory and LTP were improved after administration of two sub-efficacious doses of the dual substrate PDE type 2 inhibitor BAY60 7550 (0.3 mg/kg) at the early and late consolidation phase, respectively. Taken together, combinations of sub-efficacious doses of cAMP- and cGMP-specific PDE-Is have an additive effect on long-term synaptic plasticity and memory formation and might prove a superior alternative to single PDE-I treatment.
•cGMP and cAMP act in sequence during memory formation and long-term potentiation.•Combined phosphodiesterase inhibitors display therapeutic synergy to improve memory.•Low-dosed combination treatment might minimize adverse side-effects.
•Multi-fragmented fractures of the distal femur are very rare and have a high incidence of complications.•The classifications currently in use often do not describe all fracture patterns present ...today due to high-energy trauma.•The lack of cases described in the literature leads the surgeon into difficulties with both diagnosis and treatment.
Distal growth core fractures of the femur are the third most common fracture in patients older than 10 years. These fractures result from high-energy trauma and have a high risk of evolving into growth disorders. The classification most used to describe these types of fractures is that described by Salter and Harris. Special clinical cases often occur in clinical practice that are not described in the classifications used. In our study, we analyzed and further focused on new fracture patterns related to pediatric epiphyseal detachments not easily described by the normal classifications currently used in the literature.
From January 2020 to December 2022, we treated 2 male clinical cases with epiphyseal detachments of the distal femur that could not be classified according to the Salter and Harris classification. age of the patients was 10 and 11 years, respectively; for both patients, the traumatic mechanism was a direct trauma to the right knee at high speed using an electric scooter; Serious clinical and radiographic follow-ups were performed at month 1, month 3, month 6, month 12, and month 24 from the date of surgery.
Distal femur fractures represent a challenge for the orthopedics because they have a high incidence of complications. In our experience, there has been an increase in this type of injury caused using recently developed electric vehicles, which can reach considerable speeds. The Salter Harris classification is among the most widely used for fractures involving the growth physis. This classification proved to be rather limiting in the present case, so we decided to classify the fracture as 'Salter Harris III equivalent'.
The fracture examined is a very rare fracture of the distal femur and is not reflected in the classifications currently in use. The patient presented an excellent clinical and radiographic result after surgery with the presence of a shortening of the affected femur in relation to the contralateral one, which suggests that the growth deficit may continue and increase over time for which reason future studies until skeletal maturity will be necessary to quantify the damage to the growth physis.
Recent evidence demonstrates that Crocus sativus L. (saffron) counteracts oxidative stress, mitochondrial dysfunction and neuroinflammation, closely linked to initiation and progression of major ...brain pathologies. Interestingly, saffron constituents such as crocin, crocetin and safranal can exert antioxidant or toxic effects depending on their endogenous concentration. According to the hormesis principles, at low dose they act as antioxidants in a wide range of brain diseases by upregulating Nrf2 signaling pathway and the expression of vitagenes, such as NAD(P)H-quinone oxidoreductase (NQO1), glutathione transferase (GT), heme oxygenase-1 (HO-1), sirtuin-1 (Sirt1) and thioredoxin (Trx) system. Importantly, neuronal dysregulation of Nrf2 pathway can be a prominent cause of selective susceptibility, under neuroinflammatory conditions, due to the high vulnerability of brain cells to oxidative stress. Here we discuss natural inducers from saffron targeting Nrf2/vitagene pathway for development of new therapeutical strategies to suppress oxidative stress and neuroinflammation and consequently cognitive dysfunction. In this review we also focus on the hormetic effect of saffron active constituents, summarizing their neuroprotective and anti-neuroinflammatory properties, as well as pharmacological perspectives in brain disorders.
•Saffron and its active constituents exert anti-inflammatory and antioxidants effects acting via transcription of vitagenes.•Saffron preparations are promising agents for therapeutic applications in the treatment of neurodegenerative disorders.•The dose-response pattern of saffron within a hormetic response is able to modulate oxidative stress.
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