Progressive nigrostriatal terminal dysfunction and degeneration in the engrailed1 heterozygous mouse model of Parkinson's disease

Nordstrom, U.,Beauvais, G.,Ghosh, A.,Pulikkaparambil Sasidharan, B.C.,Lundblad, M.,Fuchs, J.,Joshi, R.L.,Lipton, J.W.,Roholt, A.,Medicetty, S.,Feinstein, T.N.,Steiner, J.A.,Escobar Galvis, M.L.,Prochi Blackwell Science ; Academic Press 2015 Neurobiology of disease Vol.73 No.-

Current research on Parkinson's disease (PD) pathogenesis requires relevant animal models that mimic the gradual and progressive development of neuronal dysfunction and degeneration that characterizes the disease. Polymorphisms in engrailed 1 (En1), a homeobox transcription factor that is crucial for both the development and survival of mesencephalic dopaminergic neurons, are associated with sporadic PD. This suggests that En1 mutant mice might be a promising candidate PD model. Indeed, a mouse that lacks one En1 allele exhibits decreased mitochondrial complex I activity and progressive midbrain dopamine neuron degeneration in adulthood, both features associated with PD. We aimed to further characterize the disease-like phenotype of these En1<SUP>+/-</SUP> mice with a focus on early neurodegenerative changes that can be utilized to score efficacy of future disease modifying studies. We observed early terminal defects in the dopaminergic nigrostriatal pathway in En1<SUP>+/-</SUP> mice. Several weeks before a significant loss of dopaminergic neurons in the substantia nigra could be detected, we found that striatal terminals expressing high levels of dopaminergic neuron markers TH, VMAT2, and DAT were dystrophic and swollen. Using transmission electron microscopy, we identified electron dense bodies consistent with abnormal autophagic vacuoles in these terminal swellings. In line with these findings, we detected an up-regulation of the mTOR pathway, concurrent with a downregulation of the autophagic marker LC3B, in ventral midbrain and nigral dopaminergic neurons of the En1<SUP>+/-</SUP> mice. This supports the notion that autophagic protein degradation is reduced in the absence of one En1 allele. We imaged the nigrostriatal pathway using the CLARITY technique and observed many fragmented axons in the medial forebrain bundle of the En1<SUP>+/-</SUP> mice, consistent with axonal maintenance failure. Using in vivo electrochemistry, we found that nigrostriatal terminals in the dorsal striatum were severely deficient in dopamine release and reuptake. Our findings support a progressive retrograde degeneration of En1<SUP>+/-</SUP> nigrostriatal neurons, akin to what is suggested to occur in PD. We suggest that using the En1<SUP>+/-</SUP> mice as a model will provide further key insights into PD pathogenesis, and propose that axon terminal integrity and function can be utilized to estimate dopaminergic neuron health and efficacy of experimental PD therapies.

Lithography potentials of UV-nanoimprint

A. Fuchs,M. Bender,U. Plachetka,L. Kock,N. Koo,T. Wahlbrink,H. Kurz 한국물리학회 2008 Current Applied Physics Vol.8 No.6

In the past decade nanoimprint has been developed to a serious alternative for next generation lithography (NGL). In this work, the most recent developments of UV-nanoimprint Lithography (UV-NIL) with special emphasis to the work accomplished at AMO and the IHT-RWTH Aachen are reviewed and functional applications demonstrated. Further the potentials of various UV-NIL concepts are evaluated and possible interests in certain application areas are discussed. In the past decade nanoimprint has been developed to a serious alternative for next generation lithography (NGL). In this work, the most recent developments of UV-nanoimprint Lithography (UV-NIL) with special emphasis to the work accomplished at AMO and the IHT-RWTH Aachen are reviewed and functional applications demonstrated. Further the potentials of various UV-NIL concepts are evaluated and possible interests in certain application areas are discussed.

Phylogenetic differences in calcium permeability of the auditory hair cell cholinergic nicotinic receptor.

Lipovsek, Marcela,Im, Gi Jung,Franchini, Luc?a F,Pisciottano, Francisco,Katz, Eleonora,Fuchs, Paul Albert,Elgoyhen, Ana Bel?n National Academy of Sciences 2012 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.109 No.11

<P>The α9 and α10 cholinergic nicotinic receptor subunits assemble to form the receptor that mediates efferent inhibition of hair cell function within the auditory sensory organ, a mechanism thought to modulate the dynamic range of hearing. In contrast to all nicotinic receptors, which serve excitatory neurotransmission, the activation of α9α10 produces hyperpolarization of hair cells. An evolutionary analysis has shown that the α10 subunit exhibits signatures of positive selection only along the mammalian lineage, strongly suggesting the acquisition of a unique function. To establish whether mammalian α9α10 receptors have acquired distinct functional properties as a consequence of this evolutionary pressure, we compared the properties of rat and chicken recombinant and native α9α10 receptors. Our main finding in the present work is that, in contrast to the high (pCa(2+)/pMonovalents 10) Ca(2+) permeability reported for rat α9α10 receptors, recombinant and native chicken α9α10 receptors have a much lower permeability (2) to this cation, comparable to that of neuronal α4β2 receptors. Moreover, we show that, in contrast to α10, α7 as well as α4 and β2 nicotinic subunits are under purifying selection in vertebrates, consistent with the conserved Ca(2+) permeability reported across species. These results have important consequences for the activation of signaling cascades that lead to hyperpolarization of hair cells after α9α10 gating at the cholinergic-hair cell synapse. In addition, they suggest that high Ca(2+) permeability of the α9α10 cholinergic nicotinic receptor might have evolved together with other features that have given the mammalian ear an expanded high-frequency sensitivity.</P>

Experssion of the Escherichia coli Thioredoxin Gene is Negatively Regulated

Jae-Hoon Sa,Mi Ae Namgung,chung-Jin Lem,James A Fuchs 강원대학교 기초과학연구소 1997 기초과학연구 Vol.8 No.-

Regulation of the Escherichia coli thioredoxin gene (trxA) was studied using trxA-lac translational fusion constructed in the vector pMC1403. Synthes of β of galactosidase from the trxA-Iac fusion was found to be repressed in the presence of lactose. A switch of carbon source from glucose to lactose and an addition of cyclic AMP (cAMP) caused a decrease in βgalactosidase synthesis from the trxA-lac fusion. The repression effect of exogenous cAMP was not observed in the crp mutant strain. The β-galactosidase synthesis from the trxA-lac fusion lacking a plausible cAMP-CRP binding site was not lowered in the presence of lactose or in the addition of cAMP. Expression of the chromosomal trxA gene was reduced by exogenous cAMP. These findings indicate that the expression of the trxA gene is controlled by cAMP in a negative manner

Si(0 0 1) surface optical anisotropies induced by π-conjugated overlayers and oxidation

W.G. Schmidt,A. Hermann,F. Fuchs,F. Bechstedt 한국물리학회 2006 Current Applied Physics Vol.6 No.3

A density functional (DFT–GGA) study on the modification of the Si(001) surface optical response upon adsorption of 9,10-phenanthrenequinone and oxidation is presented. In the first case it is found that intramolecular p–p* transitions as well as adsorption-modified Si bulk states contribute to the optical signal. The molecular contributions differ strongly from the respective signals of gas-phase molecules, indicating the need for a cautious interpretation of experimental data. The calculations for oxidized Si structures show that local Si lattice deformations accompanying the oxidation of Si bulk bonds directly at the silicon–silicon oxide interface give rise to pronounced optical anisotropies that explain the experimental findings very well. In contrast, calculations for translationally invariant oxide structures fail to reproduce the experiment. This indicates the oxidation to occur layer-by-layer and strong disorder of the silicon oxide layers immediately above the interface.

Interfraction variation and dosimetric changes during image-guided radiation therapy in prostate cancer patients

Fuchs, Frederik,Habl, Gregor,Devecka, Michal,Kampfer, Severin,Combs, Stephanie E.,Kessel, Kerstin A. The Korean Society for Radiation Oncology 2019 Radiation Oncology Journal Vol.37 No.2

Purpose: The aim of this study was to identify volume changes and dose variations of rectum and bladder during radiation therapy in prostate cancer (PC) patients. Materials and Methods: We analyzed 20 patients with PC treated with helical tomotherapy. Daily image guidance was performed. We re-contoured the entire bladder and rectum including its contents as well as the organ walls on megavoltage computed tomography once a week. Dose variations were analyzed by means of Dmedian, Dmean, Dmax, V₁₀ to V₇₅, as well as the organs at risk (OAR) volume. Further, we investigated the correlation between volume changes and changes in Dmean of OAR. Results: During treatment, the rectal volume ranged from 62% to 223% of its initial volume, the bladder volume from 22% to 375%. The average Dmean ranged from 87% to 118% for the rectum and 58% to 160% for the bladder. The Pearson correlation coefficients between volume changes and corresponding changes in Dmean were -0.82 for the bladder and 0.52 for the rectum. The comparison of the dose wall histogram (DWH) and the dose volume histogram (DVH) showed that the DVH underestimates the percentage of the rectal and bladder volume exposed to the high dose region. Conclusion: Relevant variations in the volume of OAR and corresponding dose variations can be observed. For the bladder, an increase in the volume generally leads to lower doses; for the rectum, the correlation is weaker. Having demonstrated remarkable differences in the dose distribution of the DWH and the DVH, the use of DWHs should be considered.

Interfraction variation and dosimetric changes during imageguided radiation therapy in prostate cancer patients

Frederik Fuchs,Gregor Habl,Michal Deveč,ka,Severin Kampfer,Stephanie E,Combs,Kerstin A,Kessel 대한방사선종양학회 2019 Radiation Oncology Journal Vol.37 No.2

Purpose: The aim of this study was to identify volume changes and dose variations of rectum and bladder during radiation therapy in prostate cancer (PC) patients. Materials and Methods: We analyzed 20 patients with PC treated with helical tomotherapy. Daily image guidance was performed. We re-contoured the entire bladder and rectum including its contents as well as the organ walls on megavoltage computed tomography once a week. Dose variations were analyzed by means of Dmedian, Dmean, Dmax, V 10 to V 75 , as well as the organs at risk (OAR) volume. Further, we investigated the correlation between volume changes and changes in Dmean of OAR. Results: During treatment, the rectal volume ranged from 62% to 223% of its initial volume, the bladder volume from 22% to 375%. The average Dmean ranged from 87% to 118% for the rectum and 58% to 160% for the bladder. The Pearson correlation coefficients between volume changes and corresponding changes in Dmean were -0.82 for the bladder and 0.52 for the rectum. The comparison of the dose wall histogram (DWH) and the dose volume histogram (DVH) showed that the DVH underestimates the percentage of the rectal and bladder volume exposed to the high dose region. Conclusion: Relevant variations in the volume of OAR and corresponding dose variations can be observed. For the bladder, an increase in the volume generally leads to lower doses; for the rectum, the correlation is weaker. Having demonstrated remarkable differences in the dose distribution of the DWH and the DVH, the use of DWHs should be considered.

Cell Cycle Regulation of the Operon encoding Ribonucleotide Reductase in E. Coli

James A . Fuchs 忠北大學校 遺傳工學硏究所 1994 遺傳工學硏究 Vol.8 No.1

Postnatal signalling with homeoprotein transcription factors

Prochiantz, Alain,Fuchs, Julia,Di Nardo, Ariel A. Royal Society 2014 Philosophical transactions. Biological sciences Vol.369 No.1652

<P>Homeoprotein (HP) transcription factors were originally identified for their embryonic cell-autonomous developmental functions. In this review, we discuss their postnatal and adult physiological functions based on the study of Otx2, Engrailed-1 and Engrailed-2 (collectively Engrailed). For Engrailed, we discuss its function in the cell-autonomous regulation of ventral midbrain dopaminergic neuron survival and physiology and in the non-cell-autonomous maintenance of axons. For Otx2, we describe how the protein is expressed in the choroid plexus and transported into cortical parvalbumin cells where it regulates plasticity in the visual cortex. These two examples illustrate how the understanding of HP postnatal and adult functions, including signalling functions, may lead to the identification of disease-associated genetic pathways and to the development of original therapeutic strategies.</P>

Effect of Cyclic AMP on the Two Promoters of Escherichia coli Thioredoxin Gene

Lim, Chang Jin,Sa, Jae Hoon,Fuchs, James A 생화학분자생물학회 1998 BMB Reports Vol.30 No.5

Thioredoxin is a multi-functional protein which is ubiquitous in microorganisms. animals and plants. Previously. expression of the E. coli thioredoxin gene was found to be negatively regulated by cAMP. In the present study. the effect of cAMP on two separate promoters of the E. coli thioredoxin gene was investigated. Cyclic AMP had a repressible effect on P1 and P1P2 promoter activity of the constructs. This effect was also observed in the cya strain. The P2 promoter construct gave very high β-galactosidase activity. and its expression was not affected by exogenous cAMP It was assumed that a cis-acting negative element. probably the cAMP-CRP binding site, might have been deleted in the P1 promoter construct. Repression of the thioredoxin gene expression by cAMP appeared to be independent of ppGpp.