Field-Induced Slow Magnetic Relaxation In the First Dy(III)-centered 12-Metallacrown-4 Double-Decker

The reaction of Dy(O2CMe)3•xH2O and Ga(NO3)3•xH2O led to the isolation of (nBu4N)[GaIII8DyIII(OH)4(shi)8] (1). The compound possesses a unique chemical structure enclosing the central magnetic DyIII ion between diamagnetic GaIII-based metallacrown 12-MC-4 ligands. The double-decker complex exhibits field-induced single-molecule magnet (SMM) behaviour with an effective energy barrier (Ueff) of 39 K (27.1 cm-1). Consistent with the observed slow relaxation of magnetization, theoretical calculations suggest a ground state mainly determined by |±11/2> in the easy axis direction

A nonlinear spring mechanism incorporating a bistable composite plate for vibration isolation

The High Static Low Dynamic Stiffness (HSLDS) concept is a design strategy for a nonlinear anti-vibration mount that seeks to increase isolation by lowering the natural frequency of the mount whilst maintaining the same static load bearing capacity. It has previously been proposed that an HSLDS mount could be implemented by connecting linear springs in parallel with the transverse flexure of a composite bistable plate — a plate that has two stable shapes between which it may snap. Using a bistable plate in this way will lead to lightweight and efficient designs of HSLDS mounts. This paper experimentally demonstrates the feasibility of this idea. Firstly, the quasi-static force–displacement curve of a mounted bistable plate is determined experimentally. Then the dynamic response of a nonlinear mass–spring system incorporating this plate is measured. Excellent agreement is obtained when compared to theoretical predictions based on the measured force–displacement curve, and the system shows a greater isolation region and a lower peak response to base excitation than the equivalent linear system

Mantra 2.0: An online collaborative resource for drug mode of action and repurposing by network analysis

Elucidation of molecular targets of a compound (mode of action, MoA) and of its off-targets is a crucial step in drug development. We developed an online collaborative resource (MANTRA 2.0) that supports this process by exploiting similarities between drug-induced transcriptional profiles. Drugs are organised in a network of nodes (drugs) and edges (similarities) highlighting “communities” of drugs sharing a similar MoA. A user can upload gene expression profiles (GEPs) before and after drug treatment in one or multiple cell types. An automated processing pipeline transforms the GEPs into a unique drug ”node” embedded in the drug-network. Visual inspection of the neighbouring drugs and communities helps in revealing its MoA, and to suggest new applications of known drugs (drug repurposing). MANTRA 2.0 allows storing and sharing user-generated network nodes, thus making MANTRA 2.0 a collaborative ever-growing resource

A Vanadium(III) Complex with Blue and NIR-II Spin-Flip Luminescence in Solution

Luminescence from Earth-abundant metal ions in solution at room temperature is a very challenging objective due to the intrinsically weak ligand field splitting of first-row transition metal ions, which leads to efficient nonradiative deactivation via metal-centered states. Only a handful of 3dn metal complexes (n ≠ 10) show sizable luminescence at room temperature. Luminescence in the near-infrared spectral region is even more difficult to achieve as further nonradiative pathways come into play. No Earth-abundant first-row transition metal complexes have displayed emission >1000 nm at room temperature in solution up to now. Here, we report the vanadium(III) complex mer-[V(ddpd)2][PF6]3 yielding phosphorescence around 1100 nm in valeronitrile glass at 77 K as well as at room temperature in acetonitrile with 1.8 × 10–4% quantum yield (ddpd = N,N′-dimethyl-N,N′-dipyridine-2-ylpyridine-2,6-diamine). In addition, mer-[V(ddpd)2][PF6]3 shows very strong blue fluorescence with 2% quantum yield in acetonitrile at room temperature. Our comprehensive study demonstrates that vanadium(III) complexes with d2 electron configuration constitute a new class of blue and NIR-II luminophores, which complement the classical established complexes of expensive precious metals and rare-earth elements

Synthetic long non-coding RNAs [SINEUPs] rescue defective gene expression in vivo

Non-coding RNAs provide additional regulatory layers to gene expression as well as the potential to being exploited as therapeutic tools. Non-coding RNA-based therapeutic approaches have been attempted in dominant diseases, however their use for treatment of genetic diseases caused by insufficient gene dosage is currently more challenging. SINEUPs are long antisense non-coding RNAs that up-regulate translation in mammalian cells in a gene-specific manner, although, so far evidence of SINEUP efficacy has only been demonstrated in in vitro systems. We now show that synthetic SINEUPs effectively and specifically increase protein levels of a gene of interest in vivo. We demonstrated that SINEUPs rescue haploinsufficient gene dosage in a medakafish model of a human disorder leading to amelioration of the disease phenotype. Our results demonstrate that SINEUPs act through mechanisms conserved among vertebrates and that SINEUP technology can be successfully applied in vivo as a new research and therapeutic tool for gene-specific up-regulation of endogenous functional proteins

miR-181a/b downregulation exerts a protective action on mitochondrial disease models.

Mitochondrial diseases (MDs) are a heterogeneous group of devastating and often fatal disorders due to defective oxidative phosphorylation. Despite the recent advances in mitochondrial medicine, effective therapies are still not available for these conditions. Here, we demonstrate that the microRNAs miR-181a and miR-181b (miR-181a/b) regulate key genes involved in mitochondrial biogenesis and function and that downregulation of these miRNAs enhances mitochondrial turnover in the retina through the coordinated activation of mitochondrial biogenesis and mitophagy. We thus tested the effect of miR-181a/b inactivation in different animal models of MDs, such as microphthalmia with linear skin lesions and Leber\u27s hereditary optic neuropathy. We found that miR-181a/b downregulation strongly protects retinal neurons from cell death and significantly ameliorates the disease phenotype in all tested models. Altogether, our results demonstrate that miR-181a/b regulate mitochondrial homeostasis and that these miRNAs may be effective gene-independent therapeutic targets for MDs characterized by neuronal degeneration

An integrated genomic approach to dissect the genetic landscape regulating the cell-to-cell transfer of α-synuclein

Neuropathological and experimental evidence suggests that the cell-to-cell transfer of α-synuclein has an important role in the pathogenesis of Parkinson's disease (PD). However, the mechanism underlying this phenomenon is not fully understood. We undertook a small interfering RNA (siRNA), genome-wide screen to identify genes regulating the cell-to-cell transfer of α-synuclein. A genetically encoded reporter, GFP-2A-αSynuclein-RFP, suitable for separating donor and recipient cells, was transiently transfected into HEK cells stably overexpressing α-synuclein. We find that 38 genes regulate the transfer of α-synuclein-RFP, one of which is ITGA8, a candidate gene identified through a recent PD genome-wide association study (GWAS). Weighted gene co-expression network analysis (WGCNA) and weighted protein-protein network interaction analysis (WPPNIA) show that those hits cluster in networks that include known PD genes more frequently than expected by random chance. The findings expand our understanding of the mechanism of α-synuclein spread