The long noncoding RNA Synage regulates synapse stability and neuronal function in the cerebellum

The brain is known to express many long noncoding RNAs (lncRNAs); however, whether and how these lncRNAs function in modulating synaptic stability remains unclear. Here, we report a cerebellum highly expressed lncRNA, Synage, regulating synaptic stability via at least two mechanisms. One is through the function of Synage as a sponge for the microRNA miR-325-3p, to regulate expression of the known cerebellar synapse organizer Cbln1. The other function is to serve as a scaffold for organizing the assembly of the LRP1-HSP90AA1-PSD-95 complex in PF-PC synapses. Although somewhat divergent in its mature mRNA sequence, the locus encoding Synage is positioned adjacent to the Cbln1 loci in mouse, rhesus macaque, and human, and Synage is highly expressed in the cerebella of all three species. Synage deletion causes a full-spectrum cerebellar ablation phenotype that proceeds from cerebellar atrophy, through neuron loss, on to synapse density reduction, synaptic vesicle loss, and finally to a reduction in synaptic activity during cerebellar development; these deficits are accompanied by motor dysfunction in adult mice, which can be rescued by AAV-mediated Synage overexpression from birth. Thus, our study demonstrates roles for the lncRNA Synage in regulating synaptic stability and function during cerebellar development.Subject terms: RNA, Cell biology, Molecular biology, Neuroscience     

MiR‐342 controls Mycobacterium tuberculosis susceptibility by modulating inflammation and cell death

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb) that places a heavy strain on public health. Host susceptibility to Mtb is modulated by macrophages, which regulate the balance between cell apoptosis and necrosis. However, the role of molecular switches that modulate apoptosis and necrosis during Mtb infection remains unclear. Here, we show that Mtb‐susceptible mice and TB patients have relatively low miR‐342‐3p expression, while mice with miR‐342‐3p overexpression are more resistant to Mtb. We demonstrate that the miR‐342‐3p/SOCS6 axis regulates anti‐Mtb immunity by increasing the production of inflammatory cytokines and chemokines. Most importantly, the miR‐342‐3p/SOCS6 axis participates in the switching between Mtb‐induced apoptosis and necrosis through A20‐mediated K48‐linked ubiquitination and RIPK3 degradation. Our findings reveal several strategies by which the host innate immune system controls intracellular Mtb growth via the miRNA‐mRNA network and pave the way for host‐directed therapies targeting these pathways.     

Molecular Evolution of Threonine Dehydratase in Bacteria

Threonine dehydratase converts L-threonine to 2-ketobutyrate. Several threonine dehydratases exist in bacteria, but their origins and evolutionary pathway are unknown. Here we analyzed all the available threonine dehydratases in bacteria and proposed an evolutionary pathway leading to the genes encoding three different threonine dehydratases CTD, BTD1 and BTD2. The ancestral threonine dehydratase might contain only a catalytic domain, but one or two ACT-like subdomains were fused during the evolution, resulting BTD1 and BTD2, respectively. Horizontal gene transfer, gene fusion, gene duplication, and gene deletion may occur during the evolution of this enzyme. The results are important for understanding the functions of various threonine dehydratases found in bacteria.     

Inverted Design for High‐Performance Supercapacitor Via Co(OH)2‐Derived Highly Oriented MOF Electrodes

Metal organic frameworks (MOFs) are considered as promising candidates for supercapacitors because of high specific area and potential redox sites. However, their shuffled orientations and low conductivity nature lead to severely‐degraded performance. Designing an accessibly‐manipulated and efficient method to address those issues is of outmost significance for MOF application in supercapacitors. It is the common way that MOFs scarify themselves as templates or precursors to prepare target products. But to reversely think it, using target products to prepare MOF could be the way to unlock the bottleneck of MOFs' performance in supercapacitors. Herein, a novel strategy using Co(OH)₂ as both the template and precursor to fabricate vertically‐oriented MOF electrode is proposed. The electrode shows a double high specific capacitance of 1044 Fg^?1 and excellent rate capability compared to MOF in powder form. An asymmetric supercapacitor was also fabricated, which delivers a maximum energy density of 28.5 W h kg^?1 at a power density of 1500 W kg^?1, and the maximum of 24000 W kg^?1 can be obtained with a remaining energy density of 13.3 W h kg^?1. Therefore, the proposed strategy paves the way to unlock the inherent advantages of MOFs and also inspires for advanced MOF synthesis with optimum performance.     

Effect of land use type on metals accumulation and risk assessment in soil in the peri-urban area of Beijing,China

Heavy metal concentrations of As, Cd, Cu, Hg, Ni, Pb, and Zn were investigated for 107 soil samples collected from crop land, orchard land, greenhouse land, and wood land in the peri-urban area of Beijing, China. The mean concentrations of As, Cd, Cu, Hg, Ni, Pb, and Zn in all soil samples were 8.40, 0.20, 24.7, 0.08, 25.0, 23.0, and 77.1 mg/kg, dw, respectively. Among the four land use types, the Cd concentration in greenhouse land was significantly higher than the other three kinds of land uses (p < .05), and Cu and Zn concentrations in greenhouse land were significantly higher than in crop land and wood land (p < .05). Based on principal component analysis, elevated Cu, Zn, and Cd concentrations in greenhouse land might have originated from high application rates of manure and fertilizer. According to an ecological risk analysis, the four land use types can be ranked in the following order: greenhouse land > orchard land > crop land > wood land. However, the degree of non-cancer risk for both adults and children in different land uses decreased in the order of greenhouse land > orchard land > wood land > crop land.     

Chitosan IFN-γ-pDNA Nanoparticle (CIN) Therapy for Allergic Asthma

Background  

Allergic subjects produce relatively low amounts of IFN-γ, a pleiotropic Th-1 cytokine that downregulates Th2-associated airway inflammation and hyperresponsiveness (AHR), the hallmarks of allergic asthma. Adenovirus-mediated IFN-γ gene transfer reduces AHR, Th2 cytokine levels and lung inflammation in mice, but its use would be limited by the frequency of gene delivery required; therefore, we tested chitosan/IFN-γ pDNA nanoparticles (CIN) for in situ production of IFN-γ and its in vivo effects.     

Aligning the proteome and genome of the silkworm, Bombyx mori

A technology of mass spectrometry (MS) was used in this study for the large-scale proteomic identification and verification of protein-encoding genes present in the silkworm (Bombyx mori) genome. Peptide sequences identified by MS were compared with those from an open reading frame (ORF) library of the B. mori genome and a cDNA library, to validate the coding attributes of ORFs. Two databases were created. The first was based on a 9× draft sequence of the silkworm genome and contained 14,632 putative proteins. The second was based on a B. mori pupal cDNA library containing 3,187 putative proteins of at least 30 amino acid residues in length. A total of 81,000 peptide sequences with a threshold score of 60% were generated by the MS/MS analysis, and 55,400 of these were chosen for a sequence alignment. By searching these two databases, 6,649 and 250 proteins were matched, which accounted for approximately 45.4% and 7.8% of the peptide sequences and putative proteins, respectively. Further analyses carried out by several bioinformatic tools suggested that the matches included proteins with predicted transmembrane domains (1,393) and preproteins with a signal peptide (976). These results provide a fundamental understanding of the expression and function of silkworm proteins.     

Extracellular matrix-mediated signaling by dentin phosphophoryn involves activation of the Smad pathway independent of bone morphogenetic protein

Cells have ingenious mechanisms for interpreting complex signals from their external microenvironment. Previously, we have shown that phosphophoryn (PP) regulates the expression of bone/dentin marker genes via the integrin/MAPK signaling pathway (Jadlowiec, J., Koch, H., Zhang, X., Campbell, P. G., Seyedain, M., and Sfeir, C. (2004) J. Biol. Chem. 279, 53323-53330). We hypothesize that other signaling pathways important for mineralized tissue morphogenesis such as the Smad pathway could be involved in PP signaling. We determined activation of the Smad pathway in human adult mesenchymal stem cells following treatment with recombinant PP (rPP). We observed that PP enhanced phosphorylation of Smad1 within 30 min and Smad1 translocation to the nucleus within 1 h. PP up-regulated the expression of Smad1 target genes, Smad6, Dlx5, and Runx2. The timing of PP activation of Smad1 implies this is a direct effect; however, we also investigated the possible involvement of bone morphogenetic proteins in PP stimulation of the Smad pathway. PP was shown to up-regulate Bmp-2 gene expression 12 h post-treatment with PP, which is much later than initial detection of Smad1 phosphorylation at 30 min. Furthermore, addition of Noggin did not block Smad1 phosphorylation by PP. We propose that PP could signal via the Smad pathway by either directly stimulating the phosphorylation of Smad1 via integrins or other mechanisms. These might include integrin/bone morphogenetic protein receptor interactions or involvement of PP with other growth factors leading to the modulation of intracellular signaling. It is noteworthy that a non-transforming growth factor-beta family member activates the Smad pathway. The role of PP in regulating the Smad pathway raises very interesting questions regarding the role of PP during bone and tooth development.