Evidence for Strain-Induced Ferroelectric Order in Epitaxial Thin-Film KTaO3

In perovskite-structure epitaxial films, it has been theoretically predicted that the polarization and the coherence of polar order can increase with increasing crystallographic strain. Experimental evidence of strain-induced long-range ferroelectric order has not been obtained thus far, posing the fundamental question of whether or not strain can induce the long-range polar order. Here we demonstrate the existence of strain-induced ferroelectric order in quantum paraelectric KTaO3 by combining experimental investigations of epitaxial KTaO3 films and density-functional-theory calculations. The long-range ferroelectric order does exist under a large enough epitaxial strain. We suggest that a region of short-range polar order might appear between paraelectric and ferroelectric states in the strain-temperature phase diagrams.Peer reviewe

AAV-mediated photoreceptor transduction of the pig cone-enriched retina

Recent success in clinical trials supports the use of adeno-associated viral (AAV) vectors for gene therapy of retinal diseases caused by defects in the retinal pigment epithelium (RPE). In contrast, evidence of the efficacy of AAV-mediated gene transfer to retinal photoreceptors, the major site of inherited retinal diseases, is less robust. In addition, although AAV-mediated RPE transduction appears efficient, independently of the serotype used and species treated, AAV-mediated photoreceptor gene transfer has not been systematically investigated thus so far in large animal models, which also may allow identifying relevant species-specific differences in AAV-mediated retinal transduction. In the present study, we used the porcine retina, which has a high cone/rod ratio. This feature allows to properly evaluate both cone and rod photoreceptors transduction and compare the transduction characteristics of AAV2/5 and 2/8, the two most efficient AAV vector serotypes for photoreceptor targeting. Here we show that AAV2/5 and 2/8 transduces both RPE and photoreceptors. AAV2/8 infects and transduces photoreceptor more efficiently than AAV2/5, similarly to what we have observed in the murine retina. The use of the photoreceptor-specific rhodopsin promoter restricts transgene expression to porcine rods and cones, and results in photoreceptor transduction levels similar to those obtained with the ubiquitous promoters tested. Finally, immunological, toxicological and biodistribution studies support the safety of AAV subretinal administration to the large porcine retina. The data presented here on AAV-mediated transduction of the cone-enriched porcine retina may affect the development of gene-based therapies for rare and common severe photoreceptor diseases

CCR3 and Choroidal Neovascularization

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly in industrialized countries. The “wet” AMD, characterized by the development of choroidal neovacularization (CNV), could result in rapid and severe loss of central vision. The critical role of vascular endothelial growth factor A (VEGF-A) in CNV development has been established and VEGF-A neutralization has become the standard care for wet AMD. Recently, CCR3 was reported to play an important role in CNV development and that CCR3 targeting was reported to be superior to VEGF-A targeting in CNV suppression. We investigated the role of CCR3 in CNV development using the Matrigel induced CNV and found that in both rats and mice, CNV was well-developed in the control eyes as well as in eyes treated with CCR3 antagonist SB328437 or CCR3 neutralizing antibodies. No statistically significant difference in CNV areas was found between the control and SB328437 or CCR3-ab treated eyes. Immunostaining showed no specific expression of CCR3 in or near CNV. In contrast, both VEGF-A neutralizing antibodies and rapamycin significantly suppressed CNV. These results indicate that CCR3 plays no significant role in CNV development and question the therapeutic approach of CCR3 targeting to suppress CNV. On the other hand, our data support the therapeutic strategies of VEGF-A and mTOR (mammalian target of rapamycin) targeting for CNV

Hemotin, a regulator of phagocytosis encoded by a small ORF and xonserved across metazoans

Translation of hundreds of small ORFs (smORFs) of less than 100 amino acids has recently been revealed in vertebrates and Drosophila. Some of these peptides have essential and conserved cellular functions. In Drosophila, we have predicted a particular smORF class encoding ~80 aa hydrophobic peptides, which may function in membranes and cell organelles. Here, we characterise hemotin, a gene encoding an 88aa transmembrane smORF peptide localised to early endosomes in Drosophila macrophages. hemotin regulates endosomal maturation during phagocytosis by repressing the cooperation of 14-3-3ζ with specific phosphatidylinositol (PI) enzymes. hemotin mutants accumulate undigested phagocytic material inside enlarged endo-lysosomes and as a result, hemotin mutants have reduced ability to fight bacteria, and hence, have severely reduced life span and resistance to infections. We identify Stannin, a peptide involved in organometallic toxicity, as the Hemotin functional homologue in vertebrates, showing that this novel regulator of phagocytic processing is widely conserved, emphasizing the significance of smORF peptides in cell biology and disease

Nr2e3 is a Genetic Modifier That Rescues Retinal Degeneration and Promotes Homeostasis in Multiple Models of Retinitis Pigmentosa

Recent advances in viral vector engineering, as well as an increased understanding of the cellular and molecular mechanism of retinal diseases, have led to the development of novel gene therapy approaches. Furthermore, ease of accessibility and ocular immune privilege makes the retina an ideal target for gene therapies. In this study, the nuclear hormone receptor gene Nr2e3 was evaluated for efficacy as broad-spectrum therapy to attenuate early to intermediate stages of retinal degeneration in five unique mouse models of retinitis pigmentosa (RP). RP is a group of heterogenic inherited retinal diseases associated with over 150 gene mutations, affecting over 1.5 million individuals worldwide. RP varies in age of onset, severity, and rate of progression. In addition, ~40% of RP patients cannot be genetically diagnosed, confounding the ability to develop personalized RP therapies. Remarkably, Nr2e3 administered therapy resulted in reduced retinal degeneration as observed by increase in photoreceptor cells, improved electroretinogram, and a dramatic molecular reset of key transcription factors and associated gene networks. These therapeutic effects improved retinal homeostasis in diseased tissue. Results of this study provide evidence that Nr2e3 can serve as a broad-spectrum therapy to treat multiple forms of RP

Rescue of Photoreceptor Degeneration by Curcumin in Transgenic Rats with P23H Rhodopsin Mutation

The P23H mutation in the rhodopsin gene causes rhodopsin misfolding, altered trafficking and formation of insoluble aggregates leading to photoreceptor degeneration and autosomal dominant retinitis pigmentosa (RP). There are no effective therapies to treat this condition. Compounds that enhance dissociation of protein aggregates may be of value in developing new treatments for such diseases. Anti-protein aggregating activity of curcumin has been reported earlier. In this study we present that treatment of COS-7 cells expressing mutant rhodopsin with curcumin results in dissociation of mutant protein aggregates and decreases endoplasmic reticulum stress. Furthermore we demonstrate that administration of curcumin to P23H-rhodopsin transgenic rats improves retinal morphology, physiology, gene expression and localization of rhodopsin. Our findings indicate that supplementation of curcumin improves retinal structure and function in P23H-rhodopsin transgenic rats. This data also suggest that curcumin may serve as a potential therapeutic agent in treating RP due to the P23H rhodopsin mutation and perhaps other degenerative diseases caused by protein trafficking defects

Low-temperature relaxor state induced by epitaxial compression in PbSc0.5Nb0.5O3 films

International audienceThe use of high-performance perovskite-structure epitaxial relaxor ferroelectric films [S. H. Baek et al., Science 334, 958 (2011)] is hindered by the lack of knowledge of epitaxial effects therein. It is experimentally shown here that a biaxial epitaxial compression can favor the relaxor state over ferroelectricity. The absence of the ferroelectric transition and the existence of the low-temperature relaxor state are evidenced by a combination of x-ray diffraction, dielectric, polarization, and optical studies of PbSc0.5Nb0.5O3 films epitaxially grown on La0.5Sr0.5CoO3/MgO(001). This finding is beyond existing models of polarization in perovskite-structure epitaxial films and beyond the established ability to induce ferroelectricity by an epitaxial strain

The influence of administration of biotin and zinc chelate (Zn-methionine) to cows in the first and second trimester of lactation on their health and productivity

In cattle, the prevention of diseases might be possible using dietary methods, with nutritional optimization of feed rations. For years significant influence has been associated with the addition of biotin, methionine and zinc (each given individually, or as chelate – Zn-methionine). The aim of this study was to evaluate the influence of biotin or biotin + Zn-methionine additives on the health and performance of cows, in the first and second trimester of lactation. This study was carried out in 3 groups of cows, 30 animals in each group. In the first group cows were fed the usual fodder used on the farm. In the second group biotin at 10 mg/day/cow was added. In the third group both biotin at 10 mg/day/cow and Zn-methionine at 5 g/day/cow were added. The administration of biotin increased the milk yield and reduced the occurrence of retained placenta, as well as endometritis puerperalis. However, the high doses of biotin suppressed ovulation and oestrus symptoms in the investigated cows (low progesterone levels on days 15, 21 and 45 after calving). Zn-methionine in comparison to biotin had a lower effect on the milk yield in the cows. Moreover, its supplementation improved the milk content, as well as some of the blood parameters; it also decreased the number of somatic cells in milk. The concurrent administration of biotin and zinc-methionine seemed to be a good method for the prophylaxis of subacute mastitis and for the improvement of the high yielding dairy cows’ productivity