Disruption of mitochondrial complex I induces progressive parkinsonism

Loss of functional mitochondrial complex I (MCI) in the dopaminergic neurons of the substantia nigra is a hallmark of Parkinson’s disease1. Yet, whether this change contributes to Parkinson’s disease pathogenesis is unclear2. Here we used intersectional genetics to disrupt the function of MCI in mouse dopaminergic neurons. Disruption of MCI induced a Warburg-like shift in metabolism that enabled neuronal survival, but triggered a progressive loss of the dopaminergic phenotype that was first evident in nigrostriatal axons. This axonal deficit was accompanied by motor learning and fine motor deficits, but not by clear levodopa-responsive parkinsonism—which emerged only after the later loss of dopamine release in the substantia nigra. Thus, MCI dysfunction alone is sufficient to cause progressive, human-like parkinsonism in which the loss of nigral dopamine release makes a critical contribution to motor dysfunction, contrary to the current Parkinson’s disease paradigm.Electron microscopy tissue processing and imaging was performed at the Northwestern University Center for Advanced Microscopy, supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. This study was supported by grants from the Michael J. Fox Foundation (to D.J.S.), the JPB Foundation (to D.J.S.), the IDP Foundation (to D.J.S.), the Flanagan Fellowship (to P.G.-R.) and the European Research Council ERC Advanced Grant PRJ201502629 (to J.L.-B.)

Current trends in drug metabolism and pharmacokinetics.

Pharmacokinetics (PK) is the study of the absorption, distribution, metabolism, and excretion (ADME) processes of a drug. Understanding PK properties is essential for drug development and precision medication. In this review we provided an overview of recent research on PK with focus on the following aspects: (1) an update on drug-metabolizing enzymes and transporters in the determination of PK, as well as advances in xenobiotic receptors and noncoding RNAs (ncRNAs) in the modulation of PK, providing new understanding of the transcriptional and posttranscriptional regulatory mechanisms that result in inter-individual variations in pharmacotherapy; (2) current status and trends in assessing drug-drug interactions, especially interactions between drugs and herbs, between drugs and therapeutic biologics, and microbiota-mediated interactions; (3) advances in understanding the effects of diseases on PK, particularly changes in metabolizing enzymes and transporters with disease progression; (4) trends in mathematical modeling including physiologically-based PK modeling and novel animal models such as CRISPR/Cas9-based animal models for DMPK studies; (5) emerging non-classical xenobiotic metabolic pathways and the involvement of novel metabolic enzymes, especially non-P450s. Existing challenges and perspectives on future directions are discussed, and may stimulate the development of new research models, technologies, and strategies towards the development of better drugs and improved clinical practice

Imidazolium-based titanosilicate nanospheres as active catalysts in carbon dioxide conversion:Towards a cascade reaction from alkenes to cyclic carbonates

Porous silica-based nanospheres bearing titanium centres as single site were successfully synthesized employing a time- and energy-efficient procedure. The influence of the post-synthesis treatment on the insertion of Ti was investigated via DR UV-Vis and XPS spectroscopy and the titanium content was quantified through ICP-OES analysis. The textural and structural properties of the different solids were evaluated via XRD, TEM and N2 physisorption. The resulting materials were thereafter covalently functionalized with imidazolium chloride, followed by characterization via 29Si and 13C solid-state NMR, N2 physisorption and chemical combustion analysis. The bi-functional catalysts were tested in the challenging conversion of CO2 with cyclohexene oxide to the corresponding cyclic carbonate as well as with various other epoxides with excellent results. The insertion of Ti as single site played a key role substantially improving the activity of the solids. The most active bi-functional material was successfully recovered and reused through multiple cycle without loss of the catalytic activity. Moreover, the cyclohexene epoxidation reaction was tested as well employing the mono-functionalized Ti-based material. The catalytic mixture, composed by the mono-functional and bi-functional solids, was efficiently used to convert the cyclohexene into cyclohexene oxide and subsequently the cyclohexene oxide into the corresponding carbonate thus opening the prospect for a cascade reaction

Author Correction: Disruption of mitochondrial complex I induces progressive parkinsonism

In the version of this article initially published, the two bottom-left panels in Extended Data Fig. 8b duplicated the top-left and bottom-right panels of Fig. 4d presenting open field traces in mice. The panels have now been replaced with new images. The errors have been corrected in the online version of the article.Loss of functional mitochondrial complex I (MCI) in the dopaminergic neurons of the substantia nigra is a hallmark of Parkinson’s disease1. Yet, whether this change contributes to Parkinson’s disease pathogenesis is unclear2. Here we used intersectional genetics to disrupt the function of MCI in mouse dopaminergic neurons. Disruption of MCI induced a Warburg-like shift in metabolism that enabled neuronal survival, but triggered a progressive loss of the dopaminergic phenotype that was first evident in nigrostriatal axons. This axonal deficit was accompanied by motor learning and fine motor deficits, but not by clear levodopa-responsive parkinsonism—which emerged only after the later loss of dopamine release in the substantia nigra. Thus, MCI dysfunction alone is sufficient to cause progressive, human-like parkinsonism in which the loss of nigral dopamine release makes a critical contribution to motor dysfunction, contrary to the current Parkinson’s disease paradigm.Electron microscopy tissue processing and imaging was performed at the Northwestern University Center for Advanced Microscopy, supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. This study was supported by grants from the Michael J. Fox Foundation (to D.J.S.), the JPB Foundation (to D.J.S.), the IDP Foundation (to D.J.S.), the Flanagan Fellowship (to P.G.-R.) and the European Research Council ERC Advanced Grant PRJ201502629 (to J.L.-B.).Peer reviewe

Klf5 maintains the balance of primitive endoderm versus epiblast specification during mouse embryonic development by suppression of Fgf4

We developed a versatile method for three-dimensional shape measurement where a specific particle can be selected on the substrate and its cross-sectional shape and size can be measured. A non-contact fast measurement is possible for the particle in the resonance domain. We applied rigorous coupled-wave analysis to the particle and calculated the diffraction patterns, comparing the patterns with the experimental results to obtain the size and shape. The shape and position of the focusing spot on the scattering particle was controlled precisely. With this method, the category of the analyzable object is extended to more shapes, such as rectangles and triangles, in addition to a conventional ellipsoid

Effect of raw and purified carbon nanotubes and iron oxide nanoparticles on the growth of wheatgrass prepared from the cotyledons of common wheat (triticum aestivum)

The increase in global production of nanomaterials has raised concern as to their possible effects on plants that could ultimately affect the human population. The effects on the hydroponic growth of wheatgrass of four types of nanomaterials were studied: raw-single walled carbon nanotubes (SWCNTs), purified-SWCNTs, multi walled carbon nanotubes (MWCNTs), and iron oxide nanoparticles (n-FeOx) as a model of the catalyst residue typically present in CNTs. The germination rate (GR), mean germination time (MGT), shoot length, and a visual score of the plants' growth were determined for wheatgrass over the course of two weeks as a function of exposure to the nanomaterials dispersed in either water or THF (as well as appropriate controls). Raw-SWCNTs, MWCNTs, and n-FeOx show little impact suggesting that the catalyst residue (iron oxide) present in CNTs has little effect. Exposure to purified-SWCNTs dispersed in water shows increased GR (and shoot length), while wheatgrass exposed to purified-SWCNT dispersed in THF had retarded GR, suggesting that SWCNTs act as a carrier for adsorbed organic solvents whose effects are detrimental. A similar but lesser effect was observed for MWCNTs. Interestingly raw-SWCNTs showed no solvent effect, suggesting that the reduction of hydrophobicity of the SWCNTs through functionalisation enables the adsorption and subsequent release of harmful organic solvents. The positive effect of purified SWCNTs when dispersed in water is likely a function of their highly hydrophobic nature facilitating enhanced uptake of water