Synthetic alpha-synuclein fibrils cause mitochondrial impairment and selective dopamine neurodegeneration in part via iNOS-mediated nitric oxide production

Intracellular accumulation of α-synuclein (α-syn) are hallmarks of synucleinopathies, including Parkinson’s disease (PD). Exogenous addition of preformed α-syn fibrils (PFFs) into primary hippocampal neurons induced α-syn aggregation and accumulation. Likewise, intrastriatal inoculation of PFFs into mice and non-human primates generates Lewy bodies and Lewy neurites associated with PD-like neurodegeneration. Herein, we investigate the putative effects of synthetic human PFFs on cultured rat ventral midbrain dopamine (DA) neurons. A time- and dose-dependent accumulation of α-syn was observed following PFFs exposure that also underwent phosphorylation at serine 129. PFFs treatment decreased the expression levels of synaptic proteins, caused alterations in axonal transport-related proteins, and increased H2AX Ser139 phosphorylation. Mitochondrial impairment (including modulation of mitochondrial dynamics-associated protein content), enhanced oxidative stress, and an inflammatory response were also detected in our experimental paradigm. In attempt to unravel a potential molecular mechanism of PFFs neurotoxicity, the expression of inducible nitric oxide synthase was blocked; a significant decline in protein nitration levels and protection against PFFs-induced DA neuron death were observed. Combined exposure to PFFs and rotenone resulted in an additive toxicity. Strikingly, many of the harmful effects found were more prominent in DA rather than non-DA neurons, suggestive of higher susceptibility to degenerate. These findings provide new insights into the role of α-syn in the pathogenesis of PD and could represent a novel and valuable model to study DA-related neurodegeneration.     

Structural,elemental, optical and magnetic study of Fe doped ZnO and impurity phase formation

We have prepared a series of(ZnO)1-x(Fe2O3)x≤0.10bulk samples with various concentrations of Fe dopant by ball milling and investigated their structural, compositional, optical and magnetic properties by means of X-ray diffraction(XRD), X-ray photoelectron spectroscopy(XPS),Raman spectrometer and vibrating sample magnetometer(VSM), respectively. Information about different impurity phases was obtained through Rietveld refinements of XRD data analysis. XPS results showed different valence states(Fe2+ tand Fe3+) supported by shaking satellite peaks in samples. With increasing Fe doping percentage, the crystal quality deteriorated and a shift of E2 low band(characteristic of ZnO) has been observed in Raman spectra. Energy band gap estimated from reflectance UV–vis spectroscopy showed shift for all bulk samples. The magnetic behavior was examined using a vibrating sample magnetometer(VSM), indicating ferromagnetic behavior at room temperature(300 K). The effective magnetic moment per Fe atom decreases with increase in doping percentage which indicates that ferromagnetic behavior arises from the substitution of Fe ions in the ZnO lattice.     

Inhibition of Rho-associated kinase relieves C5a-induced proteinuria in murine nephrotic syndrome

Childhood nephrotic syndrome is mainly caused by minimal change disease which is named because only subtle ultrastructural alteration could be observed at electron microscopic level in the pathological kidney. Glomerular podocytes are presumed to be the target cells whose protein sieving capability is compromised by a yet unidentified permeability perturbing factor. In a cohort of children with non-hereditary idiopathic nephrotic syndrome, we found the complement fragment C5a was elevated in their sera during active disease. Administration of recombinant C5a induced profound proteinuria and minimal change nephrotic syndrome in mice. Purified glomerular endothelial cells, instead of podocytes, were demonstrated to be responsible for the proteinuric effect elicited by C5a. Further studies depicted a signaling pathway involving Rho/Rho-associated kinase/myosin activation leading to endothelial cell contraction and cell adhesion complex breakdown. Significantly, application of Rho-associated kinase inhibitor, Y27632, prevented the protein leaking effects observed in both C5a-treated purified endothelial cells and mice. Taken together, our study identifies a previously unknown mechanism underlying nephrotic syndrome and provides a new insight toward identifying Rho-associated kinase inhibition as an alternative therapeutic option for nephrotic syndrome.     

超薄高分子材料热管(英文)

热管具有远高于大多数金属的导热性能,已被广泛应用于电子元器件的散热方面.由于电子元器件正朝着微型化、薄型化、片式化和高功率等趋势发展,因此散热元件必须同时具备轻薄和高导热系数的特点.本文介绍了一种由高分子材料制造的超薄热管的设计和制造过程.其厚度为0.30 mm,大小为2 cm×6 cm,输入功率为9.54 W时,有效传热系数为541 W/(m K).管壳材料为kapton薄膜,吸液芯和蒸汽腔均由光阻SU8组成,光阻SU8柱子的大小和柱子之间的间隔差异为吸液芯提供了毛细血力;另外,通过原子层积电镀,SU8光阻和kapton薄膜都覆盖上一层极薄的Ti O2膜,改善了表面和吸液芯的亲水性能,同时实现了密封.     

Conserved amino acids participate in the structure networks deputed to intramolecular communication in the lutropin receptor

The luteinizing hormone receptor (LHR) is a G protein-coupled receptor (GPCR) particularly susceptible to spontaneous pathogenic gain-of-function mutations. Protein structure network (PSN) analysis on wild-type LHR and two constitutively active mutants, combined with in vitro mutational analysis, served to identify key amino acids that are part of the regulatory network responsible for propagating communication between the extracellular and intracellular poles of the receptor. Highly conserved amino acids in the rhodopsin family GPCRs participate in the protein structural stability as network hubs in both the inactive and active states. Moreover, they behave as the most recurrent nodes in the communication paths between the extracellular and intracellular sides in both functional states with emphasis on the active one. In this respect, non-conservative loss-of-function mutations of these amino acids is expected to impair the most relevant way of communication between activating mutation sites or hormone-binding domain and G protein recognition regions.     

Technical approaches to induce selective cell death of pluripotent stem cells

Despite the recent promising results of clinical trials using human pluripotent stem cell (hPSC)-based cell therapies for age-related macular degeneration (AMD), the risk of teratoma formation resulting from residual undifferentiated hPSCs remains a serious and critical hurdle for broader clinical implementation. To mitigate the tumorigenic risk of hPSC-based cell therapy, a variety of approaches have been examined to ablate the undifferentiated hPSCs based on the unique molecular properties of hPSCs. In the present review, we offer a brief overview of recent attempts at selective elimination of undifferentiated hPSCs to decrease the risk of teratoma formation in hPSC-based cell therapy.     

Collective cell migration has distinct directionality and speed dynamics

When a constraint is removed, confluent cells migrate directionally into the available space. How the migration directionality and speed increase are initiated at the leading edge and propagate into neighboring cells are not well understood. Using a quantitative visualization technique—Particle Image Velocimetry (PIV)—we revealed that migration directionality and speed had strikingly different dynamics. Migration directionality increases as a wave propagating from the leading edge into the cell sheet, while the increase in cell migration speed is maintained only at the leading edge. The overall directionality steadily increases with time as cells migrate into the cell-free space, but migration speed remains largely the same. A particle-based compass (PBC) model suggests cellular interplay (which depends on cell–cell distance) and migration speed are sufficient to capture the dynamics of migration directionality revealed experimentally. Extracellular Ca²⁺ regulated both migration speed and directionality, but in a significantly different way, suggested by the correlation between directionality and speed only in some dynamic ranges. Our experimental and modeling results reveal distinct directionality and speed dynamics in collective migration, and these factors can be regulated by extracellular Ca²⁺ through cellular interplay. Quantitative visualization using PIV and our PBC model thus provide a powerful approach to dissect the mechanisms of collective cell migration.