{ScnGdn} Heterometallic Rings: Tunable Ring Topology for Spin-Wave Excitations.

Data carriers using spin waves in spintronic and magnonic logic devices offer operation at low power consumption and free of Joule heating yet requiring noncollinear spin structures of small sizes. Heterometallic rings can provide such an opportunity due to the controlled spin-wave transmission within such a confined space. Here, we present a series of {ScnGdn} (n = 4, 6, 8) heterometallic rings, which are the first Sc-Ln clusters to date, with tunable magnetic interactions for spin-wave excitations. By means of time- and temperature-dependent spin dynamics simulations, we are able to predict distinct spin-wave excitations at finite temperatures for Sc4Gd4, Sc6Gd6, and Sc8Gd8. Such a new model is previously unexploited, especially due to the interplay of antiferromagnetic exchange, dipole-dipole interaction, and ring topology at low temperatures, rendering the importance of the latter to spin-wave excitations.

Studies of the Temperature Dependence of the Structure and Magnetism of a Hexagonal-Bipyramidal Dysprosium(III) Single-Molecule Magnet.

The hexagonal-bipyramidal lanthanide(III) complex [Dy(OtBu)Cl(18-C-6)][BPh4] (1; 18-C-6 = 1,4,7,10,13,16-hexaoxacyclooctadecane ether) displays an energy barrier for magnetization reversal (Ueff) of ca. 1000 K in a zero direct-current field. Temperature-dependent X-ray diffraction studies of 1 down to 30 K reveal bending of the Cl-Ln-OtBu angle at low temperature. Using ab initio calculations, we show that significant bending of the O-Dy-Cl angle upon cooling from 273 to 100 K leads to a ca. 10% decrease in the energy of the excited electronic states. A thorough exploration of the temperature and field dependencies of the magnetic relaxation rate reveals that magnetic relaxation is dictated by five mechanisms in different regimes: Orbach, Raman-I, quantum tunnelling of magnetization, and Raman-II, in addition to the observation of a phonon bottleneck effect.

Ligand Fluorination to Mitigate the Raman Relaxation of DyIII Single-Molecule Magnets: A Combined Terahertz, Far-IR and Vibronic Barrier Model Study.

The fast Raman relaxation process via a virtual energy level has become a puzzle for how to chemically engineer single-molecule magnets (SMMs) with better performance. Here, we use the trifluoromethyl group to systematically substitute the methyl groups in the axial position of the parent bis-butoxide pentapyridyl dysprosium(III) SMM. The resulting complexes-[Dy(OLA )2 py5 ][BPh4 ] (LA =CH(CF3 )2 - 1, CH2 CF3 - 2, CMe2 CF3 - 3)-show progressively enhanced TB hys (@100 Oe s-1 ) from 17 K (for 3), 20 K (for 2) to 23 K (for 1). By experimentally identifying the varied under barrier relaxation energy in the 5-500 cm-1 regime, we are able to identify that the C-F bond related vibration energy of the axial ligand ranging from 200 to 350 cm-1 is the key variant for this improvement. Thus, this finding not only reveals a correlation between the structure and the Raman process but also provides a paradigm for how to apply the vibronic barrier model to analyze multi-phonon relaxation processes in lanthanide SMMs.

Tetraanionic arachno-Carboranyl Ligand Imparts Strong Axiality to Terbium(III) Single-Molecule Magnets.

A family of fully sandwiched arachno-lanthanacarborane complexes formulated as {η6 -[µ-1,2-[o-C6 H4 (CH2 )2 ]-1,2-C2 B10 H10 ]2 Ln}{Li5 (THF)10 } (Ln=Tb, Dy, Ho, Er, Y) is successfully synthesized, where the "carbons-adjacent" carboranyl ligand (arachno-R2 -C2 B10 H10 4- ) bears four negative charges and coordinates to the central lanthanide ions using the hexagonal η6 C2 B4 face. Thus, the central lanthanide cations are pseudo-twelve-coordinate and have an approximate pseudo-D6h symmetry or hexagonal-prismatic geometry. As the crystal field effect imparted by this geometry is still unknown, we thoroughly investigated the magnetic properties of this series of complexes and found that the crystal field imposed by this ligand causes a relation of Tb>Dy>Ho>Er for the energy gaps between the ground and the first excited states, which is of striking resemblance to the ferrocenophane and phthalocyanine ligands although the latter two ligands give disparate local coordination geometries. Moreover, the effective energy barrier to magnetization reversal of 445(10) K, the observable hysteresis loop up to 4 K and the relaxation time of the yttrium-diluted sample reaching 193(17) seconds at 2 K under an optimized field for the Tb analogue of this family of arachno-lanthanacarborane complexes, render a new benchmark for Tb3+ -based single-molecule magnets.

A Local D4h Symmetric Dysprosium(III) Single-Molecule Magnet with an Energy Barrier Exceeding 2000†K*.

Three six-coordinate DyIII single-molecule magnets (SMMs) [Dy(Ot Bu)2 (L)4 ]+ with local D4h symmetry are obtained by optimizing the equatorial ligands. One of the compounds with L=4-phenylpyridine shows an energy barrier (Ueff ) of 2075(11) K, which is the third largest Ueff , and the first Ueff >2000 K for SMMs with axial-type symmetry so far. Ab initio analysis indicates that the exceptional uniaxial magnetic anisotropy is deeply related to the axially compressed octahedral geometry. This work provides a new insight into the local D4h symmetry for high-performance SMMs.

Magnetic Anisotropy: Structural Correlation of a Series of Chromium(II)-Amidinate Complexes.

Systematic substituent variations on amidinate ligands bring delicate changes of CrN4 coordination in a family of chromium(II) complexes with the common formula of Cr(RNC(CH3)NR)2, where R = iPr (1), Cy (2), Dipp (Dipp = 2, 6-diisopropylphenyl) (3), and tBu (4). With the largest substituent group, 4 shows the largest distortion of the N4 coordination geometry from square-planar to seesaw shape, which leads to its field-induced single-molecule magnet (SMM) behavior. This is an indication that 4 has the strongest axial magnetic anisotropy and/or optimized magnetic relaxation process. Combined with high-frequency/field electron paramagnetic resonance (HF-EPR) experiments and ab initio calculations, we deduce that the smallest energy gap between ground 4Ψ0 and the first excited 4Ψ1 orbitals in 4 contributes the most to its strongest magnetic anisotropy. Moreover, the lower E value of 4 ensures its being a field-induced SMM. Specifically, the D and E values were found to be correlated to the dihedral angle between the ΔN1CrN2 and ΔN3CrN4 triangles, indicating that distortion from ideal square-planar geometry to the seesaw help increase axial magnetic anisotropy and suppress the transversal part. Thus, the study on this system not only expands the family of Cr(II)-based SMMs but also contributes to a deeper understanding of magneto-structural correlation in four-coordinate Cr(II) SMMs.

Identification of a novel RPGR mutation associated with X-linked cone-rod dystrophy in a Chinese family.

BACKGROUND: Cone-rod dystrophy (CORD) is a group of inherited retinal dystrophies, characterized by decreased visual acuity, color vision defects, photophobia, and decreased sensitivity in the central visual field. Our study has identified a novel pathogenic variant associated with X-linked cone-rod dystrophy (XLCORD) in a Chinese family. METHODS: All six family members, including the proband, affected siblings, cousins and female carriers, have underwent thorough ophthalmic examinations. The whole exome sequencing was performed for the proband, followed by Sanger sequencing for spilt-sample validation. A mammalian expression vector (AAV-MCS) with mutated retinitis pigmentosa GTPase regulator (RPGR) sequence was expressed in HEK293 T cells. The mutated protein was verified by Western blotting and immunohistochemistry. RESULTS: A novel mutation in the RPGR gene (c.2383G > T, p.E795X) is identified to be responsible for CORD pathogenesis. CONCLUSIONS: Our findings have expanded the spectrum of CORD-associated mutations in RPGR gene and serve as a basis for genetic diagnosis for X-linked CORD.

A Study of Magnetic Relaxation in Dysprosium(III) Single-Molecule Magnets.

Although the development of single-molecule magnets (SMMs) is rapid, there are only two families of high energy barrier (Ueff ) dysprosium(III) SMMs known so far: the cyclopentadienyl (Cp) family with a sandwich structure and the pentagonal-bipyramidal (PB) family with D5h symmetry. These high-barrier SMMs, which usually possess Ueff >500 cm-1 allow the separate study of the four magnetic relaxation paths, namely, direct, quantum tunnelling, Raman and Orbach processes, in detail. Whereas the first family is chemically more challenging to modify the Cp rings, it is shown herein that the latter family, with the common formulae [DyX1 X2 (Leq )5 ]+ , such as X1 /X2 =- OCMe3 , - OSiMe3 , - OPh, Cl- or Br- ; Leq =THF/pyridine/4-methylpyridine, can be readily fine-tuned with a range of axial and equatorial ligands by simple substitution reactions. This allows unambiguous confirmation that the Ueff mainly depends on the identity of X1 and X2 , rather than on Leq . More importantly, the fitted parameters are barrier dependent. If X1 is an O donor and X2 is a halide, 500

Intraocular VEGF deprivation induces degeneration and fibrogenic response in retina.

VEGF is a critical driver of ocular neovascularization under disease conditions. Current therapeutic strategies rely on intraocular delivery of VEGF-antagonizing reagents, which results in sustained suppression of pathogenic vascularization. Although significant advancement has been achieved in VEGF antagonism, substantial adverse effects have been reported in retrospective clinical studies. To study mechanisms for VEGF antagonism-associated adverse effects in visual system, we intravitreally delivered recombinant adeno-associated virus-mediated expression of soluble Fms-related tyrosine kinase-1 (rAAV.sFLT-1), the extracellular domain of VEGF receptor, and analyzed the morphology and functions of retinal tissue. Here, we confirmed that intraocular VEGF antagonism induced retinal degeneration and gliosis. The functional deficit in retinal response to visual stimulation was also demonstrated in rAAV.sFLT-1-treated eyes by electroretinogram. Moreover, high-throughput RNA sequencing analysis suggests that VEGF antagonism activates retinal degeneration, inflammation, and other adverse effects. Taken together, our findings have shed light on pathogenic mechanisms for VEGF antagonism-associated adverse effects and potential therapeutic targets.-Xiao, M., Liu, Y., Wang, L., Liang, J., Wang, T., Zhai, Y., Wang, Y., Liu, S., Liu, W., Luo, X., Wang, F., Sun, X. Intraocular VEGF deprivation induces degeneration and fibrogenic response in retina.

Dimerized p-Semiquinone Radical Anions Stabilized by a Pair of Rare-Earth Metal Ions.

Here we report stable p-quinone-radical-bridged rare-earth complexes involving the ligand tetramethylquinone (QMe4•-). The complexes, {Y[(QMe4)•-Cl2(THF)3]}2 (1) and {Gd[(QMe4)•-Cl2(THF)3]}2 (2), where THF = tetrahydrofuran, are sufficiently stable that we can measure the single-crystal structures and perform magnetic and electron paramagnetic resonance measurements. These studies show the presence of a semiquinone form and that the magnetic interaction between the radicals in the dimer is strong and antiferromagnetic.

Dysprosiacarboranes as Organometallic Single-Molecule Magnets.

The dicarbollide ion, nido-C2 B9 H11 2- is isoelectronic with cyclopentadienyl. Herein, we make dysprosiacarboranes, namely [(C2 B9 H11 )2 Ln(THF)2 ][Na(THF)5 ] (Ln=Dy, 1Dy) and [(THF)3 (µ-H)3 Li]2 [{η5 -C6 H4 (CH2 )2 C2 B9 H9 }Dy{η2 :η5 -C6 H4 (CH2 )2 C2 B9 H9 }2 Li] 3Dy and show that dicarbollide ligands impose strong magnetic axiality on the central DyIII ion. The effective energy barrier (Ueff ) for the loss of magnetization can be varied by the substitution pattern on the dicarbollide. This finding is demonstrated by comparing complexes of nido-C2 B9 H11 2- and nido-[o-xylylene-C2 B9 H9 ]2- , which show a Ueff of 430(5) K and 804(7) K, respectively. The blocking temperature defined by the open hysteresis temperature of 3Dy reaches 6.8 K. Moreover, the linear complex [Dy(C2 B9 H11 )2 ]- is predicted to have comparable properties with the linear [Dy(CpMe3 )2 ]+ complex. As such, carboranyl ligands and their derivatives may provide a new type of organometallic ligand for high-performance single-molecule magnets.

Inhibition of Mitochondrial Fission Preserves Photoreceptors after Retinal Detachment.

Photoreceptor degeneration is a leading cause of visual impairment worldwide. Separation of neurosensory retina from the underlying retinal pigment epithelium is a prominent feature preceding photoreceptor degeneration in a variety of retinal diseases. Although ophthalmic surgical procedures have been well developed to restore retinal structures, postoperative patients usually experience progressive photoreceptor degeneration and irreversible vision loss that is incurable at present. Previous studies point to a critical role of mitochondria-mediated apoptotic pathway in photoreceptor degeneration, but the upstream triggers remain largely unexplored. In this study, we show that after experimental retinal detachment induction, photoreceptors activate dynamin-related protein 1 (Drp1)-dependent mitochondrial fission pathway and subsequent apoptotic cascades. Mechanistically, endogenous reactive oxygen species (ROS) are necessary for Drp1 activation in vivo, and exogenous ROS insult is sufficient to activate Drp1-dependent mitochondrial fission in cultured photoreceptors. Accordingly, inhibition of Drp1 activity effectively preserves mitochondrial integrity and rescues photoreceptors. Collectively, our data delineate an ROS-Drp1-mitochondria axis that promotes photoreceptor degeneration in retinal diseased models.

Air-Stable Hexagonal Bipyramidal Dysprosium(III) Single-Ion Magnets with Nearly Perfect D6h Local Symmetry.

Eight-coordinated DyIII centres with D6h symmetry are expected to act as high-performance single-molecule magnets (SMMs) due to the simultaneous fulfilment of magnetic axiality and a high coordination number (a requisite for air stability). But the experimental realization is challenging due to the requirement of six coordinating atoms in the equatorial plane of the hexagonal bipyramid; this is usually too crowded for the central DyIII ion. Here a hexaaza macrocyclic Schiff base ligand and finetuned axial alkoxide/phenol-type ligands are used to show that a family of hexagonal bipyramidal DyIII complexes can be isolated. Among them, three complexes possess nearly perfect D6h local symmetry. The highest effective magnetic reversal barrier is found at 1338(3) K and an open hysteresis temperature of 6 K at the field sweeping rate of 1.2 mT s-1 ; this represents a new record for D6h SMMs.

Identification of novel PROM1 mutations responsible for autosomal recessive maculopathy with rod-cone dystrophy.

PURPOSE: To characterize two patients with macular and rod-cone dystrophy and identify the genetic basis for disease. METHOD: Ophthalmic examinations were performed for the family and the peripheral blood samples were collected for whole exome sequencing. The mutated sequences of PROM1 gene were cloned and expressed in cultured cell lines after transient transfection followed by analysis with confocal microscopy and bridge-PCR. RESULT: We reported that two patients, brothers in a family, were diagnosed with macular and rod-cone dystrophy. Phenotypically, both patients experience progressive visual impairment and nyctalopia. The fundus examination showed macular and choroid dystrophy with pigment deposits in the macular region. Functionally, photoreceptor response to electrophysiological stimulation was significantly compromised with more severe decline in rods. Genetic analysis by whole exome sequencing revealed two novel compound heterogeneous point mutations in PROM1 gene that co-segregate with patients in an autosomal recessive manner. Specifically, the c.C1902G(p.Y634X) nonsense mutation results in a truncated, labile, and mislocalized protein, while the c.C1682+3A>G intronic mutation disrupts messenger RNA splicing. CONCLUSION: Our findings have identified two novel deleterious mutations in PROM1 gene that are associated with hereditary macular and rod-cone dystrophy in human.

OBSERVATION OF VITREOUS FEATURES USING ENHANCED VITREOUS IMAGING OPTICAL COHERENCE TOMOGRAPHY IN HIGHLY MYOPIC RETINOSCHISIS.

PURPOSE: To observe features of the posterior vitreous and vitreoretinal interface in highly myopic eyes with retinoschisis using enhanced vitreous imaging optical coherence tomography. METHODS: Comprehensive ophthalmologic examination and enhanced vitreous imaging optical coherence tomography were performed in 77 eyes of 63 patients with highly myopic retinoschisis. Two different modes of spectral domain optical coherence tomography were employed to estimate retinoschisis and the posterior vitreous features in optical coherence tomography images, respectively. The types and distribution of vitreoretinal interface abnormalities were also analyzed. RESULTS: Complete posterior vitreous detachment (PVD) was identified in 55 eyes (71.4%) with a Weiss ring. Residual cortex was found in 39 eyes (70.9%) with complete PVD. Vitreoretinal interface changes, including vitreoretinal adhesion and epiretinal membrane (ERM), most frequently appeared in the macular area (47.3%), followed by the inferior arched vessels region (34.5%). In partial PVD eyes, vitreoretinal traction, vitreoretinal adhesion, and epiretinal membrane tended to be observed in the inferior and superior arched vessels regions (54.5 and 40.9%, respectively). Among all types of vitreoretinal interface abnormalities, epiretinal membrane comprised the largest proportion (46.8%) despite the status of PVD. The presence of inner layers of retinoschisis connoted a relatively high possibility of vitreoretinal interface abnormalities occurring. CONCLUSION: Enhanced vitreous imaging optical coherence tomography reveals a high prevalence of vitreoretinal interface abnormalities in highly myopic eyes with retinoschisis. Vitreous cortex tends to remain on the macular area in eyes with complete PVD. Our findings may lead to better guidance for the surgical treatment of highly myopic retinoschisis.

Autophagy activated by SIRT6 regulates Aß induced inflammatory response in RPEs.

Age-associated dysfunction of retinal pigment epithelial cells (RPEs) is considered to be the initial trigger of retinal diseases such as age-related macular degeneration. Although autophagy is upregulated in RPEs during the course of aging, little is known about how autophagy is regulated and its functional role in RPEs. In this study, we found that expression of Sirtuin 6 (SIRT6) and autophagic markers are upregulated in RPEs of aged mice where subretinal deposition of amyloid-ß is accumulated and in amyloid-ß stimulated RPEs. In addition, gain and loss-of-function studies confirmed the positive role of SIRT6 in regulating autophagy. Interesting, inhibition of autophagy attenuates amyloid-ß stimulated inflammatory response in RPEs. Collectively, our findings uncover the autophagy modulated by SIRT6 may be a proinflammatory mechanism for amyloid-ß induced RPE dysfunction.

Bis-Alkoxide Dysprosium(III) Crown Ether Complexes Exhibit Tunable Air Stability and Record Energy Barrier.

High-performance and air-stable single-molecule magnets (SMMs) can offer great convenience for the fabrication of information storage devices. However, the controversial requisition of high stability and magnetic axiality is hard to balance for lanthanide-based SMMs. Here, a family of dysprosium(III) crown ether complexes possessing hexagonal-bipyramidal (pseudo-D6h symmetry) local coordination geometry with tunable air stability and effective energy barrier for magnetization reversal (Ueff) are shown. The three complexes share the common formula of [Dy(18-C-6)L2][I3] (18-C-6 = 1,4,7,10,13,16-hexaoxacyclooctadecane; L = I, 1; L = OtBu 2 and L = 1-AdO 3). 1 is highly unstable in the air. 2 can survive in the air for a few minutes, while 3 remains unchanged in the air for more than 1 week. This is roughly in accordance with the percentage of buried volumes of the axial ligands. More strikingly, 2 and 3 show progressive enhancement of Ueff and 3 exhibits a record high Ueff of 2427(19) K, which significantly contributes to the 100 s blocking temperature up to 11 K for Yttrium-diluted sample, setting a new benchmark for solid-state air-stable SMMs.

A C,S bonded quasi-two-coordinate chromium(II) complex showing field-induced slow magnetic relaxation behaviour.

A C,S bonded quasi-two-coordinate Cr(II) complex, Cr(SAr*)2 (HSAr* = HSC6H3-2,6(C6H2-2,4,6-Pri3)2), has been synthesized according to literature precedent. Magnetic measurements, high-frequency/field electron paramagnetic resonance (HF-EPR) experiments and ab initio calculation studies show that the field-induced slow magnetic relaxation behaviour is caused by relatively weak axial magnetic anisotropy.

Targeting C3b/C4b and VEGF with a bispecific fusion protein optimized for neovascular age-related macular degeneration therapy.

Antiangiogenesis therapies targeting vascular endothelial growth factor (VEGF) have revolutionized the treatment of neovascular ocular diseases, including neovascular age-related macular degeneration (nAMD). Compelling evidence has implicated the vital role of complement system dysregulation in AMD pathogenesis, implying it as a potential therapeutic strategy for geographic atrophy in dry AMD and to enhance the efficacy of anti-VEGF monotherapies in nAMD. This study reports the preclinical assessment and phase 1 clinical outcomes of a bispecific fusion protein, efdamrofusp alfa (code: IBI302), which is capable of neutralizing both VEGF isoforms and C3b/C4b. Efdamrofusp alfa showed superior efficacy over anti-VEGF monotherapy in a mouse laser-induced choroidal neovascularization (CNV) model after intravitreal delivery. Dual inhibition of VEGF and the complement activation was found to further inhibit macrophage infiltration and M2 macrophage polarization. Intravitreal efdamrofusp alfa demonstrated favorable safety profiles and exhibited antiangiogenetic efficacy in a nonhuman primate laser-induced CNV model. A phase 1 dose-escalating clinical trial (NCT03814291) was thus conducted on the basis of the preclinical data. Preliminary results showed that efdamrofusp alfa was well tolerated in patients with nAMD. These data suggest that efdamrofusp alfa might be effective for treating nAMD and possibly other complement-related ocular conditions.

A giant spin molecule with ninety-six parallel unpaired electrons.

Unpaired electrons which are essential for organic radicals and magnetic materials are hardly to align parallel, especially upon the increasing of spin numbers. Here, we show that the antiferromagnetic interaction in the largest Cr(III)-RE (rare earth) cluster {Cr10RE18} leads to 96 parallel electrons, forming a ground spin state S T of 48 for RE = Gd. This is so far the third largest ground spin state achieved in one molecule. Moreover, by using the classical Monte Carlo simulation, the exchange coupling constants J i j can be determined. Spin dynamics simulation reveals that the strong Zeeman effects of 18 Gd(III) ions stabilize the ground ferrimagnetic state and hinder the magnetization reversals of these spins. In addition, the dysprosium(III) analog is an exchange-biasing single-molecule magnet. We believe that the ferrimagnetic approach and analytical protocol established in this work can be applied generally in constructing and analyzing giant spin molecules.