Oxidation of the catecholaminergic neurotransmitter dopamine (1) at physiological pH normally results in formation of black, insoluble melanin polymer. In this study, it is demonstrated that L-cysteine (CySH) can divert the melanin pathway by scavenging the proximate o-quinone oxidation product of 1 to give 5-S-cysteinyldopamine (8). This cysteinyl conjugate is further oxidized in the presence of free CySH to give 7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H- 1,4-benzothiazine-3-carboxylic acid (11) and its 6-S-cysteinyl (12), 8-S-cysteinyl (14), and 6,8-di-S-cysteinyl (16) conjugates in addition to many other unidentified compounds. 5-S-Cysteinyldopamine (8) and dihydrobenzothiazines 11, 12, 14, and 16 are all more easily oxidized than 1. With increasing molar excesses of CySH, the formation of melanin is decreased and, ultimately, completely blocked. Preliminary experiments have revealed that when injected into the brains of laboratory mice, dihydrobenzothiazine 11 and its cysteinyl conjugates 12 and 14 are lethal and evoke profound behavioral responses including hyperactivity and tremor. On the basis of these results and other recent observations, a new hypothesis has been advanced which might help explain the selective degeneration of nigrostriatal dopaminergic neurons which occurs in idiopathic Parkinson's Disease (PD). This hypothesis proposes that in response to some form of chronic brain insult, the activity of gamma-glutamyltranspeptidase is upregulated leading to an increased rate of translocation of glutathione (GSH) into the cytoplasm of dopaminergic cell bodies in the substantia nigra (SN) para compacta. The results of this in vitro study predict that such an elevated translocation of GSH into heavily pigmented dopaminergic neurons would cause a diversion of the neuromelanin pathway with consequent depigmentation of these cells and formation of 8, all of which occur in the Parkinsonian SN. The further very facile oxidation of 8 which must occur under intraneuronal conditions where 1 is autoxidized, i.e., in neuromelanin-pigmented cells, would lead to dihydrobenzothiazine 11 and its cysteinyl conjugates which could be the endotoxins responsible for the selective degeneration of dopaminergic SN neurons in PD. The ease of autoxidation of 8 is suggested to account for the low levels of this conjugate found in the degenerating and Parkinsonian SN.(ABSTRACT TRUNCATED AT 400 WORDS)

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Recently emerged metal halide perovskites have been widely recognized as a promising class of semiconductor materials for next-generation optoelectronic devices, owing to their useful photonic and electronic properties. [1][2][3] Particularly, Lead-free 0D metal halide perovskites are emerging environmentally friendly materials exhibiting large exciton binding energy, which have recently attracted great attention for their excellent light emission properties and favorable stability. Herein, solvent evaporation crystallization at room temperature is adopted to fabricate 0D Cs 3 Cu 2 I 5 perovskite millimeter-sized crystals, which show strong blue photoluminescence (PL) with quantum yield of up to 89%, a large Stockes shift and long (microsecond) PL lifetime, originating from selftrapped excitons. UV pumped light-emitting diodes are demonstrated by using Cs 3 Cu 2 I 5 powder as a solid-state phosphor, and the precursor solution of these perovskite crystals is used as a fluorescent ink. Furthermore, blue-emitting composite Cs 3 Cu 2 I 5 /polyvinylidene fluoride films are produced by spin coating through the solvent evaporation and followed patterning using a direct laser writing technology, which are potentially useful for displays. Finally, the solvent evaporation crystallization method is expanded to fabricate yellow emissive CsCu 2 I 3 crystals by changing the chemical molar ratio of precursor.

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Lead halide perovskites have drawn extensive attention over recent decades owing to their outstanding photoelectric performances. However, their toxicity and instability are big issues that need to be solved for further commercialization. Herein, we adopt a facile dry ball milling method to synthesize lead-free Cs 3 Cu 2 X 5 ( X = I , Cl) perovskites with photoluminescence (PL) quantum yield up to 60%. The optical features including broad emission spectrum, large Stokes shift, and long PL lifetime can be attributed to self-trapped exciton recombination. The as-synthesized blue emissive Cs 3 Cu 2 I 5 and green emissive Cs 3 Cu 2 Cl 5 lead-free perovskite powders have good thermal stability and photostability. Furthermore, UV-pumped phosphor-converted light-emitting diodes were obtained by using Cs 3 Cu 2 I 5 and Cs 3 Cu 2 Cl 5 as phosphors.

Electron tomography (ET) plays an important role in revealing biological structures, ranging from macromolecular to subcellular scale. Due to limited tilt angles, ET reconstruction always suffers from the 'missing wedge' artifacts, thus severely weakens the further biological interpretation. In this work, we developed an algorithm called Iterative Compressed-sensing Optimized Non-uniform fast Fourier transform reconstruction (ICON) based on the theory of compressed-sensing and the assumption of sparsity of biological specimens. ICON can significantly restore the missing information in comparison with other reconstruction algorithms. More importantly, we used the leave-one-out method to verify the validity of restored information for both simulated and experimental data. The significant improvement in sub-tomogram averaging by ICON indicates its great potential in the future application of high-resolution structural determination of macromolecules in situ.

Viruses are the most abundant biological entities and carry a wide variety of genetic material, including the ability to encode host-like proteins. Here we show that viruses carry sequences with significant homology to several human peptide hormones including insulin, insulin-like growth factors (IGF)-1 and -2, FGF-19 and -21, endothelin-1, inhibin, adiponectin, and resistin. Among the strongest homologies were those for four viral insulin/IGF-1-like peptides (VILPs), each encoded by a different member of the family VILPs show up to 50% homology to human insulin/IGF-1, contain all critical cysteine residues, and are predicted to form similar 3D structures. Chemically synthesized VILPs can bind to human and murine IGF-1/insulin receptors and stimulate receptor autophosphorylation and downstream signaling. VILPs can also increase glucose uptake in adipocytes and stimulate the proliferation of fibroblasts, and injection of VILPs into mice significantly lowers blood glucose. Transfection of mouse hepatocytes with DNA encoding a VILP also stimulates insulin/IGF-1 signaling and DNA synthesis. Human microbiome studies reveal the presence of these in blood and fecal samples. Thus, VILPs are members of the insulin/IGF superfamily with the ability to be active on human and rodent cells, raising the possibility for a potential role of VILPs in human disease. Furthermore, since only 2% of viruses have been sequenced, this study raises the potential for discovery of other viral hormones which, along with known virally encoded growth factors, may modify human health and disease.

Previous studies demonstrated that oxidation of dopamine (DA) in the presence of L-cysteine (CySH) at pH 7.4 gives a complex mixture of cysteinyl conjugates of the neurotransmitter that can be easily further oxidized to a number of dihydrobenzothiazines (DHBTs) along with unidentified yellow products. In this investigation, three of these products have been identified. 7-(2 Aimoethyl)-5-hydroxy-1,4-benzothiazine-3-carboxylic acid (BT-1) is formed as a result of oxidation of 5-S-cysteinyldopamine (5-S-CyS-DA) and 7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid (DHBT-1). Regioisomers 6-(2-aminoethyl)-1,8,9,10-tetrahydrobenzo[1,2-b:4,3-b']bis[1,4] thiazine-9-carboxylic acid (12) and 6-(2-aminoethyl)-1,2,3,10-tetrahydrobenzo[1,2-b:4,3-b']bis[1,4] thiazine-2-carboxylic acid (13) are formed by oxidation of 2,5-bi-S-CyS-DA), 6-S-cysteinyl-7-(2-aminoethyl)-3-4-dihydro-5-hydroxy-2H-1, 4-benzothiazine-3-carboxylic acid (DHBT-2) and 6-S-cysteinyl-8(2-aminoethyl)-3,4-dihydro-2H-1,4-benzothiazine-3-carboxy lic acid (DHBT-6). 2,5-Bi-S-CyS-DA, DHBT-2, and DHBT-6 are major early products of DA oxidation in the presence of CySH. However, because these three compounds are the most easily oxidized products formed in this reaction, they are subsequently transformed into 12 and 13, the latter regioisomer always being the major product. Both 12 (LD50 = 18.5 micrograms) and 13 (LD50 = 1.5 microgram) are lethal when administered into the brains of mice and evoke hyperactivity and tremor. The potential relevance of the in vitro chemistry described in this and earlier reports to reaction that might occur in neuromelanin-pigmented dopaminergic neurons in Parkinson's disease is discussed.