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Spinal muscular atrophy (SMA) is caused by a deficiency of the ubiquitously expressed survival motor neuron (SMN) protein. The main pathological hallmark of SMA is the degeneration of lower motor neurons (MNs) with subsequent denervation and atrophy of skeletal muscle. However, increasing evidence indicates that low SMN levels not only are detrimental to the central nervous system (CNS) but also directly affect other peripheral tissues and organs, including skeletal muscle. To better understand the potential primary impact of SMN deficiency in muscle, we explored the cellular, ultrastructural, and molecular basis of SMA myopathy in the SMNΔ7 mouse model of severe SMA at an early postnatal period (P0-7) prior to muscle denervation and MN loss (preneurodegenerative [PND] stage). This period contrasts with the neurodegenerative (ND) stage (P8-14), in which MN loss and muscle atrophy occur. At the PND stage, we found that SMN∆7 mice displayed early signs of motor dysfunction with overt myofiber alterations in the absence of atrophy. We provide essential new ultrastructural data on focal and segmental lesions in the myofibrillar contractile apparatus. These lesions were observed in association with specific myonuclear domains and included abnormal accumulations of actin-thin myofilaments, sarcomere disruption, and the formation of minisarcomeres. The sarcoplasmic reticulum and triads also exhibited ultrastructural alterations, suggesting decoupling during the excitation–contraction process. Finally, changes in intermyofibrillar mitochondrial organization and dynamics, indicative of mitochondrial biogenesis overactivation, were also found. Overall, our results demonstrated that SMN deficiency induces early and MN loss-independent alterations in myofibers that essentially contribute to SMA myopathy. This strongly supports the growing body of evidence indicating the existence of intrinsic alterations in the skeletal muscle in SMA and further reinforces the relevance of this peripheral tissue as a key therapeutic target for the disease. [ABSTRACT FROM AUTHOR]

In spectral wave models, the nonlinear triad source term accounts for the transfer of energy to the bound higher harmonics. This paper presents an extension to commonly used spectral models that resolves the evolution of the bound wave energy by keeping track of the energy that has been bound by the triad interactions. This extension is referred to as the bound wave evolution (BWE) model. From this, the spatial evolution of the bound wave height is obtained, which serves as a proxy for the nonlinear wave shape. The accuracy of these bound wave heights, and thus wave shape predictions, is highly dependent on the accuracy of the triad source term. Therefore, in this study, the capability of the LTA and SPB triad formulations to capture the growth of the bound wave height is evaluated. For both of these formulations, it is found that slope dependent calibration parameters are required. Overall, despite being computationally more expensive, the SPB method proves to be significantly more accurate in predicting the bound wave evolution. In the shoaling zone, where the bound wave energy is dominated by triads, the BWE model is well capable of predicting the nonlinear wave's shape. In the surf zone, however, where a combination of triads and wave breaking control the spectral evolution, the BWE model over-predicts the bound wave height. Nevertheless, this paper shows the promising capabilities of spectral models to predict the nonlinear wave shape. [ABSTRACT FROM AUTHOR]

Centronuclear myopathies (CNM) are rare congenital disorders characterized by muscle weakness and structural defects including fiber hypotrophy and organelle mispositioning. The main CNM forms are caused by mutations in: the MTM1 gene encoding the phosphoinositide phosphatase myotubularin (myotubular myopathy), the DNM2 gene encoding the mechanoenzyme dynamin 2, the BIN1 gene encoding the membrane curvature sensing amphiphysin 2, and the RYR1 gene encoding the skeletal muscle calcium release channel/ryanodine receptor. MTM1, BIN1, and DNM2 proteins are involved in membrane remodeling and trafficking, while RyR1 directly regulates excitation-contraction coupling (ECC). Several CNM animal models have been generated or identified, which confirm shared pathological anomalies in T-tubule remodeling, ECC, organelle mispositioning, protein homeostasis, neuromuscular junction, and muscle regeneration. Dynamin 2 plays a crucial role in CNM physiopathology and has been validated as a common therapeutic target for three CNM forms. Indeed, the promising results in preclinical models set up the basis for ongoing clinical trials. Another two clinical trials to treat myotubular myopathy by MTM1 gene therapy or tamoxifen repurposing are also ongoing. Here, we review the contribution of the different CNM models to understanding physiopathology and therapy development with a focus on the commonly dysregulated pathways and current therapeutic targets. [ABSTRACT FROM AUTHOR]

In this research, we investigated the second-order nonlinear optical (NLO) properties of multicomponent hybrid materials formed by meso-tetraphenylporphyrin P (both as free base and ZnII complex), carrying in 2 or 2,12 β-pyrrolic position an electron donor ferrocene (Fc), and/or an electron acceptor fullerene (C60) moiety, connected to the porphyrin core via an ethynyl or an ethynylphenyl spacer. We measured the NLO response by the electric-field-induced second-harmonic generation (EFISH) technique in CH2Cl2 solution with a 1907 nm incident wavelength, recording for all the investigated compounds unexpected negative values of μβ1907. Since density functional theory (DFT) calculations evidenced for P-Fc dyads almost null ground state dipole moments and very low values for P-C60 dyads and Fc-P-C60 triads, our EFISH results suggested a significant contribution to γEFISH of the purely electronic cubic term γ(−2ω; ω, ω, 0), which prevails on the quadratic dipolar orientational one μβ(−2ω; ω, ω)/5kT, as confirmed by computational evidence. [ABSTRACT FROM AUTHOR]

The reactions between the bis(1,10-phenantro[5,6-b])tetrathiafulvalene triad (L) and the metallo-precursors Yb(hfac)3(H2O)2 (hfac− = 1,1,1,5,5,5-hexafluoroacetylacetonato anion) and Dy(facam)3 (facam− = 3-trifluoro-acetyl-(+)-camphorato anion) lead to the formation of two dinuclear complexes of formula [Yb2(hfac)6(L)]·2(C7H16) ((1)·2(C7H16)) and [Dy2((+)facam)6(L)]·2(C6H14) ((2)·2(C6H14)). The X-ray structures reveal that the L triad bridges two terminal Yb(hfac)3 or Dy(facam)3 units. (1)·2(C7H16) behaved as a near infrared YbIII centered emitter and a field-induced Single-Molecule Magnet (SMM) while (2)·2(C6H14) displayed SMM behavior in both zero- and in-dc field. The magnetization mainly relaxes through a Raman process for both complexes under an optimal applied magnetic field. [ABSTRACT FROM AUTHOR]

This review is focused on the description and discussion of the alterations of astrocytes and microglia interplay in models of Alzheimer's disease (AD). AD is an age-related neurodegenerative pathology with a slowly progressive and irreversible decline of cognitive functions. One of AD's histopathological hallmarks is the deposition of amyloid beta (Aβ) plaques in the brain. Long regarded as a non-specific, mere consequence of AD pathology, activation of microglia and astrocytes is now considered a key factor in both initiation and progression of the disease, and suppression of astrogliosis exacerbates neuropathology. Reactive astrocytes and microglia overexpress many cytokines, chemokines, and signaling molecules that activate or damage neighboring cells and their mutual interplay can result in virtuous/vicious cycles which differ in different brain regions. Heterogeneity of glia, either between or within a particular brain region, is likely to be relevant in healthy conditions and disease processes. Differential crosstalk between astrocytes and microglia in CA1 and CA3 areas of the hippocampus can be responsible for the differential sensitivity of the two areas to insults. Understanding the spatial differences and roles of glia will allow us to assess how these interactions can influence the state and progression of the disease, and will be critical for identifying therapeutic strategies. [ABSTRACT FROM AUTHOR]

The paper presents the Triads Geometric Consistency Index ( T - G C I ), a measure for evaluating the inconsistency of the pairwise comparison matrices employed in the Analytic Hierarchy Process (AHP). Based on the Saaty's definition of consistency for AHP, the new measure works directly with triads of the initial judgements, without having to previously calculate the priority vector, and therefore is valid for any prioritisation procedure used in AHP. The T - G C I is an intuitive indicator defined as the average of the log quadratic deviations from the unit of the intensities of all the cycles of length three. Its value coincides with that of the Geometric Consistency Index ( G C I ) and this allows the utilisation of the inconsistency thresholds as well as the properties of the G C I when using the T - G C I . In addition, the decision tools developed for the G C I can be used when working with triads ( T - G C I ), especially the procedure for improving the inconsistency and the consistency stability intervals of the judgements used in group decision making. The paper further includes a study of the computational complexity of both measures ( T - G C I and G C I ) which allows selecting the most appropriate expression, depending on the size of the matrix. Finally, it is proved that the generalisation of the proposed measure to cycles of any length coincides with the T - G C I . It is not therefore necessary to consider cycles of length greater than three, as they are more complex to obtain and the calculation of their associated measure is more difficult. [ABSTRACT FROM AUTHOR]

Josephus liked to organize material in three-part structures, which imparted a sense of completion by indicating to readers that an end had been reached. This study focuses on Books 18–20 of Josephus's Antiquities, which are organized as such a triad: Book 18 opens Roman rule in Judea and adumbrates the final clash and catastrophe, Book 19 creates some suspense by detailing two possible interruptions that could have changed the course of history but in the end came to nothing, and so Book 20 resumes the story from the end of Book 18 and takes it down to the destruction of Jerusalem. Moreover, all three books, together, form a unit in a larger triad: the story told, in the second half of Antiquities, of Judea's move from sovereignty under the Hasmoneans (Books 12–14), to nominal sovereignty under Herod (Books 15–17), to subjugation to Rome (Books 18–20). This focus on political history is, however, contradicted in various ways, both by Josephus's development from a Judean into a Jew of the Diaspora, who focused more on religion than on state, and by various sources used by Josephus, that pulled in other directions. [ABSTRACT FROM AUTHOR]

The reaction between the 2,2′-benzene-1,4-diylbis(6-hydroxy-4,7-di-tert-butyl-1,3-benzodithiol-2-ylium-5-olate biradical triad (L) and the metallo-precursor [Dy(hfac)3]·2H2O leads to the formation of a one-dimensional coordination polymer with the formula {[Dy(hfac)3(L)]·2C6H14}n (1). The X-ray structure reveals that the polymeric structure is formed by the bridging of the Dy(hfac)3 units with the multi-redox triad L. Single-crystal X-ray diffraction and UltraViolet-visible absorption spectroscopy confirm that the triad L in 1 is bound as a direduced, diprotonated form of o-quinone-extended tetrathiafulvalene-o-quinone (Q-exTTF-Q). Alternate Current (AC) measurements highlight a field-induced single-molecule magnet (SMM) behavior with an energy barrier of 20 K, and thus 1 can be described as a one-dimensional assembly of mononuclear SMMs bridged by the L triad. [ABSTRACT FROM AUTHOR]