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1. Avelumab for Advanced Merkel Cell Carcinoma: Global Real-World Data on Patient Response and Survival

Author

Lohray R, Verma KK, Wang LL, Haynes D, and Lewis DJ

Subjects
merkel cell carcinoma, avelumab, real-world studies, immune-checkpoint inhibitors, tumor response, adverse events., Medicine
Abstract

Rishabh Lohray,1 Kritin K Verma,2 Leo L Wang,3 Dylan Haynes,3 Daniel J Lewis3 1Baylor College of Medicine, Houston, TX, USA; 2Texas Tech University Health Sciences Center, School of Medicine, Lubbock, TX, USA; 3Department of Dermatology, University of Pennsylvania, Philadelphia, PA, USACorrespondence: Daniel J Lewis, Penn Dermatology Oncology Center, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Boulevard, Suite 1-330S, Philadelphia, PA, 19104, USA, Tel +1 215-360-0909, Fax +1 215-662-4132, Email Daniel.Lewis@pennmedicine.upenn.eduIntroduction: Avelumab is a programmed cell death-ligand 1 (PD-L1) inhibitor approved by the Food and Drug Administration for advanced Merkel cell carcinoma (MCC). Studies conducted in real-world settings have shed light on its effectiveness and safety in clinical settings.Areas Covered: Real-world studies on avelumab for MCC from North and South America, Europe, and Asia have been presented in this review. Most studies are on patients over age 70 and have a male-predominant sex ratio. Overall response rates range from 29.1% to 72.1%, (disease control rate: 60.0– 72.7%; complete response rate: 15.8%– 37.2%; partial rate: 18.2– 42.1%; stable disease: 7.1– 30.9%; progressive disease: 7.1– 40.0%) and median progression free survival ranges from 8.1 to 24.1 months depending on the population studied. Immunosuppressed patients appear to benefit from avelumab as well, with response rates equivalent to the general population. Patients receiving avelumab as a first-line agent tend to have better outcomes than those using it as a second-line therapy. Fatigue, infusion-related reactions, and dyspnea were some of the most common adverse events identified in real-world studies. Autoimmune hepatitis and thyroiditis were also observed.Conclusion: The use of avelumab as a safe and effective treatment option for advanced MCC is supported by real-world data, although additional study is required to assess long-term efficacy and safety outcomes.Keywords: Merkel cell carcinoma, avelumab, real-world studies, immune-checkpoint inhibitors, tumor response, adverse events

Published
2023

3. Clocking Auger Electrons

Author

Haynes, D. C., Wurzer, M., Schletter, A., Al-Haddad, A., Blaga, C., Bostedt, C., Bozek, J., Bucher, M., Camper, A., Carron, S., Coffee, R., Costello, J. T., DiMauro, L. F., Ding, Y., Ferguson, K., Grguraš, I., Helml, W., Hoffmann, M. C., Ilchen, M., Jalas, S., Kabachnik, N. M., Kazansky, A. K., Kienberger, R., Maier, A. R., Maxwell, T., Mazza, T., Meyer, M., Park, H., Robinson, J. S., Roedig, C., Schlarb, H., Singla, R., Tellkamp, F., Zhang, K., Doumy, G., Behrens, C., and Cavalieri, A. L.

Subjects
Physics - Atomic Physics
Abstract

Intense X-ray free-electron lasers (XFELs) can rapidly excite matter, leaving it in inherently unstable states that decay on femtosecond timescales. As the relaxation occurs primarily via Auger emission, excited state observations are constrained by Auger decay. In situ measurement of this process is therefore crucial, yet it has thus far remained elusive at XFELs due to inherent timing and phase jitter, which can be orders of magnitude larger than the timescale of Auger decay. Here, we develop a new approach termed self-referenced attosecond streaking, based upon simultaneous measurements of streaked photo- and Auger electrons. Our technique enables sub-femtosecond resolution in spite of jitter. We exploit this method to make the first XFEL time-domain measurement of the Auger decay lifetime in atomic neon, and, by using a fully quantum-mechanical description, retrieve a lifetime of $2.2^{ + 0.2}_{ - 0.3}$ fs for the KLL decay channel. Importantly, our technique can be generalised to permit the extension of attosecond time-resolved experiments to all current and future FEL facilities., Comment: Main text: 20 pages, 3 figures. Supplementary information: 17 pages, 6 figures

Published
2020
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4. First demonstration of OH suppression in a high efficiency near-infrared spectrograph

Author

Ellis, S. C., Bland-Hawthorn, J., Lawrence, J. S., Horton, A. J., Content, R., Roth, M. M., Pai, N., Zhelem, R., Case, S., Hernandez, E., Leon-Saval, S. G., Haynes, R., Min, S. S., Giannone, D., Madhav, K., Rahman, A., Betters, C., Haynes, D., Couch, W., Kewley, L. J., McDermid, R., Spitler, L., Sharp, R. G., and Veilleux, S.

Subjects
Astrophysics - Instrumentation and Methods for Astrophysics
Abstract

Ground-based near-infrared astronomy is severely hampered by the forest of atmospheric emission lines resulting from the rovibrational decay of OH molecules in the upper atmosphere. The extreme brightness of these lines, as well as their spatial and temporal variability, makes accurate sky subtraction difficult. Selectively filtering these lines with OH suppression instruments has been a long standing goal for near-infrared spectroscopy. We have shown previously the efficacy of fibre Bragg gratings combined with photonic lanterns for achieving OH suppression. Here we report on PRAXIS, a unique near-infrared spectrograph that is optimised for OH suppression with fibre Bragg gratings. We show for the first time that OH suppression (of any kind) is possible with high overall throughput (18 per cent end-to-end), and provide examples of the relative benefits of OH suppression., Comment: Accepted for publication in MNRAS

Published
2020
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5. 4MOST: Project overview and information for the First Call for Proposals

Author

de Jong, R. S., Agertz, O., Berbel, A. Agudo, Aird, J., Alexander, D. A., Amarsi, A., Anders, F., Andrae, R., Ansarinejad, B., Ansorge, W., Antilogus, P., Anwand-Heerwart, H., Arentsen, A., Arnadottir, A., Asplund, M., Auger, M., Azais, N., Baade, D., Baker, G., Baker, S., Balbinot, E., Baldry, I. K., Banerji, M., Barden, S., Barklem, P., Barthélémy-Mazot, E., Battistini, C., Bauer, S., Bell, C. P. M., Bellido-Tirado, O., Bellstedt, S., Belokurov, V., Bensby, T., Bergemann, M., Bestenlehner, J. M., Bielby, R., Bilicki, M., Blake, C., Bland-Hawthorn, J., Boeche, C., Boland, W., Boller, T., Bongard, S., Bongiorno, A., Bonifacio, P., Boudon, D., Brooks, D., Brown, M. J. I., Brown, R., Brüggen, M., Brynnel, J., Brzeski, J., Buchert, T., Buschkamp, P., Caffau, E., Caillier, P., Carrick, J., Casagrande, L., Case, S., Casey, A., Cesarini, I., Cescutti, G., Chapuis, D., Chiappini, C., Childress, M., Christlieb, N., Church, R., Cioni, M. -R. L., Cluver, M., Colless, M., Collett, T., Comparat, J., Cooper, A., Couch, W., Courbin, F., Croom, S., Croton, D., Daguisé, E., Dalton, G., Davies, L. J. M., Davis, T., de Laverny, P., Deason, A., Dionies, F., Disseau, K., Doel, P., Döscher, D., Driver, S. P., Dwelly, T., Eckert, D., Edge, A., Edvardsson, B., Youssoufi, D. El, Elhaddad, A., Enke, H., Erfanianfar, G., Farrell, T., Fechner, T., Feiz, C., Feltzing, S., Ferreras, I., Feuerstein, D., Feuillet, D., Finoguenov, A., Ford, D., Fotopoulou, S., Fouesneau, M., Frenk, C., Frey, S., Gaessler, W., Geier, S., Fusillo, N. Gentile, Gerhard, O., Giannantonio, T., Giannone, D., Gibson, B., Gillingham, P., González-Fernández, C., Gonzalez-Solares, E., Gottloeber, S., Gould, A., Grebel, E. K., Gueguen, A., Guiglion, G., Haehnelt, M., Hahn, T., Hansen, C. J., Hartman, H., Hauptner, K., Hawkins, K., Haynes, D., Haynes, R., Heiter, U., Helmi, A., Aguayo, C. Hernandez, Hewett, P., Hinton, S., Hobbs, D., Hoenig, S., Hofman, D., Hook, I., Hopgood, J., Hopkins, A., Hourihane, A., Howes, L., Howlett, C., Huet, T., Irwin, M., Iwert, O., Jablonka, P., Jahn, T., Jahnke, K., Jarno, A., Jin, S., Jofre, P., Johl, D., Jones, D., Jönsson, H., Jordan, C., Karovicova, I., Khalatyan, A., Kelz, A., Kennicutt, R., King, D., Kitaura, F., Klar, J., Klauser, U., Kneib, J., Koch, A., Koposov, S., Kordopatis, G., Korn, A., Kosmalski, J., Kotak, R., Kovalev, M., Kreckel, K., Kripak, Y., Krumpe, M., Kuijken, K., Kunder, A., Kushniruk, I., Lam, M. I, Lamer, G., Laurent, F., Lawrence, J., Lehmitz, M., Lemasle, B., Lewis, J., Li, B., Lidman, C., Lind, K., Liske, J., Lizon, J. -L., Loveday, J., Ludwig, H. -G., McDermid, R. M., Maguire, K., Mainieri, V., Mali, S., Mandel, H., Mandel, K., Mannering, L., Martell, S., Delgado, D. Martinez, Matijevic, G., McGregor, H., McMahon, R., McMillan, P., Mena, O., Merloni, A., Meyer, M. J., Michel, C., Micheva, G., Migniau, J. -E., Minchev, I., Monari, G., Muller, R., Murphy, D., Muthukrishna, D., Nandra, K., Navarro, R., Ness, M., Nichani, V., Nichol, R., Nicklas, H., Niederhofer, F., Norberg, P., Obreschkow, D., Oliver, S., Owers, M., Pai, N., Pankratow, S., Parkinson, D., Parry, I., Paschke, J., Paterson, R., Pecontal, A., Phillips, D., Pillepich, A., Pinard, L., Pirard, J., Piskunov, N., Plank, V., Plüschke, D., Pons, E., Popesso, P., Power, C., Pragt, J., Pramskiy, A., Pryer, D., Quattri, M., Queiroz, A. B. de Andrade, Quirrenbach, A., Rahurkar, S., Raichoor, A., Ramstedt, S., Rau, A., Recio-Blanco, A., Reiss, R., Renaud, F., Revaz, Y., Rhode, P., Richard, J., Richter, A. D., Rix, H. -W., Robotham, A. S. G., Roelfsema, R., Romaniello, M., Rosario, D., Rothmaier, F., Roukema, B., Ruchti, G., Rupprecht, G., Rybizki, J., Ryde, N., Saar, A., Sadler, E., Sahlén, M., Salvato, M., Sassolas, B., Saunders, W., Saviauk, A., Sbordone, L., Schmidt, T., Schnurr, O., Scholz, R. -D., Schwope, A., Seifert, W., Shanks, T., Sheinis, A., Sivov, T., Skúladóttir, Á., Smartt, S., Smedley, S., Smith, G., Smith, R., Sorce, J., Spitler, L., Starkenburg, E., Steinmetz, M., Stilz, I., Storm, J., Sullivan, M., Sutherland, W., Swann, E., Tamone, A., Taylor, E. N., Teillon, J., Tempel, E., ter Horst, R., Thi, W. -F., Tolstoy, E., Trager, S., Traven, G., Tremblay, P. -E., Tresse, L., Valentini, M., van de Weygaert, R., Ancker, M. van den, Veljanoski, J., Venkatesan, S., Wagner, L., Wagner, K., Walcher, C. J., Waller, L., Walton, N., Wang, L., Winkler, R., Wisotzki, L., Worley, C. C., Worseck, G., Xiang, M., Xu, W., Yong, D., Zhao, C., Zheng, J., Zscheyge, F., and Zucker, D.

Subjects
Astrophysics - Instrumentation and Methods for Astrophysics
Abstract

We introduce the 4-metre Multi-Object Spectroscopic Telescope (4MOST), a new high-multiplex, wide-field spectroscopic survey facility under development for the four-metre-class Visible and Infrared Survey Telescope for Astronomy (VISTA) at Paranal. Its key specifications are: a large field of view (FoV) of 4.2 square degrees and a high multiplex capability, with 1624 fibres feeding two low-resolution spectrographs ($R = \lambda/\Delta\lambda \sim 6500$), and 812 fibres transferring light to the high-resolution spectrograph ($R \sim 20\,000$). After a description of the instrument and its expected performance, a short overview is given of its operational scheme and planned 4MOST Consortium science; these aspects are covered in more detail in other articles in this edition of The Messenger. Finally, the processes, schedules, and policies concerning the selection of ESO Community Surveys are presented, commencing with a singular opportunity to submit Letters of Intent for Public Surveys during the first five years of 4MOST operations., Comment: Part of the 4MOST issue of The Messenger, published in preparation of 4MOST Community Workshop, see http://www.eso.org/sci/meetings/2019/4MOST.html

Published
2019
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6. Extreme timescale core-level spectroscopy with tailored XUV pulses

Author

Singla, R., Haynes, D. C., Hanff, K., Grguras, I., Schulz, S., Liu, H. Y., Simoncig, A., Tellkamp, F., Bajt, S., Rossnagel, K., and Cavalieri, A. L.

Subjects
Physics - Optics
Abstract

A new approach for few-femtosecond time-resolved photoelectron spectroscopy in condensed matter that balances the combined needs for both temporal and energy resolution is demonstrated. Here, the method is designed to investigate a prototypical Mott insulator, tantalum disulphide (1T-TaS2), which transforms from its charge-density-wave ordered Mott insulating state to a conducting state in a matter of femtoseconds. The signature to be observed through the phase transition is a charge-density-wave induced splitting of the Ta 4f core-levels, which can be resolved with sub-eV spectral resolution. Combining this spectral resolution with few-femtosecond time resolution enables the collapse of the charge ordered Mott state to be clocked. Precise knowledge of the sub-20-femtosecond dynamics will provide new insight into the physical mechanism behind the collapse and may reveal Mott physics on the timescale of electronic hopping., Comment: 20 pages, 6 figures

Published
2018

7. Recombination of radiation defects in solid methane - neutron sources and cryo-volcanism on celestial bodies

Author

Kirichek, O., Savchenko, E. V., Lawson, C. R., Khyzhniy, I. V., Jenkins, D. M., Uyutnov, S. A., Bludov, M. A., and Haynes, D. J.

Subjects
Condensed Matter - Materials Science, Condensed Matter - Other Condensed Matter
Abstract

Physicochemical properties of solid methane exposed to ionizing radiation have attracted significant interest in recent years. Here we present new trends in the study of radiation effects in solid methane. We particularly focus on relaxation phenomena in solid methane pre-irradiated by energetic neutrons and electron beam. We compare experimental results obtained in the temperature range from 10K to 100K with a model based on the assumption that radiolysis defect recombinations happen in two stages, at two different temperatures. In the case of slow heating up of the solid methane sample, irradiated at 10K, the first wave of recombination occurs around 20K with a further second wave taking place between 50 and 60K. We also discuss the role of the recombination mechanisms in burp phenomenon discovered by J. Carpenter in the late 1980s. An understanding of these mechanisms is vital for the designing and operation of solid methane moderators used in advanced neutron sources and could also be a possible explanation for the driving forces behind cryo-volcanism on celestial bodies., Comment: 6 pages, 2 figures, LT28 conference 2017

Published
2017
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8. Clocking Auger electrons

Author

Haynes, D. C., Wurzer, M., Schletter, A., Al-Haddad, A., Blaga, C., Bostedt, C., Bozek, J., Bromberger, H., Bucher, M., Camper, A., Carron, S., Coffee, R., Costello, J. T., DiMauro, L. F., Ding, Y., Ferguson, K., Grguraš, I., Helml, W., Hoffmann, M. C., Ilchen, M., Jalas, S., Kabachnik, N. M., Kazansky, A. K., Kienberger, R., Maier, A. R., Maxwell, T., Mazza, T., Meyer, M., Park, H., Robinson, J., Roedig, C., Schlarb, H., Singla, R., Tellkamp, F., Walker, P. A., Zhang, K., Doumy, G., Behrens, C., and Cavalieri, A. L.

Published
2021
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11. The stellar content of the Hamburg/ESO survey. V. The metallicity distribution function of the Galactic halo

Author

Schoerck, T., Christlieb, N., Cohen, J. G., Beers, T. C., Shectman, S., Thompson, I., McWilliam, A., Bessell, M. S., Norris, J. E., Melendez, J., Ramirez, S. Solange, Haynes, D., Cass, P., Hartley, M., Russell, K., Watson, F., Zickgraf, F. -J., Behnke, B., Fechner, C., Fuhrmeister, B., Barklem, P. S., Edvardsson, B., Frebel, A., Wisotzki, L., and Reimers, D.

Subjects
Astrophysics
Abstract

We determine the metallicity distribution function (MDF) of the Galactic halo by means of a sample of 1638 metal-poor stars selected from the Hamburg/ESO objective-prism survey (HES). The sample was corrected for minor biases introduced by the strategy for spectroscopic follow-up observations of the metal-poor candidates, namely "best and brightest stars first". [...] We determined the selection function of the HES, which must be taken into account for a proper comparison between the HES MDF with MDFs of other stellar populations or those predicted by models of Galactic chemical evolution. The latter show a reasonable agreement with the overall shape of the HES MDF for [Fe/H] > -3.6, but only a model of Salvadori et al. (2007) with a critical metallicity for low-mass star formation of Z_cr = 10^{-3.4} * Z_Sun reproduces the sharp drop at [Fe/H] ~-3.6 present in the HES MDF. [...] A comparison of the MDF of Galactic globular clusters and of dSph satellites to the Galaxy shows qualitative agreement with the halo MDF, derived from the HES, once the selection function of the latter is included. However, statistical tests show that the differences between these are still highly significant. [ABSTRACT ABRIDGED], Comment: Accepted for publication in A&A

Published
2008
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13. Structural studies on some fluorinated dithiadiazolyl radicals

Author

Haynes, D. A.

Subjects
547.02
Abstract

A series of partially fluorinated 1,2,3,5-dithiadizolyl aryl derivatives was prepared, in order to examine the effects of the fluorinated substituents on the solid-state structure of these molecules. 3,5-(CF3)2(C6H3CNSSN and 3-CF3C6H4CNSSN were synthesized, as well as nine isomers of CF3FC6H3CNSSN. The crystal structures of seven of these derivatives are compared, and discussed in the light of their molecular electrostatic potential maps. 3-F-4-CF3C6H3CNSSN was found to crystallize as an inclusion compound with nitrogen. The synthesis and characterisation of this inclusion compound is described, as well as the reactivity of 3-F-4-CF3C6H3CNSSN to other small molecules (Ar, CO2, O2). Several fluorinated dithiadiazolyl derivatives were synthesized in order to investigate their physical properties. EPR studies on CF3CNSSN were undertaken in order to further examine its known bistable nature. EPR studies on the novel dithiadiazolyl derivative, CF3(CF2)6CNSSN are also described, and the possibility of this radical exhibiting a liquid crystalline phase is discussed. The synthesis and solid-state structure of novel monomeric dithiadiazolyl radical, (CF3)3C6 H2CNSSN, is also described. During the course of these studies, the known dithiadiazolyl derivative, CICNSSN, was synthesized in three concomitant polymorphic forms. The solid-state structure of these compounds is described, and the competing interactions seen in the three forms are discussed in the light of the molecular electrostatic potential map and atomic partial charges of CICNSSN. A series of novel dithiatetrazocines, p-X1C6H4C2N4S2C6 H4X2 (X1, X2 = NO2, Br) was synthesized and characterized in order to study the non-linear optical properties of the unsymmetric derivative. The solid-state structures of these three derivatives are described and rationalized using their molecular electrostatic potential maps.

Published
2002

15. 511 Pleomorphic dermal sarcoma (PDS): Patterns of upstaging, recurrence, and adjuvant treatment following mohs micrographic surgery (MMS)

Author

Deitermann, A.M., primary, Lin, S.K., additional, Haynes, D., additional, Aibo, M. Ibrahim, additional, Wu, G., additional, Miller, C.J., additional, Etzkorn, J., additional, Sobanko, J., additional, Shin, T., additional, Higgins, H., additional, Giordano, C., additional, McMurray, S., additional, Zhang, J., additional, Nguyen, H., additional, and Walker, J.L., additional

Published
2023
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16. Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice.

Author

Sheppard, S.E., Bryant, L., Wickramasekara, R.N., Vaccaro, C., Robertson, B., Hallgren, J., Hulen, J., Watson, C.J., Faundes, V., Duffourd, Y., Lee, P., Simon, M.C., Cruz, X. de la, Padilla, N., Flores-Mendez, M., Akizu, N., Smiler, J., Pellegrino Da Silva, R., Li, D., March, M., Diaz-Rosado, A., Peixoto de Barcelos, I., Choa, Z.X., Lim, C.Y., Dubourg, C., Journel, H., Demurger, F., Mulhern, M., Akman, C., Lippa, N., Andrews, M., Baldridge, D., Constantino, J., Haeringen, A. van, Snoeck-Streef, I., Chow, P., Hing, A., Graham Jr, J.M., Au, M., Faivre, L., Shen, W., Mao, R., Palumbos, J., Viskochil, D., Gahl, W., Tifft, C., Macnamara, E., Hauser, N., Miller, R., Maffeo, J., Afenjar, A., Doummar, D., Keren, B., Arn, P., Macklin-Mantia, S., Meerschaut, I., Callewaert, B., Reis, A., Zweier, C., Brewer, C., Saggar, A., Smeland, M.F., Kumar, Ajith, Elmslie, F., Deshpande, C., Nizon, M., Cogne, B., Ierland, Y. van, Wilke, M., Slegtenhorst, M. van, Koudijs, S., Chen, J.Y., Dredge, D., Pier, D., Wortmann, S.B., Kamsteeg, E.J., Koch, J., Haynes, D., Pollack, L., Titheradge, H., Ranguin, K., Denommé-Pichon, A.S., Weber, S., Perez de la Fuente, R., Sanchez Del Pozo, J., Lezana Rosales, J.M., Joset, P., Steindl, K., Rauch, A., Mei, D., Mari, F., Guerrini, R., Lespinasse, J., Tran Mau-Them, F., Philippe, C., Dauriat, B., Raymond, L., Moutton, S., Cueto-González, A.M., Tan, T.Y., Mignot, C., Grotto, S., Renaldo, F., Drivas, T.G., Hennessy, L., Raper, A., Parenti, I., Kaiser, F.J., Kuechler, A., Busk, Ø.L., Islam, L., Siedlik, J.A., Henderson, L.B., Juusola, J., Person, R., Schnur, R.E., Vitobello, A., Banka, S., Bhoj, E.J., Stessman, H.A.F., Sheppard, S.E., Bryant, L., Wickramasekara, R.N., Vaccaro, C., Robertson, B., Hallgren, J., Hulen, J., Watson, C.J., Faundes, V., Duffourd, Y., Lee, P., Simon, M.C., Cruz, X. de la, Padilla, N., Flores-Mendez, M., Akizu, N., Smiler, J., Pellegrino Da Silva, R., Li, D., March, M., Diaz-Rosado, A., Peixoto de Barcelos, I., Choa, Z.X., Lim, C.Y., Dubourg, C., Journel, H., Demurger, F., Mulhern, M., Akman, C., Lippa, N., Andrews, M., Baldridge, D., Constantino, J., Haeringen, A. van, Snoeck-Streef, I., Chow, P., Hing, A., Graham Jr, J.M., Au, M., Faivre, L., Shen, W., Mao, R., Palumbos, J., Viskochil, D., Gahl, W., Tifft, C., Macnamara, E., Hauser, N., Miller, R., Maffeo, J., Afenjar, A., Doummar, D., Keren, B., Arn, P., Macklin-Mantia, S., Meerschaut, I., Callewaert, B., Reis, A., Zweier, C., Brewer, C., Saggar, A., Smeland, M.F., Kumar, Ajith, Elmslie, F., Deshpande, C., Nizon, M., Cogne, B., Ierland, Y. van, Wilke, M., Slegtenhorst, M. van, Koudijs, S., Chen, J.Y., Dredge, D., Pier, D., Wortmann, S.B., Kamsteeg, E.J., Koch, J., Haynes, D., Pollack, L., Titheradge, H., Ranguin, K., Denommé-Pichon, A.S., Weber, S., Perez de la Fuente, R., Sanchez Del Pozo, J., Lezana Rosales, J.M., Joset, P., Steindl, K., Rauch, A., Mei, D., Mari, F., Guerrini, R., Lespinasse, J., Tran Mau-Them, F., Philippe, C., Dauriat, B., Raymond, L., Moutton, S., Cueto-González, A.M., Tan, T.Y., Mignot, C., Grotto, S., Renaldo, F., Drivas, T.G., Hennessy, L., Raper, A., Parenti, I., Kaiser, F.J., Kuechler, A., Busk, Ø.L., Islam, L., Siedlik, J.A., Henderson, L.B., Juusola, J., Person, R., Schnur, R.E., Vitobello, A., Banka, S., Bhoj, E.J., and Stessman, H.A.F.

Abstract

Item does not contain fulltext, Pathogenic variants in KMT5B, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM# 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest (n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5B-related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems.

Published
2023

17. Electronic properties of novel conducting polymers

Author

Haynes, D. M.

Subjects
547.7
Abstract

For some years a dynamic international research effort has focused on developing novel molecular materials which have interesting conducting and semiconducting properties. This thesis is concerned with the investigation of several novel organic polymers which fall into this category. The first part of the work concerns the DC characterisation of three conjugated polymers: poly[2,5-dibutoxy-1-(1'2'-ethynyl)-4-benzene] (A) poly[2,5-dibutoxy-1-(1'4'-buta-1',3'-diynyl)-4-benzene] (B) and poly-p-phenylene-vinylene (C). In their intrinsic state all these materials are quantitatively similar with band gaps of approximately 2.5 eV and room temperature conductivities of around 10-15 Ω-1cm-1. Upon doping with Ferric Chloride the conductivity of Material C is observed to rise dramatically, peaking at around 15 Ω-1cm-1. In contrast Materials A and B remain insulating on doping. The temperature dependence of the conductivity and thermopower of doped films of Material C suggests that the mechanism of charge transport changes at a critical temperature (Tc). This increased with increasing doping. Above Tc the transport mechanism is thought to be associated with hopping within a band of localised states which are intrinsic to the material. Below Tc it is likely that transport occurs within localised states associated with the presence of doping ions. The second part of the work concerns the study of the electrochromic materials poly[1,4-dithienylbenzene] (D) and poly[1,3-dithienylbenzene] (E). Both materials have been electrochemically polymerised and form coherent films which undergo reversible colour changes on application of a suitable potential. Display elements based on the materials have reached the 'proof of concept' stage. The displays have contrast ratios of around 6 and exhibit lifetimes greatly in excess of 1000 cycles. The degradation of the displays has in some instances been related to the quality of the film surface and this has been investigated using image analysis techniques.

Published
1997

18. Reply to the discussion by Gell and Finlayson (2023)

Author

Bourman, R. P., primary, Murray-Wallace, C. V., additional, Wilson, C., additional, Mosley, L., additional, Tibby, J., additional, Ryan, D. D., additional, De Carli, E. D., additional, Tulley, A., additional, Belperio, A. P., additional, Haynes, D., additional, Roberts, A., additional, Westell, C., additional, Barnett, E. J., additional, Dillenburg, S., additional, Beheregaray, L. B., additional, and Hesp, P. A., additional

Published
2023
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23. Extending attosecond techniques to X-ray free-electron lasers

Author

Haynes, D.

Abstract

X-ray free-electron lasers (XFELs) stand at the forefront of cutting-edge research across almost all disciplines of physical science. In the few years for which they have been available, XFEL pulse durations have become increasingly short, and at the time of writing these machines are beginning to access X-ray pulses with durations in the attosecond range (1 attosecond = 10−18 s). Meanwhile, the burgeoning field of attosecond metrology has undergone contemporaneous and equally rapid progress this century, including in the measurement and control of attosecond dynamics via attosecond streaking spectroscopy. As XFELs cross the attosecond frontier, this thesis presents a technique termed self-referenced attosecond streaking, which unites the unparalleled time resolution of attosecond streaking with the unique and favourable properties of XFELs.The concepts and principles of XFELs are briefly described, with particular focus given to background information relevant to the developments presented here. The thesis also contains an introduction to attosecond streaking spectroscopy, a powerful time-resolved technique that uses laser fields to induce and record a time-dependent modulation of electrons’ momenta. Results of an attosecond streaking investigation of a few-attosecond photoemission delay in neon are presented and discussed. Building upon the core concepts of attosecond streaking, self-referenced streaking is introduced, bringing attosecond precision to XFEL facilities that have traditionally been restricted to femtosecond (1 fs = 10−15 s) time resolution. This is achieved by “self-referencing” the data - that is, by examining a single measurement’s energy-domain properties relative to those of thousands of other measurements and hence deducing its temporal properties. The final chapters discuss the first successful proof-of-principle experiments employing self-referenced attosecond streaking, including demonstrations of its potential for sub-femtosecond time resolution, and a look ahead to what the future may hold for the technique. X-ray Freie-Elektronen Laser (XFELs) stehen an der Spitze der Forschung in fast allen Disziplinen der physikalischen Wissenschaften. In den wenigen Jahren, seit die ersten XFELs den Betrieb aufgenommen haben, konnte die kürzeste erreichbare Photonenpulsdauer immer weiter verringert werden, sodass zum gegenwärtigen Zeitpunkt bereits Röntgenpulse mit einer Dauer im Attosekundenbereich (1 Attosekunde = 10−18 s) möglich sind. In der Zwischenzeit hat das aufkeimende Gebiet der Attosekunden-Metrologie in diesem Jahrhundert ebenso rasche Fortschritte gemacht, unter anderem bei der Messung und Kontrolle der Attosekunden-Dynamik durch Attosekunden-Streaking. Da nun XFELs den für den Bereich der Attosekundenphysik relevant werden, wird in dieser Arbeit eine Technik vorgestellt, die als self-referenced attosecond streaking bezeichnet wird und die die unvergleichliche Auflösung des Attosekunden-Streakings mit den einzigartigen und vorteilhaften Eigenschaften von XFELs vereint.Die Konzepte und Prinzipien von XFELs werden kurz beschrieben, wobei ein besonderer Schwerpunkt auf Hintergrundinformationen gelegt wird, die für die hier vorgestellten Entwicklungen relevant sind. Die Arbeit enthält außerdem eine Einführung zu Attosekunden-Streaking, eine leistungsstarke zeitaufgelöste Technik, die mittels optischer Laserfelder eine zeitabhängige Modulation der Energieverteilung frei fliegender Elektronenpakete bewirkt, wodurch deren zeitliche Struktur in einem Spektrometer messbar wird. Die Ergebnisse einer Studie mittels Attosekunden-Streaking zur Untersuchung einer Photoemissionsverzögerung von wenigen Attosekunden in Neon werden vorgestellt und diskutiert. Aufbauend auf den Kernkonzepten des Attosekunden-Streakings wird das selbstreferenzierte Streaking vorgestellt, das den XFEL-Anlagen, die traditionell auf eine Femtosekunden-Zeitauflösung beschränkt waren (1 Femtosekunde = 10−15 s), eine Attosekunden-Präzision verleiht. Erreicht wird dies durch “Selbstreferenzierung” der Daten, d.h. durch die Untersuchung der Eigenschaften einer einzelnen Messung im Energiebereich im Vergleich zu denen tausender anderer Messungen und die daraus resultierende Ableitung ihrer zeitlichen Eigenschaften. In den letzten Kapiteln werden die ersten erfolgreichen Proof-of-Principle-Experimente mit selbstreferenziertem Attosekunden-Streaking erörtert, einschließlich der Demonstration des Potenzials für zeitliche Auflösung im Sub-Femtosekundenbereich, und es wird ein Ausblick auf die Zukunft dieser Technik gegeben.

Published
2022

25. Holocene freshwater history of the Lower River Murray and its terminal lakes, Alexandrina and Albert, South Australia, and its relevance to contemporary environmental management

Author

Bourman, R. P., primary, Murray-Wallace, C. V., additional, Wilson, C., additional, Mosley, L., additional, Tibby, J., additional, Ryan, D. D., additional, De Carli, E. D., additional, Tulley, A., additional, Belperio, A. P., additional, Haynes, D., additional, Roberts, A., additional, Westell, C., additional, Barnett, E. J., additional, Dillenburg, S., additional, Beheregaray, L. B., additional, and Hesp, P. A., additional

Published
2022
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37. Germline mutation in POLR2A: a heterogeneous, multi-systemic developmental disorder characterized by transcriptional dysregulation.

Author

Hansen, AW, Arora, P, Khayat, MM, Smith, LJ, Lewis, AM, Rossetti, LZ, Jayaseelan, J, Cristian, I, Haynes, D, DiTroia, S, Meeks, N, Delgado, MR, Rosenfeld, JA, Pais, L, White, SM, Meng, Q, Pehlivan, D, Liu, P, Gingras, M-C, Wangler, MF, Muzny, DM, Lupski, JR, Kaplan, CD, Gibbs, RA, Hansen, AW, Arora, P, Khayat, MM, Smith, LJ, Lewis, AM, Rossetti, LZ, Jayaseelan, J, Cristian, I, Haynes, D, DiTroia, S, Meeks, N, Delgado, MR, Rosenfeld, JA, Pais, L, White, SM, Meng, Q, Pehlivan, D, Liu, P, Gingras, M-C, Wangler, MF, Muzny, DM, Lupski, JR, Kaplan, CD, and Gibbs, RA

Abstract

De novo germline variation in POLR2A was recently reported to associate with a neurodevelopmental disorder. We report twelve individuals harboring putatively pathogenic de novo or inherited variants in POLR2A, detail their phenotypes, and map all known variants to the domain structure of POLR2A and crystal structure of RNA polymerase II. Affected individuals were ascertained from a local data lake, pediatric genetics clinic, and an online community of families of affected individuals. These include six affected by de novo missense variants (including one previously reported individual), four clinical laboratory samples affected by missense variation with unknown inheritance-with yeast functional assays further supporting altered function-one affected by a de novo in-frame deletion, and one affected by a C-terminal frameshift variant inherited from a largely asymptomatic mother. Recurrently observed phenotypes include ataxia, joint hypermobility, short stature, skin abnormalities, congenital cardiac abnormalities, immune system abnormalities, hip dysplasia, and short Achilles tendons. We report a significantly higher occurrence of epilepsy (8/12, 66.7%) than previously reported (3/15, 20%) (p value = 0.014196; chi-square test) and a lower occurrence of hypotonia (8/12, 66.7%) than previously reported (14/15, 93.3%) (p value = 0.076309). POLR2A-related developmental disorders likely represent a spectrum of related, multi-systemic developmental disorders, driven by distinct mechanisms, converging at a single locus.

Published
2021

38. Haploinsufficiency of PRR12 causes a spectrum of neurodevelopmental, eye, and multisystem abnormalities

Author

Chowdhury, F, Wang, L, Al-Raqad, M, Amor, DJ, Baxova, A, Bendova, S, Biamino, E, Brusco, A, Caluseriu, O, Cox, NJ, Froukh, T, Gunay-Aygun, M, Hancarova, M, Haynes, D, Heide, S, Hoganson, G, Kaname, T, Keren, B, Kosaki, K, Kubota, K, Lemons, JM, Magrina, MA, Mark, PR, McDonald, MT, Montgomery, S, Morley, GM, Ohnishi, H, Okamoto, N, Rodriguez-Buritica, D, Rump, P, Sedlacek, Z, Schatz, K, Streff, H, Uehara, T, Walia, JS, Wheeler, PG, Wiesener, A, Zweier, C, Kawakami, K, Wentzensen, IM, Lalani, SR, Siu, VM, Bi, W, Balci, TB, Chowdhury, F, Wang, L, Al-Raqad, M, Amor, DJ, Baxova, A, Bendova, S, Biamino, E, Brusco, A, Caluseriu, O, Cox, NJ, Froukh, T, Gunay-Aygun, M, Hancarova, M, Haynes, D, Heide, S, Hoganson, G, Kaname, T, Keren, B, Kosaki, K, Kubota, K, Lemons, JM, Magrina, MA, Mark, PR, McDonald, MT, Montgomery, S, Morley, GM, Ohnishi, H, Okamoto, N, Rodriguez-Buritica, D, Rump, P, Sedlacek, Z, Schatz, K, Streff, H, Uehara, T, Walia, JS, Wheeler, PG, Wiesener, A, Zweier, C, Kawakami, K, Wentzensen, IM, Lalani, SR, Siu, VM, Bi, W, and Balci, TB

Abstract

PURPOSE: Proline Rich 12 (PRR12) is a gene of unknown function with suspected DNA-binding activity, expressed in developing mice and human brains. Predicted loss-of-function variants in this gene are extremely rare, indicating high intolerance of haploinsufficiency. METHODS: Three individuals with intellectual disability and iris anomalies and truncating de novo PRR12 variants were described previously. We add 21 individuals with similar PRR12 variants identified via matchmaking platforms, bringing the total number to 24. RESULTS: We observed 12 frameshift, 6 nonsense, 1 splice-site, and 2 missense variants and one patient with a gross deletion involving PRR12. Three individuals had additional genetic findings, possibly confounding the phenotype. All patients had developmental impairment. Variable structural eye defects were observed in 12/24 individuals (50%) including anophthalmia, microphthalmia, colobomas, optic nerve and iris abnormalities. Additional common features included hypotonia (61%), heart defects (52%), growth failure (54%), and kidney anomalies (35%). PrediXcan analysis showed that phecodes most strongly associated with reduced predicted PRR12 expression were enriched for eye- (7/30) and kidney- (4/30) phenotypes, such as wet macular degeneration and chronic kidney disease. CONCLUSION: These findings support PRR12 haploinsufficiency as a cause for a novel disorder with a wide clinical spectrum marked chiefly by neurodevelopmental and eye abnormalities.

Published
2021

44. Metadata

Author

Haynes, D.

Subjects
Information privacy, business.industry, Information literacy, 05 social sciences, Internet privacy, Intellectual property, 050905 science studies, Metadata, Good governance, Politics, General Earth and Planetary Sciences, Data Protection Act 1998, Social media, Business, 0509 other social sciences, 050904 information & library sciences, Z665, General Environmental Science
Abstract

The use and management of metadata raises many ethical and eventually political issues. The security revelations by Edward Snowden in 2014 demonstrate the key role that metadata plays in surveillance. Privacy has become a particularly hot topic in recent months and much of the debate has centred on the misuse of metadata from social media and the potentially invasive effect this has on individuals. Metadata also has a key role in delivering reliable sources of information, although this has to go hand in hand with user education and improved information literacy. Access to information is a fundamental right and the appropriate use of metadata can help improve access to health, agriculture and education as well as contributing to economic development. Metadata is a route to good governance, but it must also be handled appropriately to maintain information privacy, a fundamental human right.

Published
2017

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