Familial dysautonomia (FD), a hereditary sensory and autonomic neuropathy, is caused by missplicing of exon 20, resulting from an intronic mutation in the inhibitor of kappa light polypeptide gene enhancer in B cells, kinase complex-associated protein (IKBKAP) gene encoding IKK complex-associated protein (IKAP)/elongator protein 1 (ELP1). A newly established splicing reporter assay allowed us to visualize pathogenic splicing in cells and to screen small chemicals for the ability to correct the aberrant splicing of IKBKAP. Using this splicing reporter, we screened our chemical libraries and identified a compound, rectifier of aberrant splicing (RECTAS), that rectifies the aberrant IKBKAP splicing in cells from patients with FD. Here, we found that the levels of modified uridine at the wobble position in cytoplasmic tRNAs are reduced in cells from patients with FD and that treatment with RECTAS increases the expression of IKAP and recovers the tRNA modifications. These findings suggest that the missplicing of IKBKAP results in reduced tRNA modifications in patients with FD and that RECTAS is a promising therapeutic drug candidate for FD. IKAP is currently known as elongator protein 1 (ELP1), an integral component of the human Elongator complex, which was originally identified in Saccharomyces cerevisiae and shown to be well conserved among species (1). Although multiple functions of IKAP/ELP1 in JNK signaling, neuronal development during embryogenesis, exocytosis, and actin cytoskeleton regulation have been reported (reviewed in refs. 2, 3), yeast genetic analyses have shown that the Elongator complex is also required for the formation of the C5-substituent of 5-carbamoylmethyl (ncm 5 ), 5-methoxycarbonylmethyl (mcm 5 ), and its derivatives at the wobble uridine in tRNAs recognizing purine-ending codons (4, 5). Most recently, it was demonstrated that conditional IKAP/Elp1 KO in mouse testes results in male infertility by disrupting meiotic progression, along with the reduction of modified nucleosides [5-methoxycarbonylmethyl uridine (mcm 5 U), 5-carbamoylmethyl uridine (ncm 5 U), and 5-methoxycarbonylmethyl-2-thiouridine (mcm 5 s 2 U)] of total tRNAs in the testes (6). These modifications are highly likely to play critical roles in the maintenance of translational fidelity, suggesting that the defects in these modifications lead to the mistranslation of various proteins.Familial dysautonomia (FD; Riley-Day syndrome), an autosomal recessive neurodegenerative disease, is characterized by impaired development and progressive degeneration of the sensory and autonomic nerves. Patients who have FD exhibit various symptoms, including cardiovascular instability, recurrent pneumonia, vomiting/dysautonomic crisis, gastrointestinal dysfunction, decreased sensitivity to pain and temperature, and defective lacrimation. FD is a very common disorder in the Ashkenazi Jewish population, with a carrier frequency of 1 in 27. More than 99% of patients who have FD harbor a homozygous mutation in intron 20 (IVS20 + 6T > C: FD mutation)...

In contrast to polar cation displacements driving oxides into noncentrosymmetric and ferroelectric states, inversion-preserving anion displacements, such as rotations or tilts of oxygen octahedra about cation coordination centers, are exceedingly common. More than one nonpolar rotational mode in layered perovskites can lift inversion symmetry and combine to induce an electric polarization through a hybrid improper ferroelectric (HIF) mechanism. This form of ferroelectricity expands the compositional palette to new ferroelectric oxides because its activity derives from geometric rather than electronic origins. Here, the new Ruddlesden-Popper HIF Sr 3 Zr 2 O 7 , which is the first ternary lead-free zirconate ferroelectric, is reported and room-temperature polarization switching is demonstrated. This compound undergoes a first-order ferroelectric-to-paraelectric transition, involving an unusual change in the "sense" of octahedral rotation while the octahedral tilt remains unchanged. Our experimental and first-principles study shows that the paraelectric polymorph competes with the polar phase and emerges from a trilinear coupling of rotation and tilt modes interacting with an antipolar mode. This form of hybrid improper "antiferroelectricity" is recently predicted theoretically but has remained undetected. This work establishes the importance of understanding anharmonic interactions among lattice degrees of freedom, which is important for the discovery of new ferroelectrics and likely to influence the design of next-generation thermoelectrics.

Hybrid improper ferroelectricity, which utilizes nonpolar but ubiquitous rotational/tilting distortions to create polarization, offers an attractive route to the discovery of new ferroelectric and multiferroic materials because its activity derives from geometric rather than electronic origins. Design approaches based on group theory and first principles can be utilized to explore the crystal symmetries of ferroelectric ground states, but in general do not make accurate predictions for some important parameters of ferroelectrics, such as Curie temperature (T C). Here, we establish a predictive and quantitative relationship between T C and the Goldschmidt tolerance factor, t, by employing n = 2 Ruddlesden-Popper (RP) A 3 B 2 O 7 as a prototypical example of hybrid improper ferroelectrics. The focus is placed on an RP system, (Sr 1−x Ca x) 3 Sn 2 O 7 (x = 0, 0.1, and 0.2), which allows for the investigation of the purely geometric (ionic-size) effect on ferroelectric transitions, due to the absence of the second-order Jahn-Teller active (d 0 and 6s 2) cations that often lead to ferroelectric distortions through electronic mechanisms. We observe a ferroelectric-to-paraelectric transition with T C = 410 K for Sr 3 Sn 2 O 7. We also find that the T C increases linearly up to 800 K with increasing the Ca 2+ content, i.e., with decreasing the value of t. Remarkably, this linear relationship is applicable to the suite of all known A 3 B 2 O 7 ferroelectrics, indicating that T C correlates with the simple crystal-chemistry descriptor, t, based on the ionic-size mismatch. This study provides a predictive guideline for estimating T C of a given material, which would complement the grouptheoretical and first-principles design approach. Additional ND and SXRD analyses, first-principles calculation results, and Mössbauer spectroscopy (PDF).

We present how the introduction of anion vacancies in oxyhydrides enables a route to access new oxynitrides, by conducting ammonolysis of perovskite oxyhydride EuTiO3-xHx (x ∼ 0.18). At 400 °C, similar to our studies on BaTiO3-xHx, hydride lability enables a low temperature direct ammonolysis of EuTi(3.82+)O2.82H0.18, leading to the N(3-)/H(-)-exchanged product EuTi(4+)O2.82N0.12□0.06. When the ammonolysis temperature was increased up to 800 °C, we observed a further nitridation involving N(3-)/O(2-) exchange, yielding a fully oxidized Eu(3+)Ti(4+)O2N with the GdFeO3-type distortion (Pnma) as a metastable phase, instead of pyrochlore structure. Interestingly, the same reactions using the oxide EuTiO3 proceeded through a 1:1 exchange of N(3-) with O(2-) only above 600 °C and resulted in incomplete nitridation to EuTiO2.25N0.75, indicating that anion vacancies created during the initial nitridation process of EuTiO2.82H0.18 play a crucial role in promoting anion (N(3-)/O(2-)) exchange at high temperatures. Hence, by using (hydride-induced) anion-deficient precursors, we should be able to expand the accessible anion composition of perovskite oxynitrides.

The effect of boron on the nucleation and growth of ferrite at austenite grain boundaries is examined theoretically under the assumption that the junction of 4-austenite grain boundaries (i.e., the 4-grain junctions) are the dominant nucleation sites of ferrite. Boron segregates to the austenite grain boundaries and reduces the grain-boundary energy; it thereby retards ferrite nucleation at the grain boundary. The retardation is expressed as a decrease in nucleation density due to an increase in the critical activation energy for nucleation, and the calculated value of the fraction of active nucleation sites is in satisfactory agreement with the experimental results. The reduction of the austenite grain-boundary energy, which we obtained by applying the Gibbs isotherm for adsorption to the boron segregation, is of the same order of magnitude as the reduction is deduced from the results of calculations for a decrease in the nucleation density based on experimental results. The growth of ferrite was calculated using DICTRA, which yielded both the volume fraction and the grain size of transformed ferrite as functions of time; the results agreed with the experimental results. This agreement suggests that the influence of boron on the growth rate is negligible. However, the increase in the size of the diffusion cell due to the addition of boron is considered to be the main reason for the slightly larger grain size of ferrite compared with that in boron-free steel; this result is also in good agreement with experimental observations.

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Crystallography and dielectric properties in Dion–Jacobson layered perovskites, CsNdNb2O7 and RbNdNb2O7, have been examined in dense polycrystalline samples, and polarization hysteresis loops that substantiate ferroelectricity have been observed at room temperature. The theoretical mechanism for the spontaneous polarization, “hybrid improper ferroelectric mechanism,” induced by a combination of two types of non-polar octahedral rotations, is confirmed in these two phases. Our samples show remanent polarizations of 2–3 μC cm−2, which are much larger than those obtained in polycrystalline samples with the hybrid improper ferroelectricity reported so far. A dielectric constant in CsNdNb2O7 exhibits an anomaly at 625 K, corresponding to the ferroelectric transition, as previously revealed by X-ray and neutron diffractometry. No dielectric anomaly is observed for RbNdNb2O7 throughout the temperature range studied here (≤773 K), which is consistent with the previous diffractometry showing the persistence of polar I2cm symmetry up to 790 K.

We report the observation of noncentrosymmetricity in the family of HRTiO4 (R = Eu, Gd, Dy) layered oxides possessing a Ruddlesden–Popper derivative structure, by second harmonic generation and synchrotron X-ray diffraction with the support of density functional theory calculations. These oxides were previously thought to possess inversion symmetry. Here, inversion symmetry is lifted by rotations of the oxygen-coordinated octahedra, a mechanism that is not active in simple perovskites. We observe a competition between rotations of the oxygen octahedra and sliding of a combined unit of perovskite–rocksalt–perovskite blocks at the proton layers. For the smaller rare earth ions, R = Eu, Gd, and Dy, which favor the octahedral rotations, noncentrosymmetricity is present but the sliding is absent. For the larger rare earth ions, R = Nd and Sm, the octahedral rotations are absent, but the sliding at the proton layers is present to optimize the length and direction of hydrogen bonding in the crystal structure. The study reveals a new mechanism for inducing noncentrosymmetricity in layered oxides, and chemical–structural effects related to rare earth ion size and hydrogen bonding that can turn this mechanism on and off. We construct a phase diagram of temperature versus rare earth ionic radius for the HRTiO4 family.