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 = Ot Bu 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.

{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.

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.

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.

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.

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 cation-dependent inverse hydrogen bonds and magnetic exchange-couplings in lanthanacarborane complexes.

Ten lanthanacarborane complexes were synthesized to study the rare B-Hδ-∙∙∙Mn+ inverse hydrogen bonds (IHBs). The average bonding energy of B-Hδ-∙∙∙Ln3+ is theoretically determined to be larger than 24 kJ/mol, which is comparable to moderately strong hydrogen bonds (21-56 kJ/mol). In addition to NMR and IR, magnetometer was used to study the exchange-coupling interaction via such B-Hδ-∙∙∙Ln3+ IHBs in detail, and the coupling constant is determined to be -2.0 cm-1, which is strong enough to compare with single-atom bridged dysprosium(III) complexes. Two imidazolin-iminato incorporated complexes have shown energy barrier for magnetization reversal larger than 1000 K, and the exchange-biasing effects are evident. Moreover, the bonding strengths of B-Hδ-∙∙∙Mn+ IHBs are cation-dependent. If M = Na, the B-Hδ-∙∙∙Na+ bonding energy is reduced to 14 kJ/mol, and the dimerization process is no longer reversible. The exchange-biasing effect is also disappeared. We believe such a finding extends our knowledge of IHBs.

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.

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.

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.

xCT regulates redox homeostasis and promotes photoreceptor survival after retinal detachment.

BACKGROUNDS: Photoreceptor degeneration underlies various retinal disorders that lead to vision impairment. Currently, no effective medication is available to rescue photoreceptors under disease conditions. Elucidation of the molecular pathways involved in photoreceptor degeneration is a prerequisite for the rational design of therapeutic interventions. Photoreceptors are among the most energy-demanding tissues that require highly active oxidative phosphorylation. Therefore, disruption of metabolic support to photoreceptors results in a redox imbalance and subsequent cell death. We hypothesize that the redox regulatory pathway could be a potential therapeutic target to rescue photoreceptors under disease conditions. METHODS: Experimental retinal detachment was induced in mice. A murine photoreceptor-derived 661w cell line treated with H2O2 was employed as an in vitro model to study the cellular response to oxidative stress. The expression and functional role of xCT, an upstream regulator of redox homeostasis, was assessed in vivo and in vitro. An xCT expression vector was constructed for an in vivo study to evaluate the therapeutic potential of this molecule. RESULTS: xCT expression was upregulated in detached retina and H2O2-stimulated 661w cells compared to the control cells. Pharmacological inhibition of xCT by sulfasalazine (SAS) promoted photoreceptor degeneration after retinal detachment and 661w cell death upon H2O2 treatment. Additionally, SAS treatment induced reactive oxidative species (ROS) accumulation, glutathione (GSH) depletion, and glutamate release in 661w cells. In contrast, xCT overexpression via viral infection protected photoreceptors from degeneration after retinal detachment. CONCLUSION: We conclude that xCT expression is upregulated in photoreceptors after retinal detachment and plays a neuroprotective role in preserving photoreceptors. Mechanistically, xCT promotes cellular homeostasis by regulating intracellular ROS and GSH levels, which are critical to photoreceptor survival after retinal detachment. Collectively, our findings identify xCT as a potential therapeutic target for protection of photoreceptors under disease conditions.

Photoreceptors Degenerate Through Pyroptosis After Experimental Retinal Detachment.

Purpose: Gasdermin D (GSDMD) is crucial in neuronal pyroptosis. GSDMD-N and GSDMD-C are two subdomains of the protein GSDMD. GSDMD-N is an executor of pyroptosis, and GSDMD-C has an inhibitory effect on pyroptotic cell death. This study evaluated the role of GSDMD in photoreceptor cell pyroptosis caused by retinal detachment (RD). Methods: RD models were established in rats, and GSDMD cleavage was detected by western blotting. The morphology of photoreceptors was assessed by transmission electron microscopy. Some rats were given subretinal injections of recombinant adeno-associated virus 2/8 (rAAV2/8)-GSDMD-C before RD surgery. We documented the expression of caspase-1 and GSDMD-N in retinas by western blot. Levels of IL-1ß, TNF-α, and monocyte chemoattractant protein-1 (MCP-1) were detected by quantitative RT-PCR. The membrane integrity of photoreceptors was evaluated by TOTO-3 iodide staining. Retinal function was measured by electroretinography, and the thickness of the outer nuclear layer was also recorded. We measured the activation of glial fibrillary acidic protein (GFAP), F4/80, and ionized calcium binding adaptor molecule 1 (Iba-1) by immunofluorescence. Results: The cleavage of GSDMD peaked at 1 day after RD. The administration of rAAV2/8-GSDMD-C reduced the pyroptosis and subsequent apoptosis of photoreceptors and preserved the retinal function after RD. Expression of IL-1, TNF-α, and MCP-1 was decreased in the rAAV2/8-GSDMD-C group. In addition, the activation of GFAP, Iba-1, and F4/80 in retinas was alleviated by administering rAAV2/8-GSDMD-C after RD. Conclusions: GSDMD participates in the pyroptosis of photoreceptor after RD. Overexpression of GSDMD-C may block GSDMD cleavage and attenuate photoreceptor degeneration.

Terbium-fluorido cluster: an energy cage for photoluminescence.

We report here that energy migration during luminescence can be extremely minimized by caging the fluorescent centers in a molecular cluster of [Tb6(µ3-F)8(piv)10(Hpiv)4DMF]·xDMF·yH2O 1. Experimental and theoretical simulations reveal that bonding terbium with fluoride is the key to reducing the non-radiative multi-phonon relaxation processes, which is disparate to the common hydroxy-based lanthanide clusters.

3-Methyladenine Alleviates Experimental Subretinal Fibrosis by Inhibiting Macrophages and M2 Polarization Through the PI3K/Akt Pathway.

Purpose: To explore the effects of 3-methyladenine (3-MA), a selective inhibitor of phosphatidylinositol-3-kinase (PI3K), on experimental subretinal fibrosis (SRF) in mice. Methods: The SRF mouse model was established by 532 nm laser photocoagulation at each fundus of mice on day 0. 3-MA was administered every 2 days from day 0 to 35. Immunofluorescence of choroidal flat mounts was performed to evaluate the size of SRF area, local macrophages, and polarization, respectively. Besides, Western blot analysis was carried out to assess the expression levels of macrophage polarization-related genes, Arg-1, Ym-1, and transforming growth factor-ß2 (TGF-ß2). Co-culture and migration experiments were used to demonstrate the inhibitory effect of 3-MA on fibroblasts. The gene knockout and Western blot analysis were used to explore the signal pathways related to macrophage polarization. Results: Compared with the control group, the 3-MA-treated group showed significantly less size of SRF area. 3-MA treatment reduced both circulating and local macrophages, and counteracted M2 polarization. Moreover, 3-MA inhibited fibroblast recruitment. Mechanistically, we proved that 3-MA inhibits macrophage M2 polarization by suppressing PI3K/Akt signal pathway rather than the PI3K-autophagy-related signal pathway. Conclusions: 3-MA exerts antifibrotic effects on experimental SRF by targeting circulating and local macrophages and M2 polarization, through PI3K/Akt signal pathway. These results support the potential use of 3-MA as a new therapeutic modality for SRF associated with neovascular age-related macular degeneration.

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.

A stable dysprosium(iii) complex with a terminal fluoride ligand showing high resolution luminescence and slow magnetic relaxation.

An air-stable dysprosium(iii) complex, [C(NH2)3]4[DyF(piv)4](piv)2 (piv = pivalate), with a terminal fluoride ligand protected by forming extensive hydrogen bonds with peripheral guanidiniums has been isolated. Though the magnetic data failed to determine the energy barrier for the magnetic reversal (Ueff) accurately, the fine emission spectrum of the 4F9/2→6H15/2 transition at 4.2 K and ab initio calculations reveal that the Ueff is about 376(20) K, which is among the highest for high-coordinate (coordination numbers ≥ 9) lanthanide mononuclear magnets.

Understanding a pentagonal-bipyramidal holmium(iii) complex with a record energy barrier for magnetisation reversal.

We report herein three pentagonal-bipyramidal holmium(iii) complexes sharing the formula [Ho(L)2(py)5][BPh4], where L is the alkoxide ligand. For L = (OSi(CH3)3)-, a record energy barrier for magnetization reversal (Ueff = 715(6) K) was revealed, which is due to the pure state transition of mJ = |±8〉→mJ = |±7〉→mJ = |±6〉.

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.