85 results on '"Weber JJ"'
Search Results
2. Abstract P1-01-17: The impact of triple negativity on lymph node positivity in breast cancer.
- Author
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Weber, JJ, primary, Bellin, LS, additional, Milbourn, DE, additional, and Wong, J, additional
- Published
- 2012
- Full Text
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3. Selective preoperative magnetic resonance imaging in women with breast cancer: no reduction in the reoperation rate.
- Author
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Weber JJ, Bellin LS, Milbourn DE, Verbanac KM, and Wong JH
- Published
- 2012
- Full Text
- View/download PDF
4. TOPECTOMY
- Author
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Pool Jl, Weber Jj, and Heath Rg
- Subjects
Psychiatry and Mental health ,medicine.medical_specialty ,business.industry ,General surgery ,medicine ,business ,Postoperative management ,Psychosurgery - Published
- 1949
5. Charged-particle multiplicities in pp interactions at root s=900 GeV measured with the ATLAS detector at the LHC ATLAS Collaboration
- Author
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Aad, G, Abat, E, Abbott, B, Abdallah, J, Abdelalim, A, Abdesselam, A, Abdinov, O, Abi, B, Abolins, M, Abramowicz, H, Abreu, H, Acerbi, E, Acharya, B, Ackers, M, Adams, D, Addy, T, Adelman, J, Aderholz, M, Adorisio, C, Adragna, P, Adye, T, Aefsky, S, Aguilar Saavedra, J, Aharrouche, M, Ahlen, S, Ahles, F, Ahmad, A, Ahmed, H, Ahsan, M, Aielli, G, Akdogan, T, Akesson, P, Akesson, T, Akimoto, G, Akimov, A, Aktas, A, Alam, M, Albert, J, Albrand, S, Aleksa, M, Aleksandrov, I, Aleppo, M, Alessandria, F, Alexa, C, Alexander, G, Alexandre, G, Alexopoulos, T, Alhroob, M, Aliev, M, Alimonti, G, Alison, J, Aliyev, M, Allport, P, Allwood Spiers, S, Almond, J, Aloisio, A, Alon, R, Alonso, A, Alonso, J, Alviggi, M, Amako, K, Amaral, P, Ambrosini, G, Ambrosio, G, Amelung, C, Ammosov, V, Amorim, A, Amoros, G, Amram, N, Anastopoulos, C, Andeen, T, Anders, C, Anderson, K, Andreazza, A, Andrei, V, Andrieux, M, Anduaga, X, Angerami, A, Anghinolfi, F, Anjos, N, Annovi, A, Antonaki, A, Antonelli, M, Arai, Y, Arce, A, Archambault, J, Arfaoui, S, Arguin, J, Argyropoulos, T, Arik, E, Arik, M, Armbruster, A, Arms, K, Armstrong, S, Arnaez, O, Arnault, C, Artamonov, A, Arutinov, D, Asai, M, Asfandiyarov, R, Ask, S, Asman, B, Asner, D, Asquith, L, Assamagan, K, Astbury, A, Astvatsatourov, A, Athar, B, Atoian, G, Aubert, B, Auerbach, B, Auge, E, Augsten, K, Aurousseau, M, Austin, N, Avolio, G, Avramidou, R, Axen, D, Ay, C, Azuelos, G, Azuma, Y, Baak, M, Baccaglioni, G, Bacci, C, Bach, A, Bachacou, H, Bachas, K, Bachy, G, Backes, M, Badescu, E, Bagnaia, P, Bai, Y, Bailey, D, Bain, T, Baines, J, Baker, O, Baker, M, Baker, S, Pedrosa, F, Banas, E, Banerjee, P, Banerjee, S, Banfi, D, Bangert, A, Bansal, V, Baranov, S, Barashkou, A, Barber, T, Barberio, E, Barberis, D, Barbero, M, Bardin, D, Barillari, T, Barisonzi, M, Barklow, T, Barlow, N, Barnett, B, Barnett, R, Baroncelli, A, Barone, M, Barr, A, Barreiro, F, Null, C, Barrillon, P, Bartheld, V, Bartko, H, Bartoldus, R, Bartsch, D, Bates, R, Bathe, S, Batkova, L, Batley, J, Battaglia, A, Battistin, M, Battistoni, G, Bauer, F, Bawa, H, Bazalova, M, Beare, B, Beau, T, Beauchemin, P, Beccherle, R, Becerici, N, Bechtle, R, Beck, G, Beck, H, Beckingham, M, Becks, K, Beddall, A, Bednyakov, V, Bee, C, Begel, M, Harpaz, S, Behera, P, Beimforde, M, Belanger, G, Belanger Champagne, C, Belhorma, B, Bell, P, Bell, W, Bella, G, Bellagambala, L, Bellina, F, Bellomo, G, Bellomo, M, Belloni, A, Belotskiy, K, Beltramello, O, Belymam, A, Ben Ami, S, Benary, O, Benchekroun, D, Benchouk, C, Bendel, M, Benedict, B, Benekos, N, Benhammou, Y, Benincasa, G, Benjamin, D, Benoit, M, Bensinger, J, Benslama, K, Bentvelsen, S, Beretta, M, Berge, D, Kuutmann, E, Berger, N, Berghaus, F, Berglund, E, Beringer, J, Bernardet, K, Bernat, P, Bernhard, R, Bernius, C, Berry, T, Bertin, A, Bertinelli, F, Bertolucci, S, Besana, M, Besson, N, Bethke, S, Bianchi, R, Bianco, M, Biebel, O, Bieri, M, Biesiada, J, Biglietti, M, Bilokon, H, Binder, M, Bindi, M, Binet, S, Bingul, A, Bini, C, Biscarat, C, Bischof, R, Bitenc, U, Black, K, Blair, R, Blanch, O, Blanchard, J, Blanchot, G, Blocker, C, Blocki, J, Blondel, A, Blum, W, Blumenschein, U, Boaretto, C, Bobbink, G, Bocci, A, Bocian, D, Bock, R, Boehler, M, Boehm, M, Boek, J, Boelaert, N, Boser, S, Bogaerts, J, Bogouch, A, Bohm, C, Bohm, J, Boisvert, V, Bold, T, Boldea, V, Boldyrev, A, Bondarenko, V, Bondioli, M, Bonino, R, Boonekamp, M, Boorman, G, Boosten, M, Booth, C, Booth, P, Booth, J, Bordoni, S, Borer, C, Borer, K, Borisov, A, Borissov, G, Borjanovic, I, Borroni, S, Bos, K, Boscherini, D, Bosman, M, Boterenbrood, H, Botterill, D, Bouchami, J, Boudreau, J, Bouhova Thacker, E, Boulahouache, C, Bourdarios, C, Boveia, A, Boyd, J, Boyer, B, Boyko, I, Bozhko, N, Bozovic Jelisavcic, I, Braccini, S, Bracinik, J, Braem, A, Brambilla, E, Branchini, P, Brandenburg, G, Brandt, A, Brandt, G, Brandt, O, Bratzler, U, Brau, B, Brau, J, Braun, H, Bravo, S, Brelier, B, Bremer, J, Brenner, R, Bressler, S, Breton, D, Brett, N, Bright Thomas, P, Britton, D, Brochu, F, Brock, I, Brock, R, Brodbeck, T, Brodet, E, Broggi, E, Bromberg, C, Brooijmans, G, Brooks, W, Brown, G, Brubaker, E, Null, R, Bruncko, D, Bruneliere, R, Brunet, S, Bruni, A, Bruni, G, Bruschi, M, Buanes, T, Bucci, E, Buchanan, J, Buchanan, N, Buchholz, R, Buckley, A, Budagov, I, Budick, B, Buscher, V, Bugge, L, Buira Clark, D, Buis, E, Bujor, E, Bulekov, O, Bunse, M, Buran, T, Burckhart, H, Burdin, S, Burgess, T, Burke, S, Busato, E, Bussey, R, Buszello, C, Butin, E, Butler, B, Butler, J, Buttar, C, Butterworth, J, Byatt, T, Caballero, J, Urban, S, Caccia, M, Caforio, D, Cakir, O, Calafiura, P, Calderini, G, Calfayan, P, Calkins, R, Caloba, L, Caloi, R, Calvet, D, Camard, A, Camarri, P, Cambiaghi, M, Cameron, D, Cammin, J, Campana, S, Campanelli, M, Canale, V, Canelli, F, Canepa, A, Cantero, J, Capasso, L, Garrido, M, Caprini, I, Caprini, M, Caprio, M, Capua, M, Caputo, R, Caramarcu, C, Cardarelli, R, Sas, L, Carli, T, Carlino, G, Carminati, L, Caron, B, Caron, S, Carpentieri, C, Montoya, G, Montero, S, Carter, A, Carter, J, Carvalho, J, Casadei, D, Casado, M, Cascella, M, Cas, C, Hernadez, A, Castaneda Miranda, E, Gimenez, V, Castro, N, Castrovillari, F, Cataldi, G, Cataneo, F, Catinaccio, A, Catmore, J, Cattai, A, Cattani, G, Caughron, S, Cauz, D, Cavallari, A, Cavalleri, P, Cavalli, D, Cavalli Sforza, M, Cavasinni, V, Cazzato, A, Ceradini, E, Cerna, C, Cerqueira, A, Cerri, A, Cerrito, L, Cerutti, F, Cervetto, M, Cetin, S, Cevenini, E, Chafaq, A, Chakraborty, D, Chan, K, Chapman, J, Chareyre, E, Charlton, D, Charron, S, Chatterjii, S, Chavda, V, Cheatham, S, Chekanov, S, Chekulaev, S, Chelkov, G, Chen, H, Chen, L, Chen, S, Chen, T, Chen, X, Cheng, S, Cheplakov, A, Chepurnov, V, El Moursli, R, Tcherniatine, V, Chesneanu, D, Cheu, E, Cheung, S, Chevalier, L, Chevallier, F, Chiarella, V, Chiefari, G, Chikovani, L, Childers, J, Chilingarov, A, Chiodini, G, Chizhov, V, Choudalakis, G, Chouridou, S, Christiansen, T, Christidi, I, Christov, A, Chromek Burckhart, D, Chu, M, Chudoba, J, Ciapetti, G, Cicalini, E, Ciftci, A, Ciftci, R, Cinca, D, Cindro, V, Ciobotaru, M, Ciocca, C, Ciocio, A, Cirilli, M, Citterio, M, Clark, A, Clark, P, Cleland, W, Clemens, J, Clement, B, Clement, C, Clements, D, Clifft, R, Coadou, Y, Cobal, M, Coccaro, A, Cochran, J, Coco, R, Coe, R, Coelli, S, Coggeshall, J, Cogneras, E, Cojocaru, C, Colas, J, Cole, B, Colijn, A, Collard, C, Collins, N, Collins Tooth, C, Collot, J, Colon, G, Coluccia, R, Comune, G, Muino, P, Coniavitis, E, Consonni, M, Constantinescu, S, Conta, C, Conventi, F, Cook, J, Cooke, M, Cooper, B, Cooper Sarkar, A, Cooper Smith, N, Copic, K, Cornelissen, T, Corradi, M, Correard, S, Corriveau, F, Corso Radu, A, Cortes Gonzalez, A, Cortiana, G, Costa, G, Costa, M, Costanzo, D, Costin, T, Cote, D, Torres, R, Courneyea, L, Couyoumtzelis, C, Cowan, G, Cowden, C, Cox, B, Cranmer, K, Cranshaw, J, Cristinziani, M, Crosetti, G, Crupi, R, Crepe Renaudin, S, Almenar, C, Donszelmann, T, Cuneo, S, Cunha, A, Curatolo, M, Curtis, C, Cwetanski, P, Czyczula, Z, D'Auria, S, D'Onofrio, M, D'Orazio, A, Mello, A, Da Silva, P, Da Via, C, Dabrowski, W, Dahlhoff, A, Dai, T, Dallapiccola, C, Dallison, S, Dalmau, J, Daly, C, Dam, M, Dameri, M, Danielsson, H, Dankers, R, Dannheim, D, Dao, V, Darbo, G, Darlea, G, Daum, C, Dauvergne, J, Davey, W, Davidek, T, Davidson, D, Davidson, N, Davidson, R, Davies, M, Davison, A, Dawson, I, Dawson, J, Daya, R, De, K, Null, A, De Castro, S, Salgado, P, De Cecco, S, Null, G, De Groot, N, Null, J, De La Cruz Burelo, E, De La Taille, C, De Lotto, B, De Mora, L, Branco, M, De Pedis, D, Null, S, De Salvo, A, De Sanctis, U, De Santo, A, De Regie, J, De Zorzi, G, Dean, S, Deberg, H, Dedes, G, Dedovich, D, Defay, P, Degenhardt, J, Dehchar, M, Deile, M, Del Papa, C, Del Peso, J, Del Prete, T, Dell'Acqua, A, Dell'Asta, L, Della Pietra, M, Null, V, Delmastro, M, Delpierre, P, Delruelle, N, Delsart, P, Deluca, C, Demers, S, Demichev, M, Demirkoz, B, Deng, J, Deng, W, Denisov, S, Dennis, C, Derkaoui, J, Derue, F, Dervan, R, Desch, K, Deviveiros, P, Dewhurst, A, Dewilde, B, Dhaliwal, S, Dhullipudi, R, DI CIACCIO, A, Di Ciaccio, L, Di Domenico, A, Di Girolamo, A, Di Girolamo, B, Di Luise, S, Di Mattia, A, Di Nardo, R, Di Simone, A, Di Sipio, R, Diaz, M, Gomez, M, Diblen, F, Diehl, E, Dietl, H, Dietrich, J, Dietzsch, T, Diglio, S, Yagci, K, Dingfelder, D, Dionisi, C, Dipanjan, R, Dita, P, Dita, S, Dittus, F, Djama, F, Djilkibaev, R, Djobava, T, Wemans, A, Doan, T, Dobbs, M, Dobinson, R, Dobos, D, Dobson, E, Dobson, M, Dodd, J, Dogan, O, Doglioni, C, Doherty, T, Doi, Y, Dolejsi, J, Dolenc, I, Dolezal, Z, Dolgoshein, B, Dohmae, T, Domingo, E, Donega, M, Donini, J, Dopke, J, Doria, A, Dos Anjos, A, Dosil, M, Dotti, A, Dova, M, Dowell, J, Doxiadis, A, Doyle, A, Dragic, J, Drakoulakos, D, Drasal, Z, Drees, J, Dressnandt, N, Drevermann, H, Driouichi, C, Dris, M, Drohan, J, Dubbert, J, Dubbs, T, Duchovni, E, Duckeck, G, Dudarev, A, Dudziak, F, Duhrssen, M, Dur, H, Duerdoth, I, Duflot, L, Dufour, M, Dunford, M, Yildiz, H, Dushkin, A, Duxfield, R, Dwuznik, M, Dydak, F, Dzahini, D, Duren, M, Ebenstein, W, Ebke, J, Eckert, S, Eckweiler, S, Edmonds, K, Edwards, C, Efthymiopoulos, I, Egorov, K, Ehrenfeld, W, Ehrich, T, Eifert, T, Eigen, G, Einsweiler, K, Eisenhandler, E, Ekelof, T, El Kacimi, M, Ellert, M, Elles, S, Ellinghaus, F, Ellis, K, Ellis, N, Elmsheuser, J, Elsing, M, Ely, R, Emeliyanov, D, Engelmann, R, Engl, A, Epp, B, Eppig, A, Erdmann, J, Ereditato, A, Eremin, V, Eriksson, D, Ermoline, I, Ernst, J, Ernst, M, Ernwein, J, Errede, D, Errede, S, Ertel, E, Escalier, M, Escobar, C, Curull, X, Esposito, B, Etienne, F, Etienvre, A, Etzion, E, Evans, H, Evdokimov, V, Fabbri, L, Fabre, C, Facius, K, Fakhrutdinov, R, Falciano, S, Falou, A, Fang, Y, Fanti, M, Farbin, A, Farilla, A, Farley, J, Farooque, T, Farrington, S, Farthouat, P, Fassnacht, P, Fassouliotis, D, Fatholahzadeh, B, Fayard, L, Fayette, F, Febbraro, R, Federic, R, Fedin, O, Fedorko, I, Fedorko, W, Feligioni, L, Felzmann, C, Feng, C, Feng, E, Fenyuk, A, Ferencei, J, Ferland, J, Fernandes, B, Fernando, W, Ferrag, S, Ferrando, J, Ferrara, V, Ferrari, A, Ferrari, P, Ferrari, R, Ferrer, A, Ferrer, M, Ferrere, D, Ferretti, C, Ferro, F, Fiascaris, M, Fichet, S, Fiedler, F, Filipcic, A, Filippas, A, Filthaut, F, Fincke Keeler, M, Fiolhais, M, Fiorini, L, Firan, A, Fischer, G, Fischer, P, Fisher, M, Fisher, S, Flacher, H, Flammer, J, Fleck, I, Fleckner, J, Fleischmann, P, Fleischmann, S, Fleuret, F, Flick, T, Castillo, L, Flowerdew, M, Fohlisch, F, Fokitis, M, Martin, T, Fopma, J, Forbush, D, Formica, A, Forti, A, Fortin, D, Foster, J, Fournier, D, Foussat, A, Fowler, A, Fowler, K, Fox, H, Francavilla, P, Franchino, S, Francis, D, Franklin, M, Franz, S, Fraternali, M, Fratina, S, Freestone, J, French, S, Froeschl, R, Froidevaux, D, Frost, J, Fukunaga, C, Torregrosa, E, Fuster, J, Gabaldon, C, Gabizon, O, Gadfort, T, Gadomski, S, Gagliardi, 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Heinemann, F, Heisterkamp, S, Helary, L, Heldmann, M, Heller, M, Hellman, S, Helsens, C, Hemperek, T, Henderson, R, Hendriks, P, Henke, M, Henrichs, A, Correia, A, Henrot Versille, S, Henry Couannier, F, Hensel, C, Henss, T, Jimenez, Y, Hershenhorn, A, Herten, G, Hertenberger, R, Hervas, L, Hess, M, Hessey, N, Hidvegi, A, Higon Rodriguez, E, Hill, D, Hill, J, Hill, N, Hiller, K, Hillert, S, Hillier, S, Hinchliffe, I, Hindson, D, Hines, E, Hirose, M, Hirsch, F, Hirschbuehl, D, Hobbs, J, Hod, N, Hodgkinson, M, Hodgson, P, Hoecker, A, Hoeferkamp, M, Hoffman, J, Hoffmann, D, Hohlfeld, M, Holder, M, Hollins, T, Hollyman, G, Holmes, A, Holmren, S, Holy, T, Holzbauer, J, Homer, R, Homma, Y, Horazdovsky, T, Hori, T, Horn, C, Horner, S, Horvat, S, Hostachy, J, Hott, T, Hou, S, Houlden, M, Hoummada, A, Howe, T, Howell, D, Hrivnac, J, Hruska, I, Hryn'Ova, T, Hsu, P, Hsu, S, Huang, G, Hubacek, Z, Hubaut, F, Huegging, F, Huffman, B, Hughes, E, Hughes, G, Hughes Jones, R, Hurst, P, Hurwitz, M, 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- Subjects
Settore FIS/01 - Fisica Sperimentale ,High Energy Physics::Experiment ,Nuclear Experiment ,900 gev ,minimum bias ,multiplicities ,lhc ,charged-particle ,atlas ,Settore FIS/07 - Fisica Applicata(Beni Culturali, Ambientali, Biol.e Medicin) - Abstract
The first measurements from proton–proton collisions recorded with the ATLAS detector at the LHC are presented. Data were collected in December 2009 using a minimum-bias trigger during collisions at a centre-of-mass energy of 900 GeV. The charged-particle multiplicity, its dependence on transverse momentum and pseudorapidity, and the relationship between mean transverse momentum and charged-particle multiplicity are measured for events with at least one charged particle in the kinematic range |η|500 MeVpT>500 MeV. The measurements are compared to Monte Carlo models of proton–proton collisions and to results from other experiments at the same centre-of-mass energy. The charged-particle multiplicity per event and unit of pseudorapidity at η=0η=0 is measured to be 1.333±0.003(stat.)±0.040(syst.)1.333±0.003(stat.)±0.040(syst.), which is 5–15% higher than the Monte Carlo models predict.
- Published
- 2010
6. The parkin V380L variant is a genetic modifier of Machado-Joseph disease with impact on mitophagy.
- Author
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Weber JJ, Czisch L, Pereira Sena P, Fath F, Huridou C, Schwarz N, Incebacak Eltemur RD, Würth A, Weishäupl D, Döcker M, Blumenstock G, Martins S, Sequeiros J, Rouleau GA, Jardim LB, Saraiva-Pereira ML, França MC Jr, Gordon CR, Zaltzman R, Cornejo-Olivas MR, van de Warrenburg BPC, Durr A, Brice A, Bauer P, Klockgether T, Schöls L, Riess O, and Schmidt T
- Subjects
- Humans, Male, Female, Middle Aged, Adult, Polymorphism, Single Nucleotide, Ataxin-3 genetics, Age of Onset, Repressor Proteins, Machado-Joseph Disease genetics, Machado-Joseph Disease pathology, Ubiquitin-Protein Ligases genetics, Mitophagy genetics, Mitophagy physiology
- Abstract
Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative spinocerebellar ataxia caused by a polyglutamine-coding CAG repeat expansion in the ATXN3 gene. While the CAG length correlates negatively with the age at onset, it accounts for approximately 50% of its variability only. Despite larger efforts in identifying contributing genetic factors, candidate genes with a robust and plausible impact on the molecular pathogenesis of MJD are scarce. Therefore, we analysed missense single nucleotide polymorphism variants in the PRKN gene encoding the Parkinson's disease-associated E3 ubiquitin ligase parkin, which is a well-described interaction partner of the MJD protein ataxin-3, a deubiquitinase. By performing a correlation analysis in the to-date largest MJD cohort of more than 900 individuals, we identified the V380L variant as a relevant factor, decreasing the age at onset by 3 years in homozygous carriers. Functional analysis in an MJD cell model demonstrated that parkin V380L did not modulate soluble or aggregate levels of ataxin-3 but reduced the interaction of the two proteins. Moreover, the presence of parkin V380L interfered with the execution of mitophagy-the autophagic removal of surplus or damaged mitochondria-thereby compromising cell viability. In summary, we identified the V380L variant in parkin as a genetic modifier of MJD, with negative repercussions on its molecular pathogenesis and disease age at onset., (© 2024. The Author(s).)
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- 2024
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7. A conserved asparagine residue stabilizes iron binding in Manduca sexta transferrin-1.
- Author
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Weber JJ, Geisbrecht BV, Kanost MR, and Gorman MJ
- Subjects
- Animals, Asparagine, Iron metabolism, Anions metabolism, Carbonates metabolism, Solvents, Binding Sites, Transferrin chemistry, Transferrin genetics, Transferrin metabolism, Manduca genetics, Manduca metabolism
- Abstract
Transferrin 1 (Tsf1) is an insect-specific iron-binding protein that is abundant in hemolymph and other extracellular fluids. It binds iron tightly at neutral pH and releases iron under acidic conditions. Tsf1 influences the distribution of iron in the body and protects against infection. Elucidating the mechanisms by which Tsf1 achieves these functions will require an understanding of how Tsf1 binds and releases iron. Previously, crystallized Tsf1 from Manduca sexta was shown to have a novel type of iron coordination that involves four iron-binding ligands: two tyrosine residues (Tyr90 and Tyr204), a buried carbonate anion, and a solvent-exposed carbonate anion. The solvent-exposed carbonate anion was bound by a single amino acid residue, a highly conserved asparagine at position 121 (Asn121); thus, we predicted that Asn121 would be essential for high-affinity iron binding. To test this hypothesis, we analyzed the iron-binding and -release properties of five forms of recombinant Tsf1: wild-type, a Y90F/Y204F double mutant (negative control), and three Asn121 mutants (N121A, N121D and N121S). Each of the Asn121 mutants exhibited altered spectral properties, confirming that Asn121 contributes to iron coordination. The N121D and N121S mutations resulted in slightly lower affinity for iron, especially at acidic pH, while iron binding and release by the N121A mutant was indistinguishable from that of the wild-type protein. The surprisingly minor consequences of mutating Asn121, despite its high degree of conservation in diverse insect species, suggest that Asn121 may play a role that is essential in vivo but non-essential for high affinity iron binding in vitro., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
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- 2024
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8. Editorial: The role of posttranslational modifications in polyglutamine diseases.
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Weber JJ, Costa MDC, Scaglione KM, Todi SV, and Nguyen HP
- Abstract
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
- Published
- 2023
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9. Implications of specific lysine residues within ataxin-3 for the molecular pathogenesis of Machado-Joseph disease.
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Pereira Sena P, Weber JJ, Bayezit S, Saup R, Incebacak Eltemur RD, Li X, Velic A, Jung J, Macek B, Nguyen HP, Riess O, and Schmidt T
- Abstract
Lysine residues are one of the main sites for posttranslational modifications of proteins, and lysine ubiquitination of the Machado-Joseph disease protein ataxin-3 is implicated in its cellular function and polyglutamine expansion-dependent toxicity. Despite previously undertaken efforts, the individual roles of specific lysine residues of the ataxin-3 sequence are not entirely understood and demand further analysis. By retaining single lysine residues of otherwise lysine-free wild-type and polyglutamine-expanded ataxin-3, we assessed the effects of a site-limited modifiability on ataxin-3 protein levels, aggregation propensity, localization, and stability. We confirmed earlier findings that levels of lysine-free ataxin-3 are reduced due to its decreased stability, which led to a diminished load of SDS-insoluble species of its polyglutamine-expanded form. The isolated presence of several single lysine residues within the N-terminus of polyglutamine-expanded ataxin-3 significantly restored its aggregate levels, with highest fold changes induced by the presence of lysine 8 or lysine 85, respectively. Ataxin-3 lacking all lysine residues presented a slightly increased nuclear localization, which was counteracted by the reintroduction of lysine 85, whereas presence of either lysine 8 or lysine 85 led to a significantly higher ataxin-3 stability. Moreover, lysine-free ataxin-3 showed increased toxicity and binding to K48-linked polyubiquitin chains, whereas the reintroduction of lysine 85, located between the ubiquitin-binding sites 1 and 2 of ataxin-3, normalized its binding affinity. Overall, our data highlight the relevance of lysine residues 8 and 85 of ataxin-3 and encourage further analyses, to evaluate the potential of modulating posttranslational modifications of these sites for influencing pathophysiological characteristics of the Machado-Joseph disease protein., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Pereira Sena, Weber, Bayezit, Saup, Incebacak Eltemur, Li, Velic, Jung, Macek, Nguyen, Riess and Schmidt.)
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- 2023
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10. Evidences for Mutant Huntingtin Inducing Musculoskeletal and Brain Growth Impairments via Disturbing Testosterone Biosynthesis in Male Huntington Disease Animals.
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Yu-Taeger L, Novati A, Weber JJ, Singer-Mikosch E, Pabst AS, Cheng F, Saft C, Koenig J, Ellrichmann G, Heikkinen T, Pouladi MA, Riess O, and Nguyen HP
- Subjects
- Animals, Female, Male, Mice, Rats, Brain metabolism, Disease Models, Animal, Insulin-Like Growth Factor I genetics, Insulin-Like Growth Factor I metabolism, Huntington Disease genetics, Huntington Disease metabolism, Testosterone biosynthesis, Huntingtin Protein genetics
- Abstract
Body weight (BW) loss and reduced body mass index (BMI) are the most common peripheral alterations in Huntington disease (HD) and have been found in HD mutation carriers and HD animal models before the manifestation of neurological symptoms. This suggests that, at least in the early disease stage, these changes could be due to abnormal tissue growth rather than tissue atrophy. Moreover, BW and BMI are reported to be more affected in males than females in HD animal models and patients. Here, we confirmed sex-dependent growth alterations in the BACHD rat model for HD and investigated the associated contributing factors. Our results showed growth abnormalities along with decreased plasma testosterone and insulin-like growth factor 1 (IGF-1) levels only in males. Moreover, we demonstrated correlations between growth parameters, IGF-1, and testosterone. Our analyses further revealed an aberrant transcription of testosterone biosynthesis-related genes in the testes of BACHD rats with undisturbed luteinizing hormone (LH)/cAMP/PKA signaling, which plays a key role in regulating the transcription process of some of these genes. In line with the findings in BACHD rats, analyses in the R6/2 mouse model of HD showed similar results. Our findings support the view that mutant huntingtin may induce abnormal growth in males via the dysregulation of gene transcription in the testis, which in turn can affect testosterone biosynthesis.
- Published
- 2022
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11. Calpain-mediated proteolysis as driver and modulator of polyglutamine toxicity.
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Incebacak Eltemur RD, Nguyen HP, and Weber JJ
- Abstract
Among posttranslational modifications, directed proteolytic processes have the strongest impact on protein integrity. They are executed by a variety of cellular machineries and lead to a wide range of molecular consequences. Compared to other forms of proteolytic enzymes, the class of calcium-activated calpains is considered as modulator proteases due to their limited proteolytic activity, which changes the structure and function of their target substrates. In the context of neurodegeneration and - in particular - polyglutamine disorders, proteolytic events have been linked to modulatory effects on the molecular pathogenesis by generating harmful breakdown products of disease proteins. These findings led to the formulation of the toxic fragment hypothesis , and calpains appeared to be one of the key players and auspicious therapeutic targets in Huntington disease and Machado Joseph disease. This review provides a current survey of the role of calpains in proteolytic processes found in polyglutamine disorders. Together with insights into general concepts behind toxic fragments and findings in polyglutamine disorders, this work aims to inspire researchers to broaden and deepen the knowledge in this field, which will help to evaluate calpain-mediated proteolysis as a unifying and therapeutically targetable posttranslational mechanism in neurodegeneration., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Incebacak Eltemur, Nguyen and Weber.)
- Published
- 2022
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12. A Statewide Approach to Reducing Re-excision Rates for Women With Breast-conserving Surgery.
- Author
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Schumacher JR, Lawson EH, Kong AL, Weber JJ, May J, Landercasper J, Hanlon B, Marka N, Venkatesh M, Cartmill RS, Pavuluri Quamme S, Nikolay C, and Greenberg CC
- Subjects
- Female, Hospitals, Humans, Mastectomy, Mastectomy, Segmental, Reoperation, Retrospective Studies, Breast Neoplasms surgery, Carcinoma, Ductal, Breast surgery
- Abstract
Objective: Test the effectiveness of benchmarked performance reports based on existing discharge data paired with a statewide intervention to implement evidence-based strategies on breast re-excision rates., Background: Breast-conserving surgery (BCS) is a common breast cancer surgery performed in a range of hospital settings. Studies have demonstrated variations in post-BCS re-excision rates, identifying it as a high-value improvement target., Methods: Wisconsin Hospital Association discharge data (2017-2019) were used to compare 60-day re-excision rates following BCS for breast cancer. The analysis estimated the difference in the average change preintervention to postintervention between Surgical Collaborative of Wisconsin (SCW) and nonparticipating hospitals using a logistic mixed-effects model with repeated measures, adjusting for age, payer, and hospital volume, including hospitals as random effects. The intervention included 5 collaborative meetings in 2018 to 2019 where surgeon champions shared guideline updates, best practices/challenges, and facilitated action planning. Confidential benchmarked performance reports were provided., Results: In 2017, there were 3692 breast procedures in SCW and 1279 in nonparticipating hospitals; hospital-level re-excision rates ranged from 5% to >50%. There was no statistically significant baseline difference in re-excision rates between SCW and nonparticipating hospitals (16.1% vs. 17.1%, P =0.47). Re-excision significantly decreased for SCW but not for nonparticipating hospitals (odds ratio=0.69, 95% confidence interval=0.52-0.91)., Conclusions: Benchmarked performance reports and collaborative quality improvement can decrease post-BCS re-excisions, increase quality, and decrease costs. Our study demonstrates the effective use of administrative data as a platform for statewide quality collaboratives. Using existing data requires fewer resources and offers a new paradigm that promotes participation across practice settings., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2022
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13. Phenotypic analyses, protein localization, and bacteriostatic activity of Drosophila melanogaster transferrin-1.
- Author
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Weber JJ, Brummett LM, Coca ME, Tabunoki H, Kanost MR, Ragan EJ, Park Y, and Gorman MJ
- Subjects
- Animals, Female, Iron metabolism, Male, Oxidative Stress, Paraquat toxicity, Phenotype, Drosophila melanogaster metabolism, Transferrin chemistry
- Abstract
Transferrin-1 (Tsf1) is an extracellular insect protein with a high affinity for iron. The functions of Tsf1 are still poorly understood; however, Drosophila melanogaster Tsf1 has been shown to influence iron distribution in the fly body and to protect flies against some infections. The goal of this study was to better understand the physiological functions of Tsf1 in D. melanogaster by 1) investigating Tsf1 null phenotypes, 2) determining tissue-specific localization of Tsf1, 3) measuring the concentration of Tsf1 in hemolymph, 4) testing Tsf1 for bacteriostatic activity, and 5) evaluating the effect of metal and paraquat treatments on Tsf1 abundance. Flies lacking Tsf1 had more iron than wild-type flies in specialized midgut cells that take up iron from the diet; however, the absence of Tsf1 had no effect on the iron content of whole midguts, fat body, hemolymph, or heads. Thus, as previous studies have suggested, Tsf1 appears to have a minor role in iron transport. Tsf1 was abundant in hemolymph from larvae (0.4 μM), pupae (1.4 μM), adult females (4.4 μM) and adult males (22 μM). Apo-Tsf1 at 1 μM had bacteriostatic activity whereas holo-Tsf1 did not, suggesting that Tsf1 can inhibit microbial growth by sequestering iron in hemolymph and other extracellular environments. This hypothesis was supported by detection of secreted Tsf1 in tracheae, testes and seminal vesicles. Colocalization of Tsf1 with an endosome marker in oocytes suggested that Tsf1 may provide iron to developing eggs; however, eggs from mothers lacking Tsf1 had the same amount of iron as control eggs, and they hatched at a wild-type rate. Thus, the primary function of Tsf1 uptake by oocytes may be to defend against infection rather than to provide eggs with iron. In beetles, Tsf1 plays a role in protection against oxidative stress. In contrast, we found that flies lacking Tsf1 had a typical life span and greater resistance to paraquat-induced oxidative stress. In addition, Tsf1 abundance remained unchanged in response to ingestion of iron, cadmium or paraquat or to injection of iron. These results suggest that Tsf1 has a limited role in protection against oxidative stress in D. melanogaster., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
- Published
- 2022
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14. KPNB1 modulates the Machado-Joseph disease protein ataxin-3 through activation of the mitochondrial protease CLPP.
- Author
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Abeditashi M, Weber JJ, Pereira Sena P, Velic A, Kalimeri M, Incebacak Eltemur RD, Schmidt J, Hübener-Schmid J, Hauser S, Macek B, Riess O, and Schmidt T
- Subjects
- Animals, Endopeptidases genetics, Endopeptidases metabolism, Mice, Nerve Tissue Proteins metabolism, Nuclear Proteins metabolism, Ataxin-3 genetics, Ataxin-3 metabolism, Endopeptidase Clp genetics, Endopeptidase Clp metabolism, Machado-Joseph Disease genetics, Machado-Joseph Disease metabolism, Machado-Joseph Disease pathology, Mitochondria metabolism, beta Karyopherins genetics, beta Karyopherins metabolism
- Abstract
Machado-Joseph disease (MJD) is characterized by a pathological expansion of the polyglutamine (polyQ) tract within the ataxin-3 protein. Despite its primarily cytoplasmic localization, polyQ-expanded ataxin-3 accumulates in the nucleus and forms intranuclear aggregates in the affected neurons. Due to these histopathological hallmarks, the nucleocytoplasmic transport machinery has garnered attention as an important disease relevant mechanism. Here, we report on MJD cell model-based analysis of the nuclear transport receptor karyopherin subunit beta-1 (KPNB1) and its implications in the molecular pathogenesis of MJD. Although directly interacting with both wild-type and polyQ-expanded ataxin-3, modulating KPNB1 did not alter the intracellular localization of ataxin-3. Instead, overexpression of KPNB1 reduced ataxin-3 protein levels and the aggregate load, thereby improving cell viability. On the other hand, its knockdown and inhibition resulted in the accumulation of soluble and insoluble ataxin-3. Interestingly, the reduction of ataxin-3 was apparently based on protein fragmentation independent of the classical MJD-associated proteolytic pathways. Label-free quantitative proteomics and knockdown experiments identified mitochondrial protease CLPP as a potential mediator of the ataxin-3-degrading effect induced by KPNB1. We confirmed reduction of KPNB1 protein levels in MJD by analyzing two MJD transgenic mouse models and induced pluripotent stem cells (iPSCs) derived from MJD patients. Our results reveal a yet undescribed regulatory function of KPNB1 in controlling the turnover of ataxin-3, thereby highlighting a new potential target of therapeutic value for MJD., (© 2022. The Author(s).)
- Published
- 2022
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15. Mitochondrial Dysfunction in Spinocerebellar Ataxia Type 3 Is Linked to VDAC1 Deubiquitination.
- Author
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Harmuth T, Weber JJ, Zimmer AJ, Sowa AS, Schmidt J, Fitzgerald JC, Schöls L, Riess O, and Hübener-Schmid J
- Subjects
- Ataxin-3 genetics, Ataxin-3 metabolism, Humans, Mitochondria genetics, Mitochondria metabolism, Ubiquitin-Protein Ligases genetics, Ubiquitin-Protein Ligases metabolism, Voltage-Dependent Anion Channel 1 genetics, Voltage-Dependent Anion Channel 1 metabolism, Machado-Joseph Disease genetics, Machado-Joseph Disease metabolism
- Abstract
Dysfunctional mitochondria are linked to several neurodegenerative diseases. Metabolic defects, a symptom which can result from dysfunctional mitochondria, are also present in spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, the most frequent, dominantly inherited neurodegenerative ataxia worldwide. Mitochondrial dysfunction has been reported for several neurodegenerative disorders and ataxin-3 is known to deubiquitinylate parkin, a key protein required for canonical mitophagy. In this study, we analyzed mitochondrial function and mitophagy in a patient-derived SCA3 cell model. Human fibroblast lines isolated from SCA3 patients were immortalized and characterized. SCA3 patient fibroblasts revealed circular, ring-shaped mitochondria and featured reduced OXPHOS complexes, ATP production and cell viability. We show that wildtype ataxin-3 deubiquitinates VDAC1 (voltage-dependent anion channel 1), a member of the mitochondrial permeability transition pore and a parkin substrate. In SCA3 patients, VDAC1 deubiquitination and parkin recruitment to the depolarized mitochondria is inhibited. Increased p62-linked mitophagy, autophagosome formation and autophagy is observed under disease conditions, which is in line with mitochondrial fission. SCA3 fibroblast lines demonstrated a mitochondrial phenotype and dysregulation of parkin-VDAC1-mediated mitophagy, thereby promoting mitochondrial quality control via alternative pathways.
- Published
- 2022
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16. Calpains as novel players in the molecular pathogenesis of spinocerebellar ataxia type 17.
- Author
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Weber JJ, Anger SC, Pereira Sena P, Incebacak Eltemur RD, Huridou C, Fath F, Gross C, Casadei N, Riess O, and Nguyen HP
- Subjects
- Animals, Neurons metabolism, Rats, Trinucleotide Repeat Expansion, Calpain genetics, Calpain metabolism, Spinocerebellar Ataxias metabolism
- Abstract
Spinocerebellar ataxia type 17 (SCA17) is a neurodegenerative disease caused by a polyglutamine-encoding trinucleotide repeat expansion in the gene of transcription factor TATA box-binding protein (TBP). While its underlying pathomechanism is elusive, polyglutamine-expanded TBP fragments of unknown origin mediate the mutant protein's toxicity. Calcium-dependent calpain proteases are protagonists in neurodegenerative disorders. Here, we demonstrate that calpains cleave TBP, and emerging C-terminal fragments mislocalize to the cytoplasm. SCA17 cell and rat models exhibited calpain overactivation, leading to excessive fragmentation and depletion of neuronal proteins in vivo. Transcriptome analysis of SCA17 cells revealed synaptogenesis and calcium signaling perturbations, indicating the potential cause of elevated calpain activity. Pharmacological or genetic calpain inhibition reduced TBP cleavage and aggregation, consequently improving cell viability. Our work underlines the general significance of calpains and their activating pathways in neurodegenerative disorders and presents these proteases as novel players in the molecular pathogenesis of SCA17., (© 2022. The Author(s).)
- Published
- 2022
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17. Pathophysiological interplay between O -GlcNAc transferase and the Machado-Joseph disease protein ataxin-3.
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Pereira Sena P, Weber JJ, Watchon M, Robinson KJ, Wassouf Z, Hauser S, Helm J, Abeditashi M, Schmidt J, Hübener-Schmid J, Schöls L, Laird AS, Riess O, and Schmidt T
- Subjects
- Animals, Ataxin-3 genetics, Disease Models, Animal, HEK293 Cells, Humans, Peptides, Proteasome Endopeptidase Complex, Zebrafish metabolism, Ataxin-3 metabolism, Machado-Joseph Disease metabolism, Machado-Joseph Disease pathology, N-Acetylglucosaminyltransferases metabolism
- Abstract
Aberrant O -GlcNAcylation, a protein posttranslational modification defined by the O -linked attachment of the monosaccharide N -acetylglucosamine ( O -GlcNAc), has been implicated in neurodegenerative diseases. However, although many neuronal proteins are substrates for O -GlcNAcylation, this process has not been extensively investigated in polyglutamine disorders. We aimed to evaluate the enzyme O -GlcNAc transferase (OGT), which attaches O -GlcNAc to target proteins, in Machado-Joseph disease (MJD). MJD is a neurodegenerative condition characterized by ataxia and caused by the expansion of a polyglutamine stretch within the deubiquitinase ataxin-3, which then present increased propensity to aggregate. By analyzing MJD cell and animal models, we provide evidence that OGT is dysregulated in MJD, therefore compromising the O -GlcNAc cycle. Moreover, we demonstrate that wild-type ataxin-3 modulates OGT protein levels in a proteasome-dependent manner, and we present OGT as a substrate for ataxin-3. Targeting OGT levels and activity reduced ataxin-3 aggregates, improved protein clearance and cell viability, and alleviated motor impairment reminiscent of ataxia of MJD patients in zebrafish model of the disease. Taken together, our results point to a direct interaction between OGT and ataxin-3 in health and disease and propose the O -GlcNAc cycle as a promising target for the development of therapeutics in the yet incurable MJD., Competing Interests: The authors declare no competing interest.
- Published
- 2021
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18. Phylogenetic and sequence analyses of insect transferrins suggest that only transferrin 1 has a role in iron homeostasis.
- Author
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Najera DG, Dittmer NT, Weber JJ, Kanost MR, and Gorman MJ
- Subjects
- Animals, Insect Proteins metabolism, Insecta metabolism, Phylogeny, Sequence Analysis, Protein, Transferrins metabolism, Homeostasis, Insect Proteins genetics, Insecta genetics, Iron metabolism, Transferrins genetics
- Abstract
Iron is essential to life, but surprisingly little is known about how iron is managed in nonvertebrate animals. In mammals, the well-characterized transferrins bind iron and are involved in iron transport or immunity, whereas other members of the transferrin family do not have a role in iron homeostasis. In insects, the functions of transferrins are still poorly understood. The goals of this project were to identify the transferrin genes in a diverse set of insect species, resolve the evolutionary relationships among these genes, and predict which of the transferrins are likely to have a role in iron homeostasis. Our phylogenetic analysis of transferrins from 16 orders of insects and two orders of noninsect hexapods demonstrated that there are four orthologous groups of insect transferrins. Our analysis suggests that transferrin 2 arose prior to the origin of insects, and transferrins 1, 3, and 4 arose early in insect evolution. Primary sequence analysis of each of the insect transferrins was used to predict signal peptides, carboxyl-terminal transmembrane regions, GPI-anchors, and iron binding. Based on this analysis, we suggest that transferrins 2, 3, and 4 are unlikely to play a major role in iron homeostasis. In contrast, the transferrin 1 orthologs are predicted to be secreted, soluble, iron-binding proteins. We conclude that transferrin 1 orthologs are the most likely to play an important role in iron homeostasis. Interestingly, it appears that the louse, aphid, and thrips lineages have lost the transferrin 1 gene and, thus, have evolved to manage iron without transferrins., (© 2020 Institute of Zoology, Chinese Academy of Sciences.)
- Published
- 2021
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19. Neurodegenerative phosphoprotein signaling landscape in models of SCA3.
- Author
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Sowa AS, Popova TG, Harmuth T, Weber JJ, Pereira Sena P, Schmidt J, Hübener-Schmid J, and Schmidt T
- Subjects
- Animals, Apoptosis, Ataxin-3 genetics, Cell Line, Fibroblasts, Glycogen Synthase Kinase 3 physiology, HEK293 Cells, Humans, Mice, Mice, Transgenic, Phosphatidylinositol 3-Kinases physiology, Protein Array Analysis, Proto-Oncogene Proteins c-akt physiology, TOR Serine-Threonine Kinases physiology, Ataxin-3 physiology, Machado-Joseph Disease physiopathology, Nerve Tissue Proteins physiology, Peptides metabolism, Phosphoproteins physiology, Signal Transduction physiology
- Abstract
Spinocerebellar ataxia type 3 (SCA3) is a rare neurodegenerative disorder resulting from an aberrant expansion of a polyglutamine stretch in the ataxin-3 protein and subsequent neuronal death. The underlying intracellular signaling pathways are currently unknown. We applied the Reverse-phase Protein MicroArray (RPMA) technology to assess the levels of 50 signaling proteins (in phosphorylated and total forms) using three in vitro and in vivo models expressing expanded ataxin-3: (i) human embryonic kidney (HEK293T) cells stably transfected with human ataxin-3 constructs, (ii) mouse embryonic fibroblasts (MEF) from SCA3 transgenic mice, and (iii) whole brains from SCA3 transgenic mice. All three models demonstrated a high degree of similarity sharing a subset of phosphorylated proteins involved in the PI3K/AKT/GSK3/mTOR pathway. Expanded ataxin-3 strongly interfered (by stimulation or suppression) with normal ataxin-3 signaling consistent with the pathogenic role of the polyglutamine expansion. In comparison with normal ataxin-3, expanded ataxin-3 caused a pro-survival stimulation of the ERK pathway along with reduced pro-apoptotic and transcriptional responses.
- Published
- 2021
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20. The Novel Alpha-2 Adrenoceptor Inhibitor Beditin Reduces Cytotoxicity and Huntingtin Aggregates in Cell Models of Huntington's Disease.
- Author
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Singer E, Hunanyan L, Melkonyan MM, Weber JJ, Danielyan L, and Nguyen HP
- Abstract
Huntington's disease (HD) is a monogenetic neurodegenerative disorder characterized by the accumulation of polyglutamine-expanded huntingtin (mHTT). There is currently no cure, and therefore disease-slowing remedies are sought to alleviate symptoms of the multifaceted disorder. Encouraging findings in Alzheimer's and Parkinson's disease on alpha-2 adrenoceptor (α2-AR) inhibition have shown neuroprotective and aggregation-reducing effects in cell and animal models. Here, we analyzed the effect of beditin, a novel α2- adrenoceptor (AR) antagonist, on cell viability and mHTT protein levels in cell models of HD using Western blot, time-resolved Foerster resonance energy transfer (TR-FRET), lactate dehydrogenase (LDH) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) cytotoxicity assays. Beditin decreases cytotoxicity, as measured by TUNEL staining and LDH release, in a neuronal progenitor cell model (ST Hdh cells) of HD and decreases the aggregation propensity of HTT exon 1 fragments in an overexpression model using human embryonic kidney (HEK) 293T cells. α2-AR is a promising therapeutic target for further characterization in HD models. Our data allow us to suggest beditin as a valuable candidate for the pharmaceutical manipulation of α2-AR, as it is capable of modulating neuronal cell survival and the level of mHTT.
- Published
- 2021
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21. Structural insight into the novel iron-coordination and domain interactions of transferrin-1 from a model insect, Manduca sexta.
- Author
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Weber JJ, Kashipathy MM, Battaile KP, Go E, Desaire H, Kanost MR, Lovell S, and Gorman MJ
- Subjects
- Animals, Crystallography, X-Ray, Protein Domains, Insect Proteins chemistry, Manduca chemistry, Transferrin chemistry
- Abstract
Transferrins function in iron sequestration and iron transport by binding iron tightly and reversibly. Vertebrate transferrins coordinate iron through interactions with two tyrosines, an aspartate, a histidine, and a carbonate anion, and conformational changes that occur upon iron binding and release have been described. Much less is known about the structure and functions of insect transferrin-1 (Tsf1), which is present in hemolymph and influences iron homeostasis mostly by unknown mechanisms. Amino acid sequence and biochemical analyses have suggested that iron coordination by Tsf1 differs from that of the vertebrate transferrins. Here we report the first crystal structure (2.05 Å resolution) of an insect transferrin. Manduca sexta (MsTsf1) in the holo form exhibits a bilobal fold similar to that of vertebrate transferrins, but its carboxyl-lobe adopts a novel orientation and contacts with the amino-lobe. The structure revealed coordination of a single Fe
3+ ion in the amino-lobe through Tyr90, Tyr204, and two carbonate anions. One carbonate anion is buried near the ferric ion and is coordinated by four residues, whereas the other carbonate anion is solvent exposed and coordinated by Asn121. Notably, these residues are highly conserved in Tsf1 orthologs. Docking analysis suggested that the solvent exposed carbonate position is capable of binding alternative anions. These findings provide a structural basis for understanding Tsf1 function in iron sequestration and transport in insects as well as insight into the similarities and differences in iron homeostasis between insects and humans., (© 2020 The Protein Society.)- Published
- 2021
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22. Iron binding and release properties of transferrin-1 from Drosophila melanogaster and Manduca sexta: Implications for insect iron homeostasis.
- Author
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Weber JJ, Kanost MR, and Gorman MJ
- Subjects
- Animals, Binding Sites, Hemolymph metabolism, Insecta metabolism, Spectrum Analysis methods, Drosophila melanogaster metabolism, Iron metabolism, Manduca metabolism, Transferrins chemistry, Transferrins metabolism
- Abstract
Transferrins belong to an ancient family of extracellular proteins. The best-characterized transferrins are mammalian proteins that function in iron sequestration or iron transport; they accomplish these functions by having a high-affinity iron-binding site in each of their two homologous lobes. Insect hemolymph transferrins (Tsf1s) also function in iron sequestration and transport; however, sequence-based predictions of their iron-binding residues have suggested that most Tsf1s have a single, lower-affinity iron-binding site. To reconcile the apparent contradiction between the known physiological functions and predicted biochemical properties of Tsf1s, we purified and characterized the iron-binding properties of Drosophila melanogaster Tsf1 (DmTsf1), Manduca sexta Tsf1 (MsTsf1), and the amino-lobe of DmTsf1 (DmTsf1
N ). Using UV-Vis spectroscopy, we found that these proteins bind iron, but they exhibit shifts in their spectra compared to mammalian transferrins. Through equilibrium dialysis experiments, we determined that DmTsf1 and MsTsf1 bind only one ferric ion; their affinity for iron is high (log K' = 18), but less than that of the well-characterized mammalian transferrins (log K' ~ 20); and they release iron under moderately acidic conditions (pH50 = 5.5). Iron release analysis of DmTsf1N suggested that iron binding in the amino-lobe is stabilized by the carboxyl-lobe. These findings will be critical for elucidating the mechanisms of Tsf1 function in iron sequestration and transport in insects., (Copyright © 2020 Elsevier Ltd. All rights reserved.)- Published
- 2020
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23. Calpain-1 ablation partially rescues disease-associated hallmarks in models of Machado-Joseph disease.
- Author
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Weber JJ, Haas E, Maringer Y, Hauser S, Casadei NLP, Chishti AH, Riess O, and Hübener-Schmid J
- Subjects
- Animals, Ataxin-3 genetics, Female, Machado-Joseph Disease etiology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Peptides metabolism, Phenotype, Proteolysis, Ataxin-3 metabolism, Calcium metabolism, Calpain physiology, Disease Models, Animal, Machado-Joseph Disease pathology
- Abstract
Proteolytic fragmentation of polyglutamine-expanded ataxin-3 is a concomitant and modifier of the molecular pathogenesis of Machado-Joseph disease (MJD), the most common autosomal dominant cerebellar ataxia. Calpains, a group of calcium-dependent cysteine proteases, are important mediators of ataxin-3 cleavage and implicated in multiple neurodegenerative conditions. Pharmacologic and genetic approaches lowering calpain activity showed beneficial effects on molecular and behavioural disease characteristics in MJD model organisms. However, specifically targeting one of the calpain isoforms by genetic means has not yet been evaluated as a potential therapeutic strategy. In our study, we tested whether calpains are overactivated in the MJD context and if reduction or ablation of calpain-1 expression ameliorates the disease-associated phenotype in MJD cells and mice. In all analysed MJD models, we detected an elevated calpain activity at baseline. Lowering or removal of calpain-1 in cells or mice counteracted calpain system overactivation and led to reduced cleavage of ataxin-3 without affecting its aggregation. Moreover, calpain-1 knockout in YAC84Q mice alleviated excessive fragmentation of important synaptic proteins. Despite worsening some motor characteristics, YAC84Q mice showed a rescue of body weight loss and extended survival upon calpain-1 knockout. Together, our findings emphasize the general potential of calpains as a therapeutic target in MJD and other neurodegenerative diseases., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2020
- Full Text
- View/download PDF
24. Gaming natural selection: Using board games as simulations to teach evolution.
- Author
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Muell MR, Guillory WX, Kellerman A, Rubio AO, Scott-Elliston A, Morales O, Eckhoff K, Barfknecht D, Hartsock JA, Weber JJ, and Brown JL
- Subjects
- Biological Evolution, Biology education, Games, Recreational, Selection, Genetic
- Published
- 2020
- Full Text
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25. Experiences of Care in the Emergency Department Among a Sample of Homeless Male Veterans: A Qualitative Study.
- Author
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Weber JJ, Lee RC, and Martsolf D
- Subjects
- Grounded Theory, Ill-Housed Persons psychology, Humans, Interviews as Topic, Male, Middle Aged, Qualitative Research, United States, Veterans psychology, Attitude to Health, Emergency Service, Hospital, Health Services Accessibility statistics & numerical data, Ill-Housed Persons statistics & numerical data, Veterans statistics & numerical data
- Abstract
Introduction: Homeless populations are historically high users of the emergency department for low-acuity issues that could be treated in more appropriate settings such as primary care. Veterans make up 11% of the homeless adult population and are often seen in community and Veterans Affairs Medical Center (VAMC) emergency departments. The purpose of this study was to describe the experiences of a sample of homeless male veterans as they attempt to access health care in the emergency department., Methods: Grounded theory methodology provided the overarching framework for this research project. Structured interviews were conducted with 34 male homeless veterans, with 25 discussing their ED care. Veterans were recruited and interviewed from one VAMC emergency department, an all-male emergency shelter, and 1 soup kitchen. Text units about ED use were extracted and compared from 25 recorded transcripts to identify categories., Results: Three categories defined ED experiences: "no other option," "lack of voice," and "feeling valued.", Discussion: The sample of homeless veterans in this study provided first-person knowledge about their experiences receiving care in emergency departments. These results are consistent with previous research indicating that homeless populations are high users of ED care; however, they often feel undervalued and lack of empathy from health providers. Emergency nurses are an integral part of the ED health care delivery system for the homeless, providing advocacy and much needed education about health problems and alternatives to ED care. The insight obtained about the lives and experiences of veterans in the ED is valuable to the practice of emergency nurses., (Copyright © 2019 Emergency Nurses Association. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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26. An examination of climate-driven flowering-time shifts at large spatial scales over 153 years in a common weedy annual.
- Author
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Berg CS, Brown JL, and Weber JJ
- Subjects
- Flowers, Seasons, Temperature, Climate Change, Reproduction
- Abstract
Premise: Understanding species' responses to climate change is a critical challenge facing biologists today. Though many species are widespread, few studies of climate-driven shifts in flowering time have examined large continuous spatial scales for individual species. And even fewer studies have examined these shifts at time scales greater than a few decades., Methods: We used digitized herbarium specimens and PRISM climate data to produce the spatially and temporally broadest-scale study of flowering time in a single species to date, spanning the contiguous United States and 153 years (1863-2016) for a widespread weedy annual, Triodanis perfoliata (Campanulaceae). We examined factors driving phenological shifts as well as the roles of geographic and temporal scale in understanding these trends., Results: Year was a significant factor in both geospatial and climatic analyses, revealing that flowering time has advanced by ~9 days over the past ~150 years. We found that temperature as well as vapor pressure deficit, an understudied climatic parameter associated with evapotranspiration and water stress, were strongly associated with peak flowering. We also examined how sampling at different spatiotemporal scales influences the power to detect flowering-time shifts, finding that relatively large spatial and temporal scales are ideal for detecting flowering-time shifts in this widespread species., Conclusions: Our results emphasize the importance of understanding the interplay of geospatial factors at different scales to examine how species respond to climate change., (© 2019 Botanical Society of America.)
- Published
- 2019
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27. Olesoxime in neurodegenerative diseases: Scrutinising a promising drug candidate.
- Author
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Weber JJ, Clemensson LE, Schiöth HB, and Nguyen HP
- Subjects
- Animals, Calcium metabolism, Calpain metabolism, Cholestenones chemistry, Cholesterol metabolism, Homeostasis drug effects, Humans, Mice, Mitochondria drug effects, Mitochondria metabolism, Mitochondrial Transmembrane Permeability-Driven Necrosis drug effects, Neuroprotective Agents chemistry, Oxidative Stress drug effects, Rats, Cholestenones pharmacology, Cholestenones therapeutic use, Neurodegenerative Diseases drug therapy, Neuroprotective Agents pharmacology, Neuroprotective Agents therapeutic use
- Abstract
Over the last years, the experimental compound olesoxime, a mitochondria-targeting cholesterol derivative, has emerged as a promising drug candidate for neurodegenerative diseases. Numerous preclinical studies have successfully proved olesoxime's neuroprotective properties in cell and animal models of clinical conditions such as amyotrophic lateral sclerosis, Huntington disease, Parkinson disease, peripheral neuropathy and spinal muscular atrophy. The beneficial effects were attributed to olesoxime's potential impact on oxidative stress, mitochondrial permeability transition or cholesterol homoeostasis. Although no significant benefits have been demonstrated in patients of amyotrophic lateral sclerosis, and only the first 12 months of a phase II/III clinical trial showed an improvement in motor symptoms of spinal muscular atrophy, this orphan drug may still offer undiscovered potential in the treatment of neurological diseases. In our earlier preclinical studies, we demonstrated that administration of olesoxime in mouse and rat models of Huntington disease improved psychiatric and molecular phenotypes. Aside from stabilising mitochondrial function, the drug reduced the overactivation of calpains, a class of calcium-dependent proteases entangled in neurodegenerative conditions. This observation may be credited to olesoxime's action on calcium dyshomeostasis, a further hallmark in neurodegeneration, and linked to its targets TSPO and VDAC, two proteins of the outer mitochondrial membrane associated with mitochondrial calcium handling. Further research into the mode of action of olesoxime under pathological conditions, including its effect on neuronal calcium homeostasis, may strengthen the untapped potential of olesoxime or other similar compounds as a therapeutic for neurodegenerative diseases., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
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28. Vulnerability of frontal brain neurons for the toxicity of expanded ataxin-3.
- Author
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Schmidt J, Mayer AK, Bakula D, Freude J, Weber JJ, Weiss A, Riess O, and Schmidt T
- Subjects
- Animals, Ataxin-3 metabolism, Behavior, Animal, Calcium-Calmodulin-Dependent Protein Kinase Type 2 genetics, Disease Models, Animal, Frontal Lobe pathology, Gene Expression, Genetic Association Studies, Genetic Predisposition to Disease, Immunohistochemistry, Machado-Joseph Disease pathology, Mice, Mice, Transgenic, Nerve Degeneration genetics, Nerve Degeneration metabolism, Nerve Degeneration pathology, Organ Specificity genetics, Protein Aggregates, Protein Aggregation, Pathological, Psychomotor Performance, Ataxin-3 genetics, Frontal Lobe metabolism, Machado-Joseph Disease genetics, Machado-Joseph Disease metabolism, Neurons metabolism, Trinucleotide Repeat Expansion
- Abstract
Spinocerebellar ataxia type 3 (SCA3) is caused by the expansion of CAG repeats in the ATXN3 gene leading to an elongated polyglutamine tract in the ataxin-3 protein. Previously, we demonstrated that symptoms of SCA3 are reversible in the first conditional mouse model for SCA3 directing ataxin-3 predominantly to the hindbrain. Here, we report on the effects of transgenic ataxin-3 expression in forebrain regions. Employing the Tet-off CamKII-promoter mouse line and our previously published SCA3 responder line, we generated double transgenic mice (CamKII/MJD77), which develop a neurological phenotype characterized by impairment in rotarod performance, and deficits in learning new motor tasks as well as hyperactivity. Ataxin-3 and ubiquitin-positive inclusions are detected in brains of double transgenic CamKII/MJD77 mice. After turning off the expression of pathologically expanded ataxin-3, these inclusions disappear. However, the observed phenotype could not be reversed, very likely due to pronounced apoptotic cell death in the frontal brain. Our data demonstrate that cerebellar expression is not required to induce a neurological phenotype using expanded ATXN3 as well as the pronounced sensibility of forebrain neurons for toxic ataxin-3., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2019
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29. Killing Two Angry Birds with One Stone: Autophagy Activation by Inhibiting Calpains in Neurodegenerative Diseases and Beyond.
- Author
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Weber JJ, Pereira Sena P, Singer E, and Nguyen HP
- Subjects
- Animals, Calpain chemistry, Calpain metabolism, Glycoproteins pharmacology, Glycoproteins therapeutic use, Humans, Models, Biological, Neurodegenerative Diseases drug therapy, Autophagy, Calpain antagonists & inhibitors, Neurodegenerative Diseases pathology
- Abstract
Proteolytic machineries execute vital cellular functions and their disturbances are implicated in diverse medical conditions, including neurodegenerative diseases. Interestingly, calpains, a class of Ca
2+ -dependent regulatory proteases, can modulate the degradational system of autophagy by cleaving proteins involved in this pathway. Moreover, both machineries are common players in many molecular pathomechanisms and have been targeted individually or together, as a therapeutic strategy in experimental setups. In this review, we briefly introduce calpains and autophagy, with their roles in health and disease, and focus on their direct pathologically relevant interplay in neurodegeneration and beyond. The modulation of calpain activity may comprise a promising treatment approach to attenuate the deregulation of these two essential mechanisms.- Published
- 2019
- Full Text
- View/download PDF
30. A systematic review of nurse-led interventions with populations experiencing homelessness.
- Author
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Weber JJ
- Subjects
- Child, Female, Housing, Humans, Male, United States, Delivery of Health Care methods, Ill-Housed Persons psychology, Quality of Life psychology
- Abstract
Homelessness is associated with poorer health status, and affects men, women, children, and veterans alike across the United States. With over half a million-people suffering from homelessness on any given night, it is imperative that the health care delivery system step in to help this vulnerable group. Registered nurses encounter people experiencing homelessness in hospitals, clinics, shelters, and across the public health sector. They have the necessary skills to help make positive health-related changes for homeless populations and improve their overall quality of life. Therefore, the purpose of this systematic review was to (a) assess existing nurse-led interventional studies with homeless populations, (b) highlight effective methods that nurses used to impact care, and (c) make recommendations about future research needed. PRISMA guidelines were used and multiple databases were searched for nurse-led interventional research with those experiencing homelessness. Recommendations include using a holistic nursing approach when working to improve outcomes for homeless populations to ensure optimal treatment for their complex physical, mental, and social health problems., (© 2018 Wiley Periodicals, Inc.)
- Published
- 2019
- Full Text
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31. The influence of environmental factors on breeding system allocation at large spatial scales.
- Author
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Ansaldi BH, Franks SJ, and Weber JJ
- Abstract
Plant breeding systems can vary widely among populations, yet few studies have investigated abiotic factors contributing to variation across a broad geographic range. Here we investigate variation in reproductive traits of Triodanis perfoliata (Campanulaceae), a species that exhibits dimorphic cleistogamy, a condition in which individual plants have both closed (selfing: cleistogamous: CL) and open (selfing or outcrossing: chasmogamous: CH) flowers. Chasmogamous production is theorized to be more costly because CH flowers have a larger exposed surface area and thus are more likely to lose more water than CL flowers. We examine relationships between abiotic conditions (temperature, precipitation and soil characteristics) and variation in breeding systems across 14 widespread populations using ordinary least squares models. We found that a large proportion of breeding system variation was described by climate and soil variables ( R
2 = 0.65-0.92). These results support the hypothesis that variation in the environment drives variation in breeding system allocation. Our broad geographic analyses provide a framework for mechanistic studies of cleistogamy, and employ a novel approach for examining reproductive traits and environmental variation at large scales. Given that two major components of our models were temperature and precipitation, our study further emphasizes the potential for ongoing climate change to alter plant breeding systems.- Published
- 2018
- Full Text
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32. The role of phenotypic plasticity and pollination environment in the cleistogamous, mixed mating breeding system of Triodanis perfoliata.
- Author
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Ansaldi BH, Weber JJ, and Franks SJ
- Subjects
- Environment, Flowers physiology, Phenotype, Reproduction, Campanulaceae physiology, Pollination physiology
- Abstract
The role of variable pollination environments in maintaining mixed mating systems is an active area of research. Dimorphic cleistogamy, in which a plant reproduces by both open, facultative outcrossing chasmogamous (CH) flowers and closed, cleistogamous (CL) flowers presents an excellent opportunity to study mixed mating. For example, plastic responses in allocation to an optimal floral type could serve as an adaptive strategy that maintains mixed mating under variable pollination environments. We tested for pollen limitation and plastic responses in allocation to different floral types under manipulated pollination conditions in the dimorphic cleistogamous, mixed mating annual, Triodanis perfoliata. Using a field population, we quantified pollen limitation, auto-fertility and plastic responses in the breeding system by measuring allocation to flower number and seed set of floral types. We found no evidence for pollen limitation for CH flowers, and CH flowers had low efficacy of autonomous selfing. Importantly, we found that T. perfoliata alters floral number following changes in pollination conditions, with pollen-supplemented plants having lower relative CH flower number than non-supplemented plants. Breeding system plasticity may allow for benefits from outcrossing through CH flowers, but also increased overall fitness through relatively cheap CL reproduction. After CH flowers receive pollen, subsequent production of CH flowers was reduced, which may be due to resource limitation. Our findings did not support a theoretical model predicting increased CH flowers with high pollination levels. These results increase our understanding of the role of pollination services and resource allocation in the maintenance of mixed mating systems, which also warrants further investigation., (© 2018 German Society for Plant Sciences and The Royal Botanical Society of the Netherlands.)
- Published
- 2018
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33. Mitochondrial Morphology, Function and Homeostasis Are Impaired by Expression of an N-terminal Calpain Cleavage Fragment of Ataxin-3.
- Author
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Harmuth T, Prell-Schicker C, Weber JJ, Gellerich F, Funke C, Drießen S, Magg JCD, Krebiehl G, Wolburg H, Hayer SN, Hauser S, Krüger R, Schöls L, Riess O, and Hübener-Schmid J
- Abstract
Alterations in mitochondrial morphology and function have been linked to neurodegenerative diseases, including Parkinson disease, Alzheimer disease and Huntington disease. Metabolic defects, resulting from dysfunctional mitochondria, have been reported in patients and respective animal models of all those diseases. Spinocerebellar Ataxia Type 3 (SCA3), another neurodegenerative disorder, also presents with metabolic defects and loss of body weight in early disease stages although the possible role of mitochondrial dysfunction in SCA3 pathology is still to be determined. Interestingly, the SCA3 disease protein ataxin-3, which is predominantly localized in cytoplasm and nucleus, has also been associated with mitochondria in both its mutant and wildtype form. This observation provides an interesting link to a potential mitochondrial involvement of mutant ataxin-3 in SCA3 pathogenesis. Furthermore, proteolytic cleavage of ataxin-3 has been shown to produce toxic fragments and even overexpression of artificially truncated forms of ataxin-3 resulted in mitochondria deficits. Therefore, we analyzed the repercussions of expressing a naturally occurring N-terminal cleavage fragment of ataxin-3 and the influence of an endogenous expression of the S256 cleavage fragment in vitro and in vivo . In our study, expression of a fragment derived from calpain cleavage induced mitochondrial fragmentation and cristae alterations leading to a significantly decreased capacity of mitochondrial respiration and contributing to an increased susceptibility to apoptosis. Furthermore, analyzing mitophagy revealed activation of autophagy in the early pathogenesis with reduced lysosomal activity. In conclusion, our findings indicate that cleavage of ataxin-3 by calpains results in fragments which interfere with mitochondrial function and mitochondrial degradation processes.
- Published
- 2018
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34. Generation of an induced pluripotent stem cell line from a patient with spinocerebellar ataxia type 3 (SCA3): HIHCNi002-A.
- Author
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Hayer SN, Schelling Y, Huebener-Schmid J, Weber JJ, Hauser S, and Schöls L
- Subjects
- Adult, Cell Differentiation, Cell Line, Humans, Induced Pluripotent Stem Cells metabolism, Machado-Joseph Disease metabolism, Machado-Joseph Disease pathology, Male, Ataxin-3 genetics, Ataxin-3 metabolism, Machado-Joseph Disease genetics
- Abstract
A skin biopsy of a patient with spinocerebellar ataxia type 3 (SCA3, also known as Machado-Joseph disease (MJD)) caused by a CAG trinucleotide repeat expansion in the ATXN3 gene, was used to generate an induced pluripotent stem cell line, HIHCNi002-A (iPSC-SCA3). Skin fibroblasts were reprogrammed using episomal plasmids carrying hOCT4, hSOX2, hKLF4, hL-MYC, and hLIN28. The iPSC-SCA3 line exhibits chromosomal stability with conservation of the ATXN3 repeat expansion, expresses pluripotency markers and differentiates into endo-, meso-, and ectodermal cells in vitro., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2018
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35. Calpastatin ablation aggravates the molecular phenotype in cell and animal models of Huntington disease.
- Author
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Weber JJ, Kloock SJ, Nagel M, Ortiz-Rios MM, Hofmann J, Riess O, and Nguyen HP
- Subjects
- Analysis of Variance, Animals, Autophagy drug effects, Autophagy genetics, Calpain genetics, Cytoskeletal Proteins genetics, Disease Models, Animal, Dopamine and cAMP-Regulated Phosphoprotein 32 metabolism, Glycoproteins pharmacology, HEK293 Cells, Humans, Huntingtin Protein, Mice, Mice, Inbred C57BL, Mice, Transgenic, Nerve Tissue Proteins genetics, Nuclear Proteins genetics, RNA, Small Interfering genetics, RNA, Small Interfering metabolism, Synapsins metabolism, Transfection, Calpain metabolism, Cytoskeletal Proteins deficiency, Gene Expression Regulation genetics, Huntington Disease genetics, Huntington Disease pathology, Nerve Tissue Proteins metabolism, Nuclear Proteins metabolism
- Abstract
Deciphering the molecular pathology of Huntington disease is of particular importance, not only for a better understanding of this neurodegenerative disease, but also to identify potential therapeutic targets. The polyglutamine-expanded disease protein huntingtin was shown to undergo proteolysis, which results in the accumulation of toxic and aggregation-prone fragments. Amongst several classes of proteolytic enzymes responsible for huntingtin processing, the group of calcium-activated calpains has been found to be a significant mediator of the disease protein toxicity. To confirm the impact of calpain-mediated huntingtin cleavage in Huntington disease, we analysed the effect of depleting or overexpressing the endogenous calpain inhibitor calpastatin in HEK293T cells transfected with wild-type or polyglutamine-expanded huntingtin. Moreover, we crossbred huntingtin knock-in mice with calpastatin knockout animals to assess its effect not only on huntingtin cleavage and aggregation but also additional molecular markers. We demonstrated that a reduced or ablated expression of calpastatin triggers calpain overactivation and a consequently increased mutant huntingtin cleavage in cells and in vivo. These alterations were accompanied by an elevated formation of predominantly cytoplasmic huntingtin aggregates. On the other hand, overexpression of calpastatin in cells attenuated huntingtin fragmentation and aggregation. In addition, we observed an enhanced cleavage of DARPP-32, p35 and synapsin-1 in neuronal tissue upon calpain overactivation. Our results corroborate the important role of calpains in the molecular pathogenesis of Huntington disease and endorse targeting these proteolytic enzymes as a therapeutic approach., (Copyright © 2018 Elsevier Ltd. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
36. Environment-dependent striatal gene expression in the BACHD rat model for Huntington disease.
- Author
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Novati A, Hentrich T, Wassouf Z, Weber JJ, Yu-Taeger L, Déglon N, Nguyen HP, and Schulze-Hentrich JM
- Subjects
- Animals, Disease Models, Animal, Disease Progression, Gene Expression Profiling, Gene Regulatory Networks, Huntingtin Protein deficiency, Mice, Rats, Sequence Analysis, RNA, Corpus Striatum pathology, Environmental Exposure, Gene Expression, Huntington Disease pathology
- Abstract
Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by a mutation in the huntingtin (HTT) gene which results in progressive neurodegeneration in the striatum, cortex, and eventually most brain areas. Despite being a monogenic disorder, environmental factors influence HD characteristics. Both human and mouse studies suggest that mutant HTT (mHTT) leads to gene expression changes that harbor potential to be modulated by the environment. Yet, the underlying mechanisms integrating environmental cues into the gene regulatory program have remained largely unclear. To better understand gene-environment interactions in the context of mHTT, we employed RNA-seq to examine effects of maternal separation (MS) and environmental enrichment (EE) on striatal gene expression during development of BACHD rats. We integrated our results with striatal consensus modules defined on HTT-CAG length and age-dependent co-expression gene networks to relate the environmental factors with disease progression. While mHTT was the main determinant of expression changes, both MS and EE were capable of modulating these disturbances, resulting in distinctive and in several cases opposing effects of MS and EE on consensus modules. This bivalent response to maternal separation and environmental enrichment may aid in explaining their distinct effects observed on disease phenotypes in animal models of HD and related neurodegenerative disorders.
- Published
- 2018
- Full Text
- View/download PDF
37. The best of both worlds? A review of delayed selfing in flowering plants.
- Author
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Goodwillie C and Weber JJ
- Subjects
- Flowers physiology, Phylogeny, Reproduction, Magnoliopsida physiology, Pollination physiology, Self-Fertilization physiology
- Abstract
Premise of Study: In a seminal body of theory, Lloyd showed that the fitness consequences of selfing will depend on its timing in anthesis. Selfing that occurs after opportunities for outcrossing or pollen dispersal can provide reproductive assurance when pollinators are limited and is expected to incur little cost, even when inbreeding depression is high. As a result, delayed selfing is often interpreted as a "best-of-both-worlds" mating system that combines the advantages of selfing and outcrossing., Methods: We surveyed 65 empirical studies of delayed selfing, recording floral mechanisms and examining information on inbreeding depression, autofertility, and other parameters to test the support for delayed selfing as a best-of-both-worlds strategy., Key Results: Phylogenetic distribution of the diverse floral mechanisms suggests that some basic floral structures may predispose plant taxa to evolve delayed selfing. Delayed selfing appears to serve as a best-of-both-worlds strategy in some but not all species. While the capacity for autonomous selfing is often high, it is lower, in some cases, than in related species with earlier modes of selfing. In other delayed-selfers, low inbreeding depression and reduced investment in corollas and pollen suggest limited benefits from outcrossing., Conclusions: Despite a growing literature on the subject, experimental evidence for delayed selfing is limited and major gaps in knowledge remain, particularly with respect to the stability of delayed selfing and the conditions that may favor transitions between delayed and earlier selfing. Finally, we suggest a potential role of delayed selfing in facilitating transitions from self-incompatibility to selfing., (© 2018 The Authors. American Journal of Botany is published by Wiley Periodicals, Inc. on behalf of the Botanical Society of America.)
- Published
- 2018
- Full Text
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38. Karyopherin α-3 is a key protein in the pathogenesis of spinocerebellar ataxia type 3 controlling the nuclear localization of ataxin-3.
- Author
-
Sowa AS, Martin E, Martins IM, Schmidt J, Depping R, Weber JJ, Rother F, Hartmann E, Bader M, Riess O, Tricoire H, and Schmidt T
- Subjects
- Animals, Ataxin-3 metabolism, DNA Repeat Expansion, Disease Models, Animal, Drosophila, Female, HEK293 Cells, Humans, Machado-Joseph Disease metabolism, Male, Mice, Mice, Knockout, Peptides, alpha Karyopherins metabolism, Active Transport, Cell Nucleus genetics, Ataxin-3 genetics, Machado-Joseph Disease genetics, alpha Karyopherins genetics
- Abstract
Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder caused by a CAG expansion in the ATXN3 gene leading to a polyglutamine expansion in the ataxin-3 protein. The nuclear presence and aggregation of expanded ataxin-3 are critical steps in disease pathogenesis. To identify novel therapeutic targets, we investigated the nucleocytoplasmic transport system by screening a collection of importins and exportins that potentially modulate this nuclear localization. Using cell, Drosophila , and mouse models, we focused on three transport proteins, namely, CRM1, IPO13, KPNA3, and their respective Drosophila orthologs Emb, Cdm, and Kap-α3. While overexpression of CRM1/Emb demonstrated positive effects in Drosophila , KPNA3/Kap-α3 emerged as the most promising target, as knockdown via multiple RNAi lines demonstrated its ability to shuttle both truncated and full-length expanded ataxin-3, rescue neurodegeneration, restore photoreceptor formation, and reduce aggregation. Furthermore, KPNA3 knockout in SCA3 mice resulted in an amelioration of molecular and behavioral disturbances such as total activity, anxiety, and gait. Since KPNA3 is known to function as an import protein and recognize nuclear localization signals (NLSs), this work unites ataxin-3 structure to the nuclear pore machinery and provides a link between karyopherins, NLS signals, and polyglutamine disease, as well as demonstrates that KPNA3 is a key player in the pathogenesis of SCA3., Competing Interests: The authors declare no conflict of interest.
- Published
- 2018
- Full Text
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39. Reduced cell size, chromosomal aberration and altered proliferation rates are characteristics and confounding factors in the STHdh cell model of Huntington disease.
- Author
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Singer E, Walter C, Weber JJ, Krahl AC, Mau-Holzmann UA, Rischert N, Riess O, Clemensson LE, and Nguyen HP
- Subjects
- Animals, Cell Line, Cell Size, Cell Survival, Embryo, Mammalian cytology, Embryo, Mammalian metabolism, Gene Knock-In Techniques, Huntingtin Protein metabolism, Huntington Disease metabolism, Huntington Disease pathology, Mice, Cell Proliferation physiology, Chromosome Aberrations, Huntingtin Protein genetics, Models, Biological
- Abstract
Huntington disease is a fatal neurodegenerative disorder caused by a CAG repeat expansion in the gene encoding the huntingtin protein. Expression of the mutant protein disrupts various intracellular pathways and impairs overall cell function. In particular striatal neurons seem to be most vulnerable to mutant huntingtin-related changes. A well-known and commonly used model to study molecular aspects of Huntington disease are the striatum-derived STHdh cell lines generated from wild type and huntingtin knock-in mouse embryos. However, obvious morphological differences between wild type and mutant cell lines exist, which have rarely been described and might not have always been considered when designing experiments or interpreting results. Here, we demonstrate that STHdh cell lines display differences in cell size, proliferation rate and chromosomal content. While the chromosomal divergence is considered to be a result of the cells' tumour characteristics, differences in size and proliferation, however, were confirmed in a second non-immortalized Huntington disease cell model. Importantly, our results further suggest that the reported phenotypes can confound other study outcomes and lead to false conclusions. Thus, careful experimental design and data analysis are advised when using these cell models.
- Published
- 2017
- Full Text
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40. MRI and Prediction of Pathologic Complete Response in the Breast and Axilla after Neoadjuvant Chemotherapy for Breast Cancer.
- Author
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Weber JJ, Jochelson MS, Eaton A, Zabor EC, Barrio AV, Gemignani ML, Pilewskie M, Van Zee KJ, Morrow M, and El-Tamer M
- Subjects
- Adult, Aged, Aged, 80 and over, Axilla, Chemotherapy, Adjuvant, Female, Humans, Lymphatic Metastasis, Middle Aged, Neoadjuvant Therapy, Predictive Value of Tests, Reproducibility of Results, Retrospective Studies, Treatment Outcome, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Magnetic Resonance Imaging
- Abstract
Background: In the setting where determining extent of residual disease is key for surgical planning after neoadjuvant chemotherapy (NAC), we evaluate the reliability of MRI in predicting pathologic complete response (pCR) of the breast primary and axillary nodes after NAC., Study Design: Patients who had MRI before and after NAC between June 2014 and August 2015 were identified in a prospective database after IRB approval. Post-NAC MRI of the breast and axillary nodes was correlated with residual disease on final pathology. Pathologic complete response was defined as absence of invasive and in situ disease., Results: We analyzed 129 breast cancers. Median patient age was 50.8 years (range 27.2 to 80.6 years). Tumors were human epidermal growth factor receptor 2 amplified in 52 of 129 (40%), estrogen receptor-positive/human epidermal growth factor receptor 2-negative in 45 of 129 (35%), and triple negative in 32 of 129 (25%), with respective pCR rates of 50%, 9%, and 31%. Median tumor size pre- and post-NAC MRI were 4.1 cm and 1.45 cm, respectively. Magnetic resonance imaging had a positive predictive value of 63.4% (26 of 41) and negative predictive value of 84.1% (74 of 88) for in-breast pCR. Axillary nodes were abnormal on pre-NAC MRI in 97 patients; 65 had biopsy-confirmed metastases. The nodes normalized on post-NAC MRI in 33 of 65 (51%); axillary pCR was present in 22 of 33 (67%). In 32 patients with proven nodal metastases and abnormal nodes on post-NAC MRI, 11 achieved axillary pCR. In 32 patients with normal nodes on pre- and post-NAC MRI, 6 (19%) had metastasis on final pathology., Conclusions: Radiologic complete response by MRI does not predict pCR with adequate accuracy to replace pathologic evaluation of the breast tumor and axillary nodes., (Copyright © 2017 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)
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- 2017
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41. Educational intervention for physicians to address the risk of opioid abuse.
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Pasquale MK, Sheer RL, Mardekian J, Masters ET, Patel NC, Hurwitch AR, Weber JJ, Jorga A, and Roland CL
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- Administrative Claims, Healthcare, Aged, Chronic Pain diagnosis, Chronic Pain psychology, Drug Prescriptions, Drug Users psychology, Female, Humans, Logistic Models, Male, Medicare, Middle Aged, Multivariate Analysis, Opioid-Related Disorders diagnosis, Opioid-Related Disorders prevention & control, Opioid-Related Disorders psychology, Pilot Projects, Practice Patterns, Physicians', Risk Assessment, Risk Factors, Substance-Related Disorders diagnosis, Substance-Related Disorders prevention & control, Substance-Related Disorders psychology, Time Factors, Treatment Outcome, United States, Analgesics, Opioid adverse effects, Chronic Pain drug therapy, Education, Medical, Continuing methods, Inservice Training methods, Opioid-Related Disorders etiology, Pain Management adverse effects, Pain Management methods, Physicians psychology, Substance-Related Disorders etiology
- Abstract
Objective: To evaluate the impact of a pilot intervention for physicians to support their treatment of patients at risk for opioid abuse., Setting, Design and Patients, Participants: Patients at risk for opioid abuse enrolled in Medicare plans were identified from July 1, 2012 to April 30, 2014 (N = 2,391), based on a published predictive model, and linked to 4,353 opioid-prescribing physicians. Patient-physician clusters were randomly assigned to one of four interventions using factorial design., Interventions: Physicians received one of the following: Arm 1, patient information; Arm 2, links to educational materials for diagnosis and management of pain; Arm 3, both patient information and links to educational materials; or Arm 4, no communication., Main Outcome Measures: Difference-in-difference analyses compared opioid and pain prescriptions, chronic high-dose opioid use, uncoordinated opioid use, and opioid-related emergency department (ED) visits. Logistic regression compared diagnosis of opioid abuse between cases and controls postindex., Results: Mailings had no significant impact on numbers of opioid or pain medications filled, chronic high-dose opioid use, uncoordinated opioid use, ED visits, or rate of diagnosed opioid abuse. Relative to Arm 4, odds ratios (95% CI) for diagnosed opioid abuse were Arm 1, 0.95(0.63-1.42); Arm 2, 0.83(0.55-1.27); Arm 3, 0.72(0.46-1.13). While 84.7 percent had ≥1 psychiatric diagnoses during preindex (p = 0.89 between arms), only 9.5 percent had ≥1 visit with mental health specialists (p = 0.53 between arms)., Conclusions: Although this intervention did not affect pain-related outcomes, future interventions involving care coordination across primary care and mental health may impact opioid abuse and improve quality of life of patients with pain.
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- 2017
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42. The messenger matters: Pollinator functional group influences mating system dynamics.
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Weber JJ
- Subjects
- Animals, Bees, Fruit, Pollen, Reproduction, Paternity, Pollination
- Abstract
The incredible diversity of plant mating systems has fuelled research in evolutionary biology for over a century. Currently, there is broad concern about the impact of rapidly changing pollinator communities on plant populations. Very few studies, however, examine patterns and mechanisms associated with multiple paternity from cross-pollen loads. Often, foraging pollinators collect a mixed pollen load that may result in the deposition of pollen from different sires to receptive stigmas. Coincident deposition of self- and cross-pollen leads to interesting mating system dynamics and has been investigated in numerous species. But, mixed pollen loads often consist of a diversity of cross-pollen and result in multiple sires of seeds within a fruit. In this issue of Molecular Ecology, Rhodes, Fant, and Skogen () examine how pollinator identity and spatial isolation influence multiple paternity within fruits of a self-incompatible evening primrose. The authors demonstrate that pollen pool diversity varies between two pollinator types, hawkmoths and diurnal solitary bees. Further, progeny from more isolated plants were less likely to have multiple sires regardless of the pollinator type. Moving forward, studies of mating system dynamics should consider the implications of multiple paternity and move beyond the self- and cross-pollination paradigm. Rhodes et al. () demonstrate the importance of understanding the roles that functionally diverse pollinators play in mating system dynamics., (© 2017 John Wiley & Sons Ltd.)
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- 2017
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43. A combinatorial approach to identify calpain cleavage sites in the Machado-Joseph disease protein ataxin-3.
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Weber JJ, Golla M, Guaitoli G, Wanichawan P, Hayer SN, Hauser S, Krahl AC, Nagel M, Samer S, Aronica E, Carlson CR, Schöls L, Riess O, Gloeckner CJ, Nguyen HP, and Hübener-Schmid J
- Subjects
- Brain metabolism, Cells, Cultured, Combinatorial Chemistry Techniques, Computer Simulation, Humans, Induced Pluripotent Stem Cells metabolism, Peptide Hydrolases metabolism, Protein Aggregation, Pathological metabolism, Transfection, Ataxin-3 metabolism, Calpain metabolism, Machado-Joseph Disease metabolism
- Abstract
Ataxin-3, the disease protein in Machado-Joseph disease, is known to be proteolytically modified by various enzymes including two major families of proteases, caspases and calpains. This processing results in the generation of toxic fragments of the polyglutamine-expanded protein. Although various approaches were undertaken to identify cleavage sites within ataxin-3 and to evaluate the impact of fragments on the molecular pathogenesis of Machado-Joseph disease, calpain-mediated cleavage of the disease protein and the localization of cleavage sites remained unclear. Here, we report on the first precise localization of calpain cleavage sites in ataxin-3 and on the characterization of the resulting breakdown products. After confirming the occurrence of calpain-derived fragmentation of ataxin-3 in patient-derived cell lines and post-mortem brain tissue, we combined in silico prediction tools, western blot analysis, mass spectrometry, and peptide overlay assays to identify calpain cleavage sites. We found that ataxin-3 is primarily cleaved at two sites, namely at amino acid positions D208 and S256 and mutating amino acids at both cleavage sites to tryptophan nearly abolished ataxin-3 fragmentation. Furthermore, analysis of calpain cleavage-derived fragments showed distinct aggregation propensities and toxicities of C-terminal polyglutamine-containing breakdown products. Our data elucidate the important role of ataxin-3 proteolysis in the pathogenesis of Machado-Joseph disease and further emphasize the relevance of targeting this disease pathway as a treatment strategy in neurodegenerative disorders., (© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
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- 2017
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44. Periareolar or Peritumoral Injection of Isosulfan Blue and the Effect on the Number of Sentinel Lymph Nodes Examined.
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Weber JJ and Wong JH
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Humans, Lymph Node Excision, Middle Aged, Breast Neoplasms pathology, Coloring Agents administration & dosage, Nipples, Rosaniline Dyes administration & dosage, Sentinel Lymph Node pathology, Sentinel Lymph Node Biopsy statistics & numerical data
- Abstract
The conduct of sentinel node biopsy (SLNBx) for breast cancer (BC) has evolved substantially since its original description. No national standards for the performance of SLNBx exist, therefore, we sought to determine the effect of isosulfan blue (ISB) injection technique on nodal harvesting and staging accuracy during SLNBx. Our main outcome measures included the number of SLNs examined and the number of positive axillae in patients undergoing SLNBx after injection of filtered sulfur colloid intradermally and either small volume ISB injected in the periareolar dermis (PA,∼0.75 cc) or large volume peritumoral (PT, 5 cc). Between January 1, 2009, and September 30, 2013, 1357 patients at an academic/community practice setting underwent SLNBx of which 966 (71.2%) were node negative. These patients ranged in age from 27 to 97 years (mean 60.1 years). The majority of patients (76%) underwent PT injection of ISB. There was no significant difference in the mean age of these two groups (61.2 PT vs 59.7 PA years). All were female. The majority of patients (72.7%) had T1 primaries. Nearly 73 per cent of patients were Luminal A/B, 10.8 per cent HER, and 16.4 per cent were triple negative. There was no significant difference in the distribution of T stage (P = 0.56) or breast cancer subtypes between the techniques (P = 0.59). The mean number of nodes examined was 3.1 (range, 1-18). PT patients had a mean of 3.5 (range, 1-18) nodes, whereas PA patients had a mean of 2.4 nodes (range, 1-10) (P < 0.001). The technical aspects of injecting ISB affect the number of nodes harvested during SLNBx but not staging accuracy.
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- 2017
45. In vivo assessment of riluzole as a potential therapeutic drug for spinocerebellar ataxia type 3.
- Author
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Schmidt J, Schmidt T, Golla M, Lehmann L, Weber JJ, Hübener-Schmid J, and Riess O
- Subjects
- Animals, Ataxin-3 genetics, Body Weight drug effects, Body Weight genetics, Brain drug effects, Brain metabolism, Brain pathology, Calbindins metabolism, Disease Models, Animal, Fluorescence Resonance Energy Transfer, Humans, Machado-Joseph Disease genetics, Machado-Joseph Disease pathology, Mice, Mice, Transgenic, Motor Activity drug effects, Motor Activity genetics, Neurons drug effects, Neurons metabolism, Neurons pathology, Prions genetics, RNA, Messenger metabolism, Reaction Time drug effects, Reaction Time genetics, Repressor Proteins genetics, Rotarod Performance Test, Ataxin-3 metabolism, Machado-Joseph Disease drug therapy, Neuroprotective Agents therapeutic use, Repressor Proteins metabolism, Riluzole therapeutic use
- Abstract
Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominantly inherited neurodegenerative disorder for which no curative therapy is available. The cause of this disease is the expansion of a CAG repeat in the so-called ATXN3 gene leading to an expanded polyglutamine stretch in the ataxin-3 protein. Although the function of ataxin-3 has been defined as a deubiquitinating enzyme, the pathogenic pathway underlying SCA3 remains to be deciphered. Besides others, also the glutamatergic system seems to be altered in SCA3. The antiglutamatergic substance riluzole has thus been suggested as a potential therapeutic agent for SCA3. To assess whether riluzole is effective in the treatment of SCA3 in vivo, we used a phenotypically well-characterized conditional mouse model previously generated by us. Treatment with 10 mg/kg riluzole in the drinking water was started when mice showed impairment in rotarod performance. Post-symptomatic treatment with riluzole carried out for a period of 10 months led to reduction of the soluble ataxin-3 level and an increase in ataxin-3 positive accumulations, but did not improve motor deficits measured by rotarod. There was also no positive effect on home cage behavior or body weight. We even observed a pronounced reduction of calbindin expression in Purkinje cells in riluzole-treated mice. Thus, long-term treatment with riluzole was not able to alleviate disease symptoms observed in transgenic SCA3 mice and should be considered with caution in the treatment of human patients. Assessing riluzole as a potential treatment for spinocerebellar ataxia type 3 (SCA3) had no beneficial, but rather a worsening effect on our transgenic SCA3 mouse model. We hypothesize that: Riluzole treatment enhanced glutamate release in ATXN3-expressing cells leading to an increased Ca(2+) influx resulting in Purkinje cell damage shown by loss of calbindin expression., (© 2016 International Society for Neurochemistry.)
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- 2016
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46. Mitochondria-Targeted Analogues of Metformin Exhibit Enhanced Antiproliferative and Radiosensitizing Effects in Pancreatic Cancer Cells.
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Cheng G, Zielonka J, Ouari O, Lopez M, McAllister D, Boyle K, Barrios CS, Weber JJ, Johnson BD, Hardy M, Dwinell MB, and Kalyanaraman B
- Subjects
- Animals, Apoptosis drug effects, Apoptosis radiation effects, Blotting, Western, Carcinoma, Pancreatic Ductal drug therapy, Carcinoma, Pancreatic Ductal radiotherapy, Cell Cycle drug effects, Cell Cycle radiation effects, Cell Proliferation drug effects, Cell Proliferation radiation effects, Chemoradiotherapy, Humans, Hypoglycemic Agents chemistry, Hypoglycemic Agents pharmacology, Metformin chemistry, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mitochondria pathology, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms radiotherapy, Radiation-Sensitizing Agents chemistry, Signal Transduction, Superoxides, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Carcinoma, Pancreatic Ductal pathology, Metformin pharmacology, Mitochondria drug effects, Pancreatic Neoplasms pathology, Radiation-Sensitizing Agents pharmacology
- Abstract
Metformin (Met) is an approved antidiabetic drug currently being explored for repurposing in cancer treatment based on recent evidence of its apparent chemopreventive properties. Met is weakly cationic and targets the mitochondria to induce cytotoxic effects in tumor cells, albeit not very effectively. We hypothesized that increasing its mitochondria-targeting potential by attaching a positively charged lipophilic substituent would enhance the antitumor activity of Met. In pursuit of this question, we synthesized a set of mitochondria-targeted Met analogues (Mito-Mets) with varying alkyl chain lengths containing a triphenylphosphonium cation (TPP(+)). In particular, the analogue Mito-Met10, synthesized by attaching TPP(+) to Met via a 10-carbon aliphatic side chain, was nearly 1,000 times more efficacious than Met at inhibiting cell proliferation in pancreatic ductal adenocarcinoma (PDAC). Notably, in PDAC cells, Mito-Met10 potently inhibited mitochondrial complex I, stimulating superoxide and AMPK activation, but had no effect in nontransformed control cells. Moreover, Mito-Met10 potently triggered G1 cell-cycle phase arrest in PDAC cells, enhanced their radiosensitivity, and more potently abrogated PDAC growth in preclinical mouse models, compared with Met. Collectively, our findings show how improving the mitochondrial targeting of Met enhances its anticancer activities, including aggressive cancers like PDAC in great need of more effective therapeutic options. Cancer Res; 76(13); 3904-15. ©2016 AACR., (©2016 American Association for Cancer Research.)
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- 2016
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47. The calpain-suppressing effects of olesoxime in Huntington's disease.
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Weber JJ, Ortiz Rios MM, Riess O, Clemens LE, and Nguyen HP
- Abstract
Olesoxime, a small molecule drug candidate, has recently attracted attention due to its significant beneficial effects in models of several neurodegenerative disorders including Huntington's disease. Olesoxime's neuroprotective effects have been assumed to be conveyed through a direct, positive influence on mitochondrial function. In a long-term treatment study in BACHD rats, the latest rat model of Huntington's disease, olesoxime revealed a positive influence on mitochondrial function and improved specific behavioral and neuropathological phenotypes. Moreover, a novel target of the compound was discovered, as olesoxime was found to suppress the activation of the calpain proteolytic system, a major contributor to the cleavage of the disease-causing mutant huntingtin protein into toxic fragments, and key player in degenerative processes in general. Results from a second model of Huntington's disease, the Hdh (Q111) knock-in mouse, confirm olesoxime's calpain-suppressing effects and support the therapeutic value of olesoxime for Huntington's disease and other disorders involving calpain overactivation.
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- 2016
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48. Erratum to: Separation and Characterization of Epithelial and Mesenchymal-like Murine Mammary Tumor Cells Reveals Epithelial Cell Differentiation Plasticity and Enhanced Tumorigenicity of Epithelial-enriched Tumor Cells.
- Author
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Palen KA, Jing W, Weber JJ, Tilkens SB, Chan AM, Johnson BD, and Gershan JA
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- 2016
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49. Predicting the genetic consequences of future climate change: The power of coupling spatial demography, the coalescent, and historical landscape changes.
- Author
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Brown JL, Weber JJ, Alvarado-Serrano DF, Hickerson MJ, Franks SJ, and Carnaval AC
- Subjects
- Bayes Theorem, Models, Genetic, Northwestern United States, Penstemon genetics, Southwestern United States, Climate Change, Ecosystem, Genetic Variation, Penstemon physiology, Plant Dispersal
- Abstract
Premise of the Study: Climate change is a widely accepted threat to biodiversity. Species distribution models (SDMs) are used to forecast whether and how species distributions may track these changes. Yet, SDMs generally fail to account for genetic and demographic processes, limiting population-level inferences. We still do not understand how predicted environmental shifts will impact the spatial distribution of genetic diversity within taxa., Methods: We propose a novel method that predicts spatially explicit genetic and demographic landscapes of populations under future climatic conditions. We use carefully parameterized SDMs as estimates of the spatial distribution of suitable habitats and landscape dispersal permeability under present-day, past, and future conditions. We use empirical genetic data and approximate Bayesian computation to estimate unknown demographic parameters. Finally, we employ these parameters to simulate realistic and complex models of responses to future environmental shifts. We contrast parameterized models under current and future landscapes to quantify the expected magnitude of change., Key Results: We implement this framework on neutral genetic data available from Penstemon deustus. Our results predict that future climate change will result in geographically widespread declines in genetic diversity in this species. The extent of reduction will heavily depend on the continuity of population networks and deme sizes., Conclusions: To our knowledge, this is the first study to provide spatially explicit predictions of within-species genetic diversity using climatic, demographic, and genetic data. Our approach accounts for climatic, geographic, and biological complexity. This framework is promising for understanding evolutionary consequences of climate change, and guiding conservation planning., (© 2016 Botanical Society of America.)
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- 2016
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50. Variation in heterostylous breeding systems in neighbouring populations of Oxalis alpina (Oxalidaceae).
- Author
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Weller SG, Sakai AK, Gray T, Weber JJ, Tsyusko OV, Domínguez CA, Fornoni J, and Molina-Freaner FE
- Subjects
- Arizona, Biological Evolution, Flowers physiology, Plant Breeding, Pollination, Reproduction physiology, Seeds genetics, Oxalidaceae physiology
- Abstract
Unlabelled: The heterostylous reproductive system of Oxalis alpina in the Galiuro Mts. of Arizona was investigated using field surveys, controlled crosses in the greenhouse and measurements of reproductive morphs. Although populations in the Pinaleño Mts. to the immediate east and in the Santa Catalina Mts. to the immediate west have derived distylous reproductive systems, tristyly, the ancestral reproductive system in O. alpina, has been retained in the Galiuro Mts., Population: Tristylous incompatibility relationships in the Galiuro population are modified from the ancestral condition, with significant loss of incompatibility differentiation between stamen whorls of both short- and long-styled morphs. Morphological adjustments of anther positions in the Galiuro population of O. alpina match those expected in light of incompatibility modification, with divergence of the mid-level anthers away from the position of the mid stigmas of the mid-styled morph. The occurrence of tristyly in an area of Arizona where distyly is found in adjacent mountain ranges is particularly remarkable, and indicates both the isolation of populations restricted to the upper elevations of these mountain ranges and variation in the tempo of evolution over short geographic distances., (© 2015 German Botanical Society and The Royal Botanical Society of the Netherlands.)
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- 2016
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