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2. Germline MBD4 deficiency causes a multi-tumor predisposition syndrome

Author

Palles, C., West, H.D., Chew, E., Galavotti, S., Flensburg, C., Grolleman, J.E., Jansen, E.A.M., Curley, H., Chegwidden, L., Arbe-Barnes, E.H., Lander, N., Truscott, R., Pagan, J., Bajel, A., Sherwood, K., Martin, L., Thomas, H, Georgiou, D., Fostira, F., Goldberg, Y., Adams, D.J., Biezen, S.A.M. van der, Christie, M., Clendenning, M., Thomas, L.E., Deltas, C., Dimovski, A.J., Dymerska, D., Lubinski, J., Mahmood, K., Post, R.S. van der, Sanders, M., Weitz, J., Taylor, J.C., Turnbull, C., Vreede, L., Wezel, T. van, Whalley, C., Arnedo-Pac, C., Caravagna, G., Cross, W., Chubb, D., Frangou, A., Gruber, A.J., Kinnersley, B., Noyvert, B., Church, D., Graham, T., Houlston, R., Lopez-Bigas, N., Sottoriva, A., Wedge, D., Jenkins, Mark A., Kuiper, R.P., Roberts, A.W., Cheadle, J.P., Ligtenberg, M.J.L., Hoogerbrugge, N., Koelzer, V.H., Rivas, A.D., Winship, I.M., Ponte, C.R., Buchanan, D.D., Power, D.G., Green, A., Tomlinson, I.P., Sampson, J.R., Majewski, I.J., Voer, R.M. de, Palles, C., West, H.D., Chew, E., Galavotti, S., Flensburg, C., Grolleman, J.E., Jansen, E.A.M., Curley, H., Chegwidden, L., Arbe-Barnes, E.H., Lander, N., Truscott, R., Pagan, J., Bajel, A., Sherwood, K., Martin, L., Thomas, H, Georgiou, D., Fostira, F., Goldberg, Y., Adams, D.J., Biezen, S.A.M. van der, Christie, M., Clendenning, M., Thomas, L.E., Deltas, C., Dimovski, A.J., Dymerska, D., Lubinski, J., Mahmood, K., Post, R.S. van der, Sanders, M., Weitz, J., Taylor, J.C., Turnbull, C., Vreede, L., Wezel, T. van, Whalley, C., Arnedo-Pac, C., Caravagna, G., Cross, W., Chubb, D., Frangou, A., Gruber, A.J., Kinnersley, B., Noyvert, B., Church, D., Graham, T., Houlston, R., Lopez-Bigas, N., Sottoriva, A., Wedge, D., Jenkins, Mark A., Kuiper, R.P., Roberts, A.W., Cheadle, J.P., Ligtenberg, M.J.L., Hoogerbrugge, N., Koelzer, V.H., Rivas, A.D., Winship, I.M., Ponte, C.R., Buchanan, D.D., Power, D.G., Green, A., Tomlinson, I.P., Sampson, J.R., Majewski, I.J., and Voer, R.M. de

Abstract

Contains fulltext : 251996.pdf (Publisher’s version ) (Open Access), We report an autosomal recessive, multi-organ tumor predisposition syndrome, caused by bi-allelic loss-of-function germline variants in the base excision repair (BER) gene MBD4. We identified five individuals with bi-allelic MBD4 variants within four families and these individuals had a personal and/or family history of adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma. MBD4 encodes a glycosylase involved in repair of G:T mismatches resulting from deamination of 5'-methylcytosine. The colorectal adenomas from MBD4-deficient individuals showed a mutator phenotype attributable to mutational signature SBS1, consistent with the function of MBD4. MBD4-deficient polyps harbored somatic mutations in similar driver genes to sporadic colorectal tumors, although AMER1 mutations were more common and KRAS mutations less frequent. Our findings expand the role of BER deficiencies in tumor predisposition. Inclusion of MBD4 in genetic testing for polyposis and multi-tumor phenotypes is warranted to improve disease management.

Published
2022

5. G3BPs tether the TSC complex to lysosomes and suppress mTORC1 signaling

Author

Prentzell, M.T. (Mirja Tamara), Rehbein, U. (Ulrike), Cadena Sandoval, M. (Marti), De Meulemeester, A.-S. (Ann-Sofie), Baumeister, R. (Ralf), Brohée, L. (Laura), Berdel, B. (Bianca), Bockwoldt, M. (Mathias), Carroll, B. (Bernadette), Chowdhury, S.R. (Suvagata Roy), Deimling, A. (Andreas) von, Demetriades, C. (Constantinos), Figlia, G. (Gianluca), de Araujo, M.E.G. (Mariana Eca Guimaraes), Heberle, A.M. (Alexander M.), Heiland, I. (Ines), Holzwarth, B. (Birgit), Huber, L.A. (Lukas A.), Jaworski, J. (Jacek), Kedra, M. (Magdalena), Kern, K. (Katharina), Kopach, A. (Andrii), Korolchuk, V.I. (Viktor I.), van 't Land-Kuper, I. (Ineke), Macias, M. (Matylda), Nellist, M.D. (Mark), Palm, W. (Wilhelm), Pusch, S. (Stefan), Ramos Pittol, J.M. (Jose Miguel), Reil, M. (Michèle), Reintjes, A. (Anja), Reuter, F. (Friederike), Sampson, J.R. (Julian R.), Scheldeman, C. (Chloë), Siekierska, A. (Aleksandra), Stefan, E. (Eduard), Teleman, A.A. (Aurelio A.), Thomas, L.E. (Laura E.), Torres-Quesada, O. (Omar), Trump, S. (Saskia), West, H.D. (Hannah D.), de Witte, P. (Peter), Woltering, S. (Sandra), Yordanov, T.E. (Teodor E.), Zmorzynska, J. (Justyna), Opitz, C.A. (Christiane A.), Thedieck, K. (Kathrin), Prentzell, M.T. (Mirja Tamara), Rehbein, U. (Ulrike), Cadena Sandoval, M. (Marti), De Meulemeester, A.-S. (Ann-Sofie), Baumeister, R. (Ralf), Brohée, L. (Laura), Berdel, B. (Bianca), Bockwoldt, M. (Mathias), Carroll, B. (Bernadette), Chowdhury, S.R. (Suvagata Roy), Deimling, A. (Andreas) von, Demetriades, C. (Constantinos), Figlia, G. (Gianluca), de Araujo, M.E.G. (Mariana Eca Guimaraes), Heberle, A.M. (Alexander M.), Heiland, I. (Ines), Holzwarth, B. (Birgit), Huber, L.A. (Lukas A.), Jaworski, J. (Jacek), Kedra, M. (Magdalena), Kern, K. (Katharina), Kopach, A. (Andrii), Korolchuk, V.I. (Viktor I.), van 't Land-Kuper, I. (Ineke), Macias, M. (Matylda), Nellist, M.D. (Mark), Palm, W. (Wilhelm), Pusch, S. (Stefan), Ramos Pittol, J.M. (Jose Miguel), Reil, M. (Michèle), Reintjes, A. (Anja), Reuter, F. (Friederike), Sampson, J.R. (Julian R.), Scheldeman, C. (Chloë), Siekierska, A. (Aleksandra), Stefan, E. (Eduard), Teleman, A.A. (Aurelio A.), Thomas, L.E. (Laura E.), Torres-Quesada, O. (Omar), Trump, S. (Saskia), West, H.D. (Hannah D.), de Witte, P. (Peter), Woltering, S. (Sandra), Yordanov, T.E. (Teodor E.), Zmorzynska, J. (Justyna), Opitz, C.A. (Christiane A.), and Thedieck, K. (Kathrin)

Abstract

Distinct from their contributions to stress granules, G3BPs regulate mTORC1 activity through spatial control of the TSC complex.Ras GTPase-activating protein-binding proteins 1 and 2 (G3BP1 and G3BP2, respectively) are widely recognized as core components of stress granules (SGs). We report that G3BPs reside at the cytoplasmic surface of lysosomes. They act in a non-redundant manner to anchor the tuberous sclerosis complex (TSC) protein complex to lysosomes and suppress activation of the metabolic master regulator mechanistic target of rapamycin complex 1 (mTORC1) by amino acids and insulin. Like the TSC complex, G3BP1 deficiency elicits phenotypes related to mTORC1 hyperactivity. In the context of tumors, low G3BP1 levels enhance mTORC1-driven breast cancer cell motility and correlate with adverse outcomes in patients. Furthermore, G3bp1 inhibition in zebrafish disturbs neuronal development and function, leading to white matter heterotopia and neuronal hyperactivity. Thus, G3BPs are not only core components of SGs but also a key element of lysosomal TSC-mTORC1 signaling.

Published
2021
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12. Void formation during early stages of passivation: Initial oxidation of iron nanoparticles at room temperature

Author

C.M. Wang, You Qiang, Baer, D.R., Duscher, G., Thomas, L.E., Amonette, J.E., and Antony, Jiji

Subjects
Oxidation-reduction reaction -- Analysis, Iron compounds -- Structure, Iron compounds -- Chemical properties, Transmission electron microscopes -- Observations, Physics
Abstract

Microstructure of iron nanoparticles passivated with the iron oxide shell was studied using high-resolution transmission electron microscopy and high-angle annular dark-field imaging in aberration-corrected scanning transmission microscopy. The results revealed that for particles larger than the critical size, an iron/iron-oxide core-shell structure was formed and voids reside at the interface between the oxide shell and the iron core.

Published
2005

13. Precipitation of Au nanoclusters in SrTiO3 by ion implantation

Author

Wang, C.M., Thevuthasan, S., Duscher, G., Shuthanandan, V., Zhang, Y., Thomas, L.E., and Baer, D.R.

Subjects
Nanotechnology -- Analysis, Ion implantation -- Analysis, Gold -- Analysis, Physics
Abstract

MeV ion implantation and subsequent high-temperature annealing were employed to produce Au nanoclusters in single-crystal SrTi03 (001). It is generally inferred that implantation below a critical temperature may lead to a finer Au cluster size.

Published
2004

16. Microstructure of precipitated Au nanoclusters in MgO

Author

Wang, C.M., Thevuthasan, S., Shutthanandan, V., Cavanagh, A., Jiang, W., Weber, W.J., and Thomas, L.E.

Subjects
Ion implantation -- Research, Gold -- Properties, Magnesium oxide -- Properties, Physics
Abstract

Gold nanoclusters dispersed in single crystal MgO are prepared by ion implantation at 975 K and subsequent annealing at 1275 K for 10 h. It is suggested that the density of quantum antidots should depend on the size of the Au clusters.

Published
2003

18. Ice caps in the Balkans: their extent, age and palaeoclimatic significance

Author

Hughes, P.D., Woodward, J.C., van Calsteren, P.C., Thomas, L.E., Adamson, L.E.

Abstract

Ice caps once covered large areas of Montenegro in the Balkans. The largest ice cap covered an area of >1000 km2 and covered large areas of central Montenegro, including the Durmitor, Sinjajevina and Morača massifs. A smaller ice cap, yet still covering an area of 165 km2, covered Mount Orjen on the Adriatic coast. More than 30 U-series dates from secondary carbonates cementing moraines across Montenegro indicates that the most extensive glaciation occurred during the Middle Pleistocene, correlating with a major phase of glaciation in Greece to the south during MIS 12 (c. 480-430 ka). Later, less extensive, glaciations are also recorded in the cirques and valleys and correlate with glaciations during MIS 6 (190-130 ka) and MIS 5d-2 (110-11.7 ka). The formation of large ice caps over Montenegro on mountains reaching only 2500 m indicates sustained moisture supply during Pleistocene cold stages – especially on the lower mountains of the coast such as Mount Orjen. Such sustained precipitation supply during Pleistocene cold stages is likely to have been facilitated by major temperature contrasts between the European landmass and the Mediterranean Sea, which are likely to have sustained lee-side vortices to the south of the Alps, in the Gulf of Genoa and Adriatic Sea, forming weak moisture-bearing depressions which tracked across the eastern Adriatic coastal mountains. Large ice caps on the Dinaric Alps would have blocked the inland penetration of these depressions, resulting in much drier conditions in the Balkan interior, creating favourable conditions for the deposition of thick accumulations of loess. In the Durmitor massif, the highest in Montenegro, valley glaciers were present during the Younger Dryas (12.9-11.7 ka) and confirm the influence of North Atlantic Ocean circulation on Pleistocene climate change in this part of the Mediterranean. In this same massif only one small cirque glacier survives today and exists under conditions strongly controlled by local topoclimatic controls.

Published
2012

20. Predictors of stroke in patients with impaired glucose tolerance: results from the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research trial

Author

Preiss, D., Giles, T.D., Thomas, L.E., Sun, J.L., Haffner, S.M., Holman, R.R., Standl, E., Mazzone, T., Rutten, G.E.H.M., Tognoni, G., Chiang, F.T., McMurray, J.J., Califf, R.M., Preiss, D., Giles, T.D., Thomas, L.E., Sun, J.L., Haffner, S.M., Holman, R.R., Standl, E., Mazzone, T., Rutten, G.E.H.M., Tognoni, G., Chiang, F.T., McMurray, J.J., and Califf, R.M.

Published
2013

40. 238U–230Th disequilibrium in recent basalts and dynamic melting beneath the Kenya rift

Author

Rogers, N.W., Thomas, L.E., Macdonald, R., Hawkesworth, C.J., and Mokadem, F.

Subjects
*BASALT, *IGNEOUS rocks, *PHYSICAL geology
Abstract

Abstract: Trace element and U-series isotope analyses are presented for a suite of recent (<10 ka) basalts from the axial portion of the Kenya rift. Samples from throughout the rift have LREE-enriched patterns with HREE >10×chondrite and the LREE between 60 and 200×chondrite. REE fractionation is consistent with melting a garnet lherzolite source region with between 2% and 6% modal garnet. Other trace element ratios are distinct from OIB, notably Zr/Hf which ranges from 43 to 48, whilst at a given Zr content the Zr/Hf ratio is significantly greater than that found in OIB. (238U/232Th) range from 0.362 to 1.036, (230Th/232Th) from 0.503 to 1.109, with (230Th/238U) ranging from 0.783 to 2.966. All but two samples are in 230Th excess or in secular equilibrium. Samples with elevated (238U/232Th), also have Rb/Cs>120, but unexceptional 208Pb⁎/206Pb⁎ and hence κ Pb values. These samples have experienced U and Cs loss and are excluded from further consideration. Of the unaltered samples, all have (238U/232Th) generally lower than OIB, with maximum values of <0.8, and some <0.6. The maximum (230Th/238U) is 1.39, similar to OIB. Although none of the basalts has a primary composition, (230Th/238U) does not vary systematically with indices of fractionation, and comparison with evolved rocks from Kenya indicates that 238U–230Th disequilibrium in the basalts is not the product of fractionation and crustal residence, but a product of melt generation. The maximum (230Th/238U) that can be generated by batch melting, assuming a source mineralogy consistent with the REE variation is 1.05 and so the variation in (230Th/238U) is attributed to more complex models of melt generation and/or transport. Both dynamic melting and equilibrium porous flow suggest mantle upwelling rates of ≤2 cm year−1. It is suggested that the Kenya basalts represent melts derived from lithospheric mantle that has been thermally reactivated by and incorporated into the underlying (East African) mantle plume. [Copyright &y& Elsevier]

Published
2006
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42. The microstructure of neutron irradiated type-348 stainless steel and its relation to creep and hardening

Author

Thomas, L.E. and Beeston, J.M.

Abstract

Annealed type-348 stainless steel specimens irradiated to 33 to 39 dpa at 350°C were examined by transmission electron microscopy to determine the cause of pronounced irradiation creep and hardening. The irradiation produced very high densities of 1–2 nm diameter helium bubbles, 2–20 nm diameter faulted (Frank) dislocation loops and 10 nm diameter precipitate particles. These defects account for the observed irradiation hardening but do not explain the creep strains. Too few point defects survive as faulted dislocation loops for significant creep by the stress-induced preferential absorption (SIPA) mechanism and there are not enough unfaulted dislocations for creep by climb-induced glide. Also, the irradiation-induced precipitates are face-centred cubic G-phase (a niobium nickel suicide), and cannot cause creep. It is suggested that the irradiation creep occurs by a grain-boundary movement mechanism such as diffusion accomodated grain-boundary sliding.

Published
1982
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