31 results on '"Wightman, Nicholas"'
Search Results
2. Suppression of mutant C9orf72 expression by a potent mixed backbone antisense oligonucleotide
- Author
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Tran, Hélène, Moazami, Michael P., Yang, Huiya, McKenna-Yasek, Diane, Douthwright, Catherine L., Pinto, Courtney, Metterville, Jake, Shin, Minwook, Sanil, Nitasha, Dooley, Craig, Puri, Ajit, Weiss, Alexandra, Wightman, Nicholas, Gray-Edwards, Heather, Marosfoi, Miklos, King, Robert M., Kenderdine, Thomas, Fabris, Daniele, Bowser, Robert, Watts, Jonathan K., and Brown, Jr, Robert H.
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- 2022
- Full Text
- View/download PDF
3. BET bromodomain inhibitors PFI-1 and JQ1 are identified in an epigenetic compound screen to enhance C9ORF72 gene expression and shown to ameliorate C9ORF72-associated pathological and behavioral abnormalities in a C9ALS/FTD model
- Author
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Quezada, Esteban, Cappelli, Claudio, Diaz, Iván, Jury, Nur, Wightman, Nicholas, Brown, Jr., Robert H., Montecino, Martín, and van Zundert, Brigitte
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- 2021
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- View/download PDF
4. Artificial microRNA suppresses C9ORF72 variants and decreases toxic dipeptide repeat proteins in vivo
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Cabrera, Gabriela Toro, primary, Meijboom, Katharina E., additional, Abdallah, Abbas, additional, Tran, Helene, additional, Foster, Zachariah, additional, Weiss, Alexandra, additional, Wightman, Nicholas, additional, Stock, Rachel, additional, Gendron, Tania, additional, Gruntman, Alisha, additional, Giampetruzzi, Anthony, additional, Petrucelli, Leonard, additional, Brown, Robert H., additional, and Mueller, Christian, additional
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- 2023
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- View/download PDF
5. Up-regulation of cholesterol synthesis pathways and limited neurodegeneration in a knock-inSod1mutant mouse model of ALS.
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Dominov, Janice A., primary, Madigan, Laura A., additional, Whitt, Joshua P., additional, Rademacher, Katerina L., additional, Webster, Kristin M., additional, Zhang, Hesheng, additional, Banno, Haruhiko A., additional, Tang, Siqi, additional, Zhang, Yifan, additional, Wightman, Nicholas, additional, Shychuck, Emma M., additional, Page, John, additional, Weiss, Alexandra, additional, Kelly, Karen, additional, Kucukural, Alper A., additional, Brodsky, Michael H., additional, Jaworski, Alexander, additional, Fallon, Justin R, additional, Lipscombe, Diane, additional, and Brown, Robert H., additional
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- 2023
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- View/download PDF
6. Prospective natural history study of C9orf72 ALS clinical characteristics and biomarkers
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Cammack, Alexander J., Atassi, Nazem, Hyman, Theodore, van den Berg, Leonard H., Harms, Matthew, Baloh, Robert H., Brown, Robert H., van Es, Michael A., Veldink, Jan H., de Vries, Balint S., Rothstein, Jeffrey D., Drain, Caroline, Jockel-Balsarotti, Jennifer, Malcolm, Amber, Boodram, Sonia, Salter, Amber, Wightman, Nicholas, Yu, Hong, Sherman, Alexander V., Esparza, Thomas J., McKenna-Yasek, Diane, Owegi, Margaret A., Douthwright, Catherine, McCampbell, Alexander, Ferguson, Toby, Cruchaga, Carlos, Cudkowicz, Merit, and Miller, Timothy M.
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- 2019
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7. Artificial microRNA suppresses C9ORF72 variants and decreases toxic dipeptides in vivo
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Cabrera, Gabriela Toro, primary, Meijboom, Katharina, additional, Abdallah, Abbas, additional, Tran, Helen, additional, Foster, Zachariah, additional, Weiss, Alexandra, additional, Wightman, Nicholas, additional, Stock, Rachel, additional, Gendron, Tania, additional, Gruntman, Alisha, additional, Giampetruzzi, Anthony, additional, Petrucelli, Leonard, additional, Brown, Robert, additional, and Mueller, Christian, additional
- Published
- 2022
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- View/download PDF
8. Habenaria
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Bytebier, Benny and Wightman, Nicholas
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Tracheophyta ,Liliopsida ,Asparagales ,Biodiversity ,Plantae ,Orchidaceae ,Habenaria ,Taxonomy - Abstract
Key for the Flora Zambesiaca region (adapted from la Croix & Cribb, 1995). The key for group D of Habenaria (p. 62) should be modified as follows: 1 Spur more or less straight or gently recurved.......................................................................................................... 83a. geerinckiana Spur not as above................................................................................................................................................................................2 2 Dorsal sepal 16–20 mm long; spur bent forward with a knee-like bend just below the base then recurved below flower................................................................................................................................................................................................... 83. tentaculigera Dorsal sepal 10–12 mm long; spur forming a loop near base and projecting above flower......................................... 82. goetzeana
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- 2022
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9. Habenaria geerinckiana Geerinck, Taxonomania 2007
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Bytebier, Benny and Wightman, Nicholas
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Tracheophyta ,Habenaria geerinckiana ,Liliopsida ,Asparagales ,Biodiversity ,Plantae ,Orchidaceae ,Habenaria ,Taxonomy - Abstract
Habenaria geerinckiana (Schaijes) Geerinck, Taxonomania 20: 18 (2007). Basionym: Kryptostoma geerinckiana Schaijes in Geerinck & Schaijes, Bull. Jard. Bot. Nat. Belg., 57: 483 (1987). Type:— DR CONGO. Katanga, W of Kolwezi, 23 Nov 1985, Schaijes 2697B (holotype: BR0000008814043!). Terrestrial herbs 25–40 cm tall. Tubers 3–4 × 1–2 cm, ovoid to ellipsoid, woolly. Leaves 5–10; the lowermost spreading, 2.5–3.0 × 2.0 cm, ovate; the next few suberect, up to 6.0 × 2.5 cm, lanceolate, acute; the upper ones grading into the bracts. Inflorescence 8–13 × 5–6 cm, laxly 4–7-flowered; bracts 10–30 mm long, lanceolate, reaching half the length of the ovary. Flowers green. Pedicel and ovary 15–30 mm long, ± straight. Dorsal sepal 12–15 × 15 mm, ovate, convex, projecting over column, tip recurved; lateral sepals projecting forwards, c. 13 × 4 mm, obliquely lanceolate, adnate to column and base of spur. Petals erect, bilobed, with an undivided basal part of 5–7 mm; posterior lobe 13–15 × 2–3 mm, lanceolate, the margins ciliate, adnate to dorsal sepal; anterior lobe 18–22 × 1 mm, linear, horn-shaped above the dorsal sepal. Lip trilobed, the base adnate to the column for about 5 mm; midlobe 7–10 × 1 mm, linear, reflexed; side lobes 15–20 × 1 mm, linear, curving forwards; spur c. 20 mm long, pendent, slightly recurved, apex slightly swollen. Anther locules c. 2 mm, reclinate, joined by a U-shaped connective c. 3 mm high, 7 mm long; anther canals c. 4 mm, upcurved; stigmatic arms 4–5 mm, clavate, decurved. Habitat:— Although Flore d’Afrique Central (Geerinck, 1992) mentioned the habitat as “galleries forestières”, on the type specimen and in the protologue it is described as “savanne steppique” or “savanna grassland.” The latter fits better with our habitat observations, i.e. watershed plains grassland within a diverse suffrutex community (DR Congo; Fig. 1) and on drier upper slopes of large open dambo (Zambia). Conservation status assessment:— Habenaria geerinckiana is a restricted species known from only three georeferenced collections representing two extant subpopulations, one in south-western DRC (Kolwezi District) and one in north-western Zambia (Mwinilunga District). Using these locations, the extent of occurrence (EOO) was estimated to be 3931 km 2 and the area of occupancy (AOO) 3 km 2, both of which are within the threshold for endangered status under criteria B1 and B2. This was calculated using the web-based Geospatial Conservation Assessment Tool (GeoCAT; Bachman et al., 2011). AOO was calculated based on a user-defined cell size of 1 km 2, which more accurately reflected the size of the habitat patches available at the three known localities than the IUCN default cell size of 4 km 2. The watershed plain grassland habitat in Kolwezi district has declined in extent and quality as a result of mining projects and expanding urbanisation from Kolwezi. It can be inferred that the Kolwezi subpopulation has also declined as a result, both in spatial extent occupied and number of mature individuals. The proposed conservation assessment of this species is EN B1ab(ii,iii,iv,v)+2ab(ii,iii,iv,v). Specimens examined: — DR CONGO. Katanga (Lualaba): west of Kolwezi, 10°47’30’’S, 25°17’01”E, 1490 m, 23 Nov 1985 Schaijes 2697B (BR0000008814043, photo!, holotype); south-west of Kolwezi, 10°47’11.82”S, 25°17’12.97”E, 1512 m, 22 Nov. 2021, McCleland, no specimen collected, images stored on iNaturalist at https://www.inaturalist.org/ observations/108490995, see also Fig. 2). ZAMBIA. North-Western: Mwinilunga, Muwana, Muchana Dambo, 11°24’12.7”S, 24°40’42.8”E, 1375 m, 10 Jan 2019, Wightman NcW 118 (K!, NDO!, NU spirit!; Fig.3)., Published as part of Bytebier, Benny & Wightman, Nicholas, 2022, Habenaria geerinckiana (Orchidaceae), an updated description, extended distribution and conservation assessment, pp. 223-226 in Phytotaxa 544 (2) on pages 223-226, DOI: 10.11646/phytotaxa.544.2.9, http://zenodo.org/record/6503944, {"references":["Geerinck, D. (1992) Flore d'Afrique Centrale. Orchidaceae (seconde partie). Jardin Botanique National de Belgique, Meise, pp. 736 - 737.","Bachman, S., Moat, J., Hill, A., de la Torre, J. & Scott, B. (2011) Supporting Red List threat assessments with GeoCAT: Geospatial Conservation Assessment Tool. ZooKeys 150: 117 - 126. https: // doi. org / 10.3897 / zookeys. 150.2109"]}
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- 2022
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10. Habenaria geerinckiana (Orchidaceae), an updated description, extended distribution and conservation assessment
- Author
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Bytebier, Benny and Wightman, Nicholas
- Subjects
Tracheophyta ,Liliopsida ,Asparagales ,Biodiversity ,Plantae ,Orchidaceae ,Taxonomy - Abstract
Bytebier, Benny, Wightman, Nicholas (2022): Habenaria geerinckiana (Orchidaceae), an updated description, extended distribution and conservation assessment. Phytotaxa 544 (2): 223-226, DOI: 10.11646/phytotaxa.544.2.9
- Published
- 2022
11. Habenaria geerinckiana (Orchidaceae), an updated description, extended distribution and conservation assessment
- Author
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BYTEBIER, BENNY, primary, McCLELAND, WARREN, additional, and WIGHTMAN, NICHOLAS, additional
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- 2022
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12. Ancistrorhynchus ovatus Summerhayes 1944
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Wightman, Nicholas and Bytebier, Benny
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Tracheophyta ,Ancistrorhynchus ,Liliopsida ,Asparagales ,Ancistrorhynchus ovatus ,Biodiversity ,Plantae ,Orchidaceae ,Taxonomy - Abstract
Ancistrorhynchus ovatus Summerhayes (1944: 210) (Fig. 2) Specimen: ��� ZAMBIA. Northern Province: Mporokoso District, Chimpempe Falls, Riverine island thicket vegetation of Kalungwishi River upstream of Chimpempe Falls, 1190 m, 14 Oct 2018, Wightman NcW63 (NU0091956!, NU spirit!)., Published as part of Wightman, Nicholas & Bytebier, Benny, 2021, Ancistrorhynchus (Orchidaceae), a new generic record for the Flora of Zambia, pp. 59-61 in Phytotaxa 528 (1) on page 61, DOI: 10.11646/phytotaxa.528.1.6, http://zenodo.org/record/5769270, {"references":["Summerhayes, V. S. (1944) African Orchids. XIV. Botanical Museum Leaflets Harvard University 11 (7): 201 - 214."]}
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- 2021
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13. Suppression of mutant C9orf72 expression by a potent mixed backbone antisense oligonucleotide
- Author
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Tran, Hélène, primary, Moazami, Michael P., additional, Yang, Huiya, additional, McKenna-Yasek, Diane, additional, Douthwright, Catherine L., additional, Pinto, Courtney, additional, Metterville, Jake, additional, Shin, Minwook, additional, Sanil, Nitasha, additional, Dooley, Craig, additional, Puri, Ajit, additional, Weiss, Alexandra, additional, Wightman, Nicholas, additional, Gray-Edwards, Heather, additional, Marosfoi, Miklos, additional, King, Robert M., additional, Kenderdine, Thomas, additional, Fabris, Daniele, additional, Bowser, Robert, additional, Watts, Jonathan K., additional, and Brown, Robert H., additional
- Published
- 2021
- Full Text
- View/download PDF
14. Ancistrorhynchus (Orchidaceae), a new generic record for the Flora of Zambia
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WIGHTMAN, NICHOLAS, primary and BYTEBIER, BENNY, additional
- Published
- 2021
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15. Additional file 1 of BET bromodomain inhibitors PFI-1 and JQ1 are identified in an epigenetic compound screen to enhance C9ORF72 gene expression and shown to ameliorate C9ORF72-associated pathological and behavioral abnormalities in a C9ALS/FTD model
- Author
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Quezada, Esteban, Cappelli, Claudio, Diaz, Iván, Jury, Nur, Wightman, Nicholas, Brown, Robert H., Montecino, Martín, and Zundert, Brigitte Van
- Abstract
Additional file 1: Fig. S1. Bromodomain inhibitors enhance C9ORFF72 gene promoter-driven expression in SH-SY5Y LE200 G4C2 reporter cell lines. Table S1. Epidrugs used in screening. Table S2. TaqMan probes information.
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- 2021
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16. Artificial microRNA suppresses C9ORF72variants and decreases toxic dipeptide repeat proteins in vivo
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Cabrera, Gabriela Toro, Meijboom, Katharina E., Abdallah, Abbas, Tran, Helene, Foster, Zachariah, Weiss, Alexandra, Wightman, Nicholas, Stock, Rachel, Gendron, Tania, Gruntman, Alisha, Giampetruzzi, Anthony, Petrucelli, Leonard, Brown, Robert H., and Mueller, Christian
- Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects motor neurons, causing progressive muscle weakness and respiratory failure. The presence of an expanded hexanucleotide repeat in chromosome 9 open reading frame 72 (C9ORF72) is the most frequent mutation causing familial ALS and frontotemporal dementia (FTD). To determine if suppressing expression of C9ORF72gene products can reduce toxicity, we designed a set of artificial microRNAs (amiRNA) targeting the human C9ORF72gene. Here we report that an AAV9-mediated amiRNA significantly suppresses expression of the C9ORF72mRNA, protein, and toxic dipeptide repeat proteins generated by the expanded repeat in the brain and spinal cord of C9ORF72 transgenic mice.
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- 2023
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17. SOD1Suppression with Adeno-Associated Virus and MicroRNA in Familial ALS
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Mueller, Christian, primary, Berry, James D., additional, McKenna-Yasek, Diane M., additional, Gernoux, Gwladys, additional, Owegi, Margaret A., additional, Pothier, Lindsay M., additional, Douthwright, Catherine L., additional, Gelevski, Dario, additional, Luppino, Sarah D., additional, Blackwood, Meghan, additional, Wightman, Nicholas S., additional, Oakley, Derek H., additional, Frosch, Matthew P., additional, Flotte, Terrence R., additional, Cudkowicz, Merit E., additional, and Brown, Robert H., additional
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- 2020
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18. Trade in Zambian Edible Orchids – DNA Barcoding Reveals Use of Unexpected Orchid Taxa for Chikanda
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Veldman, Sarina, Kim, Seol-Jong, van Andel, Tinde R., Font, Maria Bello, Bone, Ruth E., Bytebier, Benny, Chuba, David, Gravendeel, Barbara, Martos, Florent, Mpatwa, Geophat, Ngugi, Grace, Vinya, Royd, Wightman, Nicholas, Yokoya, Kazutoma, and de Boer, Hugo J.
- Subjects
plant_sciences - Abstract
In Zambia wild edible terrestrial orchids are used to produce a local delicacy called chikanda, which has become increasingly popular throughout the country. Commercialization puts orchid populations in Zambia and neighbouring countries at risk of overharvesting. Hitherto, no study has documented which orchid species are traded on local markets, as orchid tubers are difficult to identify morphologically. In this study, the core land-plant DNA barcoding markers rbcL and matK were used in combination with nrITS to determine which species were sold on Zambian markets. Eighty-two interviews were conducted to determine harvesting areas, as well as possible sustainability concerns. By using nrITS DNA barcoding, a total of 16 orchid species in six different genera could be identified. Both rbcL and matK proved suitable to identify the tubers up to genus- or family level. Disa robusta, Platycoryne crocea and Satyrium buchananii were identified most frequently and three previously undocumented species were encountered on the market. Few orchid species are currently listed on the global IUCN Red List. Local orchid populations and endemic species could be at risk of overharvesting due to the intensive and indiscriminate harvesting of chikanda orchids and we therefore encourage increased conservation assessment of terrestrial African orchids.
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- 2018
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19. Trade in Zambian Edible Orchids—DNA Barcoding Reveals the Use of Unexpected Orchid Taxa for Chikanda
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Veldman, Sarina, primary, Kim, Seol-Jong, additional, van Andel, Tinde, additional, Bello Font, Maria, additional, Bone, Ruth, additional, Bytebier, Benny, additional, Chuba, David, additional, Gravendeel, Barbara, additional, Martos, Florent, additional, Mpatwa, Geophat, additional, Ngugi, Grace, additional, Vinya, Royd, additional, Wightman, Nicholas, additional, Yokoya, Kazutoma, additional, and de Boer, Hugo, additional
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- 2018
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20. Trade in Zambian Edible Orchids – DNA Barcoding Reveals Use of Unexpected Orchid Taxa for Chikanda
- Author
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Veldman, Sarina, primary, Kim, Seol-Jong, additional, van Andel, Tinde R., additional, Bello Font, Maria, additional, Bone, Ruth E., additional, Bytebier, Benny, additional, Chuba, David, additional, Gravendeel, Barbara, additional, Martos, Florent, additional, Mpatwa, Geophat, additional, Ngugi, Grace, additional, Vinya, Royd, additional, Wightman, Nicholas, additional, Yokoya, Kazutoma, additional, and de Boer, Hugo J., additional
- Published
- 2018
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21. Trade in Zambian Edible Orchids-DNA Barcoding Reveals the Use of Unexpected Orchid Taxa for Chikanda
- Author
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Veldman, Sarina, Kim, Seol-Jong, van Andel, Tinde R., Font, Maria Bello, Bone, Ruth E., Bytebier, Benny, Chuba, David, Gravendeel, Barbara, Martos, Florent, Mpatwa, Geophat, Ngugi, Grace, Vinya, Royd, Wightman, Nicholas, Yokoya, Kazutoma, de Boer, Hugo J., Veldman, Sarina, Kim, Seol-Jong, van Andel, Tinde R., Font, Maria Bello, Bone, Ruth E., Bytebier, Benny, Chuba, David, Gravendeel, Barbara, Martos, Florent, Mpatwa, Geophat, Ngugi, Grace, Vinya, Royd, Wightman, Nicholas, Yokoya, Kazutoma, and de Boer, Hugo J.
- Abstract
In Zambia, wild edible terrestrial orchids are used to produce a local delicacy called chikanda, which has become increasingly popular throughout the country. Commercialization puts orchid populations in Zambia and neighbouring countries at risk of overharvesting. Hitherto, no study has documented which orchid species are traded on local markets, as orchid tubers are difficult to identify morphologically. In this study, the core land-plant DNA barcoding markers rbcL and matK were used in combination with nrITS to determine which species were sold in Zambian markets. Eighty-two interviews were conducted to determine harvesting areas, as well as possible sustainability concerns. By using nrITS DNA barcoding, a total of 16 orchid species in six different genera could be identified. Both rbcL and matK proved suitable to identify the tubers up to the genus or family level. Disa robusta, Platycoryne crocea and Satyrium buchananii were identified most frequently and three previously undocumented species were encountered on the market. Few orchid species are currently listed on the global International Union for the Conservation of Nature (IUCN) Red List. Local orchid populations and endemic species could be at risk of overharvesting due to the intensive and indiscriminate harvesting of chikanda orchids, and we therefore encourage increased conservation assessment of terrestrial African orchids.
- Published
- 2018
- Full Text
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22. Human C9ORF72 Hexanucleotide Expansion Reproduces RNA Foci and Dipeptide Repeat Proteins but Not Neurodegeneration in BAC Transgenic Mice
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Peters, Owen M., Cabrera, Gabriela Toro, Tran, Helene, Gendron, Tania F., McKeon, Jeanne E., Metterville, Jake, Weiss, Alexandra, Wightman, Nicholas, Salameh, Johnny, Kim, Juhyun, Sun, Huaming, Boylan, Kevin B., Dickson, Dennis, Kennedy, Zachary, Lin, Ziqiang, Zhang, Yong-Jie, Daughrity, Lillian, Jung, Chris, Gao, Fen-Biao, Sapp, Peter C., Horvitz, H. Robert, Bosco, Daryl A., Brown, Solange P., de Jong, Pieter, Petrucelli, Leonard, Mueller, Christian, and Brown, Robert H., Jr.
- Published
- 2015
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23. Suppression of mutant C9orf72expression by a potent mixed backbone antisense oligonucleotide
- Author
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Tran, Hélène, Moazami, Michael P., Yang, Huiya, McKenna-Yasek, Diane, Douthwright, Catherine L., Pinto, Courtney, Metterville, Jake, Shin, Minwook, Sanil, Nitasha, Dooley, Craig, Puri, Ajit, Weiss, Alexandra, Wightman, Nicholas, Gray-Edwards, Heather, Marosfoi, Miklos, King, Robert M., Kenderdine, Thomas, Fabris, Daniele, Bowser, Robert, Watts, Jonathan K., and Brown, Robert H.
- Abstract
Expansions of a G4C2repeat in the C9ORF72gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two devastating adult-onset neurodegenerative disorders. Using C9-ALS/FTD patient-derived cells and C9ORF72BAC transgenic mice, we generated and optimized antisense oligonucleotides (ASOs) that selectively blunt expression of G4C2repeat-containing transcripts and effectively suppress tissue levels of poly(GP) dipeptides. ASOs with reduced phosphorothioate content showed improved tolerability without sacrificing efficacy. In a single patient harboring mutant C9ORF72with the G4C2repeat expansion, repeated dosing by intrathecal delivery of the optimal ASO was well tolerated, leading to significant reductions in levels of cerebrospinal fluid poly(GP). This report provides insight into the effect of nucleic acid chemistry on toxicity and, to our knowledge, for the first time demonstrates the feasibility of clinical suppression of the C9ORF72gene. Additional clinical trials will be required to demonstrate safety and efficacy of this therapy in patients with C9ORF72gene mutations.
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- 2021
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24. Prospective natural history study of ALS clinical characteristics and biomarkers.
- Author
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Cammack, Alexander J., Atassi, Nazem, Hyman, Theodore, van den Berg, Leonard H., Harms, Matthew, Baloh, Robert H., Brown, Robert H., van Es, Michael A., Veldink, Jan H., de Vries, Balint S., Rothstein, Jeffrey D., Drain, Caroline, Jockel-Balsarotti, Jennifer, Malcolm, Amber, Boodram, Sonia, Salter, Amber, Wightman, Nicholas, Hong Yu, Sherman, Alexander V., and Esparza, Thomas J.
- Published
- 2019
- Full Text
- View/download PDF
25. Human C9ORF72 Hexanucleotide Expansion Reproduces RNA Foci and Dipeptide Repeat Proteins but Not Neurodegeneration in BAC Transgenic Mice
- Author
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Massachusetts Institute of Technology. Department of Biology, McGovern Institute for Brain Research at MIT, Sapp, Peter C, Horvitz, Howard Robert, Peters, Owen M., Cabrera, Gabriela Toro, Tran, Helene, Gendron, Tania F., McKeon, Jeanne E., Metterville, Jake, Weiss, Alexandra, Wightman, Nicholas, Salameh, Johnny, Kim, Juhyun, Sun, Huaming, Boylan, Kevin B., Dickson, Dennis, Kennedy, Zachary, Lin, Ziqiang, Zhang, Yong-Jie, Daughrity, Lillian, Jung, Chris, Gao, Fen-Biao, Bosco, Daryl A., Brown, Solange P., de Jong, Pieter, Petrucelli, Leonard, Mueller, Christian, Brown, Robert H., Sapp, Peter C., Massachusetts Institute of Technology. Department of Biology, McGovern Institute for Brain Research at MIT, Sapp, Peter C, Horvitz, Howard Robert, Peters, Owen M., Cabrera, Gabriela Toro, Tran, Helene, Gendron, Tania F., McKeon, Jeanne E., Metterville, Jake, Weiss, Alexandra, Wightman, Nicholas, Salameh, Johnny, Kim, Juhyun, Sun, Huaming, Boylan, Kevin B., Dickson, Dennis, Kennedy, Zachary, Lin, Ziqiang, Zhang, Yong-Jie, Daughrity, Lillian, Jung, Chris, Gao, Fen-Biao, Bosco, Daryl A., Brown, Solange P., de Jong, Pieter, Petrucelli, Leonard, Mueller, Christian, Brown, Robert H., and Sapp, Peter C.
- Abstract
A non-coding hexanucleotide repeat expansion in the C9ORF72 gene is the most common mutation associated with familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). To investigate the pathological role of C9ORF72 in these diseases, we generated a line of mice carrying a bacterial artificial chromosome containing exons 1 to 6 of the human C9ORF72 gene with approximately 500 repeats of the GGGGCC motif. The mice showed no overt behavioral phenotype but recapitulated distinctive histopathological features of C9ORF72 ALS/FTD, including sense and antisense intranuclear RNA foci and poly(glycine-proline) dipeptide repeat proteins. Finally, using an artificial microRNA that targets human C9ORF72 in cultures of primary cortical neurons from the C9BAC mice, we have attenuated expression of the C9BAC transgene and the poly(GP) dipeptides. The C9ORF72 BAC transgenic mice will be a valuable tool in the study of ALS/FTD pathobiology and therapy., National Institutes of Health (U.S.) (NIH/NINDS R01NS088689), Howard Hughes Medical Institute (Investigator), National Institute of Environmental Health Sciences (NIEHS R01ES20395), ALS Therapy Alliance (Grant OD018259), National Research Foundation of Korea (Fellowship), United States. Department of Defense (ALSRP AL130125)
- Published
- 2016
26. Screening for inhibitors of the SOD1 gene promoter: Pyrimethamine does not reduce SOD1 levels in cell and animal models
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Wright, Paul D., primary, Huang, Mickey, additional, Weiss, Alexandra, additional, Matthews, Jonathan, additional, Wightman, Nicholas, additional, Glicksman, Marcie, additional, and Brown, Robert H., additional
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- 2010
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27. Trade in Zambian edible terrestrial orchids - molecular identification reveals use of previously undocumented orchid taxa for chikanda.
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Veldman, Sarina, Kim, Seol-jong, Wightman, Nicholas, Vinya, Royd, Mpatwa, Geophat, Chuba, David, Bone, Ruth E., Yokoya, K., Bytebier, Benny, Ngugi, Grace, Martos, Florent, Bello Font, Maria, Gravendeel, Barbara, van Andel, Tinde R., de Boer, Hugo J., Veldman, Sarina, Kim, Seol-jong, Wightman, Nicholas, Vinya, Royd, Mpatwa, Geophat, Chuba, David, Bone, Ruth E., Yokoya, K., Bytebier, Benny, Ngugi, Grace, Martos, Florent, Bello Font, Maria, Gravendeel, Barbara, van Andel, Tinde R., and de Boer, Hugo J.
- Abstract
In Zambia wild edible terrestrial orchids are used to produce a local Bemba delicacy called chikanda. Over the past decades chikanda has become increasingly popular throughout the country and commercialization puts orchid populations in Zambia, as well as neighboring countries, at risk of overharvesting. Up until now no study has documented which orchid species are traded on local markets, as orchid tubers are difficult to identify to genus or species level. In this study, the core land- plant DNA barcoding markers rbcL and matK were used in combination with nrITS to determine which species were sold on Zambian markets. A total of 82 interviews were held to determine harvesting areas, as well as possible sustainability concerns. By using nrITS DNA barcoding, a total of 16 orchid species in six different genera could be identified among the market samples, from which three were previously undocumented. Both rbcL and matK proved unsuitable for species-level identification, but can be used to identify the tubers up to genus- or family level. Satyrium buchananii, Platycoryne crocea and Disa robusta were encountered most frequently. International chikanda trade- hubs were identified in Zambia on the borders with the Democratic Republic of Congo (DRC) and Angola. People involved in chikanda trade indicate that both tuber quality, as well as quantity, were decreasing and were willing to consider alternatives to chikanda trade to secure their income. Currently hardly any orchid species are listed on the Zambian IUCN Red List. Local orchid populations and endemic species could be at risk of overharvesting due to the intensive and indiscriminate harvesting of chikanda orchids and we therefore urge for updating the IUCN Red List for terrestrial African orchids.
28. RNAi-mediated silencing of SOD1 profoundly extends survival and functional outcomes in ALS mice.
- Author
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Weiss A, Gilbert JW, Flores IVR, Belgrad J, Ferguson C, Dogan EO, Wightman N, Mocarski K, Echeverria D, Summers A, Bramato B, McHugh N, Furgal R, Yamada N, Cooper D, Monopoli K, Godinho BMDC, Hassler MR, Yamada K, Greer P, Henninger N, Brown RH Jr, and Khvorova A
- Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition, with 20% of familial and 2-3% of sporadic cases linked to mutations in the cytosolic superoxide dismutase (SOD1) gene. Mutant SOD1 protein is toxic to motor neurons, making SOD1 gene lowering a promising approach, supported by preclinical data and the 2023 FDA approval of the GapmeR ASO targeting SOD1, tofersen. Despite the approval of an ASO and the optimism it brings to the field, the pharmacodynamics and pharmacokinetics of therapeutic SOD1 modulation can be improved. Here, we developed a chemically stabilized divalent siRNA scaffold (di-siRNA) that effectively suppresses SOD1 expression in vitro and in vivo . With optimized chemical modification, it achieves remarkable CNS tissue permeation and SOD1 silencing in vivo . Administered intraventricularly, di-siRNA
SOD1 extended survival in SOD1-G93A ALS mice, surpassing survival previously seen in these mice by ASO modalities, slowed disease progression, and prevented ALS neuropathology. These properties offer an improved therapeutic strategy for SOD1-mediated ALS and may extend to other dominantly inherited neurological disorders., Competing Interests: Competing interests: AK is a co-founder, on the scientific advisory board, and holds equities of Atalanta Therapeutics; AK is a founder of Comanche Pharmaceuticals, and on the scientific advisory board of Aldena Therapeutics, AlltRNA, Prime Medicine, and EVOX Therapeutics; Select authors hold patents or on patent applications relating to the divalent siRNA, SOD1-targeting oligonucleotides, and the methods described in this report. NH received compensation for other services from Myrobalan Inc. and General Dynamics during the conduct of this study, unrelated to the present work.- Published
- 2024
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29. Up-regulation of cholesterol synthesis pathways and limited neurodegeneration in a knock-in Sod1 mutant mouse model of ALS.
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Dominov JA, Madigan LA, Whitt JP, Rademacher KL, Webster KM, Zhang H, Banno H, Tang S, Zhang Y, Wightman N, Shychuck EM, Page J, Weiss A, Kelly K, Kucukural A, Brodsky MH, Jaworski A, Fallon JR, Lipscombe D, and Brown RH
- Abstract
Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disorder affecting brain and spinal cord motor neurons. Mutations in the copper/zinc superoxide dismutase gene ( SOD1 ) are associated with ∼20% of inherited and 1-2% of sporadic ALS cases. Much has been learned from mice expressing transgenic copies of mutant SOD1, which typically involve high-level transgene expression, thereby differing from ALS patients expressing one mutant gene copy. To generate a model that more closely represents patient gene expression, we created a knock-in point mutation (G85R, a human ALS-causing mutation) in the endogenous mouse Sod1 gene, leading to mutant SOD1
G85R protein expression. Heterozygous Sod1G85R mutant mice resemble wild type, whereas homozygous mutants have reduced body weight and lifespan, a mild neurodegenerative phenotype, and express very low mutant SOD1 protein levels with no detectable SOD1 activity. Homozygous mutants exhibit partial neuromuscular junction denervation at 3-4 months of age. Spinal cord motor neuron transcriptome analyses of homozygous Sod1G85R mice revealed up-regulation of cholesterol synthesis pathway genes compared to wild type. Transcriptome and phenotypic features of these mice are similar to Sod1 knock-out mice, suggesting the Sod1G85R phenotype is largely driven by loss of SOD1 function. By contrast, cholesterol synthesis genes are down-regulated in severely affected human TgSOD1G93A transgenic mice at 4 months. Our analyses implicate dysregulation of cholesterol or related lipid pathway genes in ALS pathogenesis. The Sod1G85R knock-in mouse is a useful ALS model to examine the importance of SOD1 activity in control of cholesterol homeostasis and motor neuron survival., Significance Statement: Amyotrophic lateral sclerosis is a devastating disease involving the progressive loss of motor neurons and motor function for which there is currently no cure. Understanding biological mechanisms leading to motor neuron death is critical for developing new treatments. Using a new knock-in mutant mouse model carrying a Sod1 mutation that causes ALS in patients, and in the mouse, causes a limited neurodegenerative phenotype similar to Sod1 loss-of-function, we show that cholesterol synthesis pathway genes are up-regulated in mutant motor neurons, whereas the same genes are down-regulated in transgenic SOD1 mice with a severe phenotype. Our data implicate dysregulation of cholesterol or other related lipid genes in ALS pathogenesis and provide new insights that could contribute to strategies for disease intervention.- Published
- 2023
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30. SOD1 Suppression with Adeno-Associated Virus and MicroRNA in Familial ALS.
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Mueller C, Berry JD, McKenna-Yasek DM, Gernoux G, Owegi MA, Pothier LM, Douthwright CL, Gelevski D, Luppino SD, Blackwood M, Wightman NS, Oakley DH, Frosch MP, Flotte TR, Cudkowicz ME, and Brown RH Jr
- Subjects
- Amyotrophic Lateral Sclerosis cerebrospinal fluid, Amyotrophic Lateral Sclerosis genetics, Dependovirus, Fatal Outcome, Gene Silencing, Genetic Therapy, Genetic Vectors, Humans, Injections, Spinal, Male, Meningoencephalitis, Middle Aged, Mutation, Proof of Concept Study, Spinal Cord chemistry, Spinal Cord pathology, Superoxide Dismutase-1 analysis, Superoxide Dismutase-1 genetics, Vital Capacity, Young Adult, Amyotrophic Lateral Sclerosis therapy, MicroRNAs therapeutic use, Superoxide Dismutase-1 cerebrospinal fluid
- Abstract
Two patients with familial amyotrophic lateral sclerosis (ALS) and mutations in the gene encoding superoxide dismutase 1 ( SOD1 ) were treated with a single intrathecal infusion of adeno-associated virus encoding a microRNA targeting SOD1. In Patient 1, SOD1 levels in spinal cord tissue as analyzed on autopsy were lower than corresponding levels in untreated patients with SOD1-mediated ALS and in healthy controls. Levels of SOD1 in cerebrospinal fluid were transiently and only slightly lower in Patient 1 but were not affected in Patient 2. In Patient 1, meningoradiculitis developed after the infusion; Patient 2 was pretreated with immunosuppressive drugs and did not have this complication. Patient 1 had transient improvement in the strength of his right leg, a measure that had been relatively stable throughout his disease course, but there was no change in his vital capacity. Patient 2 had stable scores on a composite measure of ALS function and a stable vital capacity during a 12-month period. This study showed that intrathecal microRNA can be used as a potential treatment for SOD1-mediated ALS., (Copyright © 2020 Massachusetts Medical Society.)
- Published
- 2020
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31. A high-throughput screen to identify inhibitors of SOD1 transcription.
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Wright PD, Wightman N, Huang M, Weiss A, Sapp PC, Cuny GD, Ivinson AJ, Glicksman MA, Ferrante RJ, Matson W, Matson S, and Brown RH Jr
- Subjects
- Animals, Blotting, Western, HeLa Cells, Humans, Mice, Mice, Transgenic, PC12 Cells, Polymerase Chain Reaction, Promoter Regions, Genetic, Rats, Structure-Activity Relationship, Superoxide Dismutase-1, Superoxide Dismutase genetics, Transcription, Genetic drug effects
- Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal degenerative motor neuron disease. Approximately 20 percent of familial ALS cases are caused by mutations in the Cu/Zn superoxide dismutase (SOD1) gene. Rodents expressing mutant SOD1 transgenes develop progressive, fatal motor neuron disease and disease onset and progression is dependent on the level of SOD1. We investigated the possibility that a reduction in SOD1 protein may be of therapeutic benefit in ALS and screened 30,000 compounds for inhibition of SOD1 transcription. The most effective inhibitor identified was N-{4-[4-(4-methylbenzoyl)-1-piperazinyl]phenyl}-2-thiophenecarboxamide (Compound ID 7687685), which in PC12 cells showed an EC50 of 10.6 microM for inhibition of SOD1 expression and an LD50 more than 30 microM. This compound was subsequently shown to reduce endogenous SOD1 levels in HeLa cells and to exhibit a modest reduction of SOD1 protein levels in mouse spinal cord tissue. These data suggest that the efficacy of compound 7687685 as an inhibitor of SOD1 gene expression is not likely to be clinically useful, although the strategy reported could be applied broadly to screening for small molecule inhibitors of gene expression.
- Published
- 2012
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