UCL University College London Eprints
UCL Eprints collects the work of UCL researchers and makes it freely available over the web, helping the worldwide scholarly community to discover UCL research. Institutional repositories like UCL Eprints complement the traditional academic publishing and scholarly communications processes. They raise the visibility of research and help to maximise its impact. UCL researchers are encouraged to deposit a copy of each journal article, conference paper, working paper, and any other research output, in the UCL Eprints at the earliest opportunity, ensuring that their research reaches as wide an audience as possible.
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Evolutionarily conserved mechanisms for the selection and maintenance of behavioural activity - Fiore, VG; Dolan, RJ; Strausfeld, NJ; Hirth, F
Survival and reproduction entail the selection of adaptive behavioural repertoires. This selection manifests as phylogenetically acquired activities that depend on evolved nervous system circuitries. Lorenz and Tinbergen already postulated that heritable behaviours and their reliable performance are specified by genetically determined programs. Here we compare the functional anatomy of the insect central complex and vertebrate basal ganglia to illustrate their role in mediating selection and maintenance of adaptive behaviours. Comparative analyses reveal that central complex and basal ganglia circuitries share comparable lineage relationships within clusters of functionally integrated neurons. These clusters are specified by genetic mechanisms that link birth time...
Drug Susceptibility Patterns in MDR-TB Patients: Challenges for Future Regimen Design. A Cross-Sectional Study - Stagg, HR; Brown, J; Ibraim, E; Riekstiņa, V; Viiklepp, P; Cīrule, A; Cocei, H; Danilovitš, M; Dravniece, G; Jackson, C; White, PJ
Globally, there is substantial concern regarding the challenges of treating complex drug resistance patterns in multidrug resistant tuberculosis cases. Utilising data from three different settings (Estonia, Latvia, Romania) we sought to contrast drug susceptibility profiles for multidrug resistant tuberculosis cases, highlight the difficulties in designing universal regimen, and inform future regimen selection. Demographic and microbiological surveillance data for multidrug resistant tuberculosis cases from 2004-13 were analysed. High levels of additional resistance to currently recommended second line drugs were seen in all settings, with extensive variability between countries. Accurate drug susceptibility testing and drug susceptibility testing data are vital to inform...
Mutant Huntingtin Does Not Affect the Intrinsic Phenotype of Human Huntington's Disease T Lymphocytes - Miller, JR; Träger, U; Andre, R; Tabrizi, SJ
Huntington's disease is a fatal neurodegenerative condition caused by a CAG repeat expansion in the huntingtin gene. The peripheral innate immune system is dysregulated in Huntington's disease and may contribute to its pathogenesis. However, it is not clear whether or to what extent the adaptive immune system is also involved. Here, we carry out the first comprehensive investigation of human ex vivo T lymphocytes in Huntington's disease, focusing on the frequency of a range of T lymphocyte subsets, as well as analysis of proliferation, cytokine production and gene transcription. In contrast to the innate immune system, the intrinsic phenotype of...
Peer Support Workers in Health: A Qualitative Metasynthesis of Their Experiences - MacLellan, J; Surey, J; Abubakar, I; Stagg, HR
OBJECTIVE: Peer support models, where an individual has a specific illness or lifestyle experience and supports others experiencing similar challenges, have frequently been used in different fields of healthcare to successfully engage hard-to-reach groups. Despite recognition of their value, the impact of these roles on the peer has not been systematically assessed. By synthesising the qualitative literature we sought to review such an impact, providing a foundation for designing future clinical peer models. METHODS: Systematic review and qualitative metasynthesis of studies found in Medline, CINAHL or Scopus documenting peer worker experiences. RESULTS: 1,528 papers were found, with 34 meeting the...
Towards a Molecular Understanding of the Link between Imatinib Resistance and Kinase Conformational Dynamics - Lovera, S; Morando, M; Pucheta-Martinez, E; Martinez-Torrecuadrada, JL; Saladino, G; Gervasio, FL
Due to its inhibition of the Abl kinase domain in the BCR-ABL fusion protein, imatinib is strikingly effective in the initial stage of chronic myeloid leukemia with more than 90% of the patients showing complete remission. However, as in the case of most targeted anti-cancer therapies, the emergence of drug resistance is a serious concern. Several drug-resistant mutations affecting the catalytic domain of Abl and other tyrosine kinases are now known. But, despite their importance and the adverse effect that they have on the prognosis of the cancer patients harboring them, the molecular mechanism of these mutations is still debated....
Flow-Based Single Cell Deposition for High-Throughput Screening of Protein Libraries - Stowe, C; Pizzey, A; Kalber, T; Badar, A; Lythgoe, M; Pule, M
The identification and engineering of proteins having refined or novel characteristics is an important area of research in many scientific fields. Protein modelling has enabled the rational design of unique proteins, but high-throughput screening of large libraries is still required to identify proteins with potentially valuable properties. Here we report on the development and evaluation of a novel fluorescent activated cell sorting based screening platform. Single bacterial cells, expressing a protein library to be screened, are electronically sorted and deposited onto plates containing solid nutrient growth media in a dense matrix format of between 44 and 195 colonies/cm2. We show...
Proactive and Reactive Response Inhibition across the Lifespan - Smittenaar, P; Rutledge, RB; Zeidman, P; Adams, RA; Brown, H; Lewis, G; Dolan, RJ
One expression of executive control involves proactive preparation for future events, and this contrasts with stimulus driven reactive control exerted in response to events. Here we describe findings from a response inhibition task, delivered using a smartphone-based platform, that allowed us to index proactive and reactive inhibitory self-control in a large community sample (n = 12,496). Change in stop-signal reaction time (SSRT) when participants are provided with advance information about an upcoming trial, compared to when they are not, provides a measure of proactive control while SSRT in the absence of advance information provides a measure of reactive control. Both...
Fission Yeast CSL Transcription Factors: Mapping Their Target Genes and Biological Roles - Převorovský, M; Oravcová, M; Tvarůžková, J; Zach, R; Folk, P; Půta, F; Bähler, J
BACKGROUND: Cbf11 and Cbf12, the fission yeast CSL transcription factors, have been implicated in the regulation of cell-cycle progression, but no specific roles have been described and their target genes have been only partially mapped. METHODOLOGY/PRINCIPAL FINDINGS: Using a combination of transcriptome profiling under various conditions and genome-wide analysis of CSL-DNA interactions, we identify genes regulated directly and indirectly by CSL proteins in fission yeast. We show that the expression of stress-response genes and genes that are expressed periodically during the cell cycle is deregulated upon genetic manipulation of cbf11 and/or cbf12. Accordingly, the coordination of mitosis and cytokinesis is...
The clinical and genetic heterogeneity of paroxysmal dyskinesias - Gardiner, AR; Jaffer, F; Dale, RC; Labrum, R; Erro, R; Meyer, E; Xiromerisiou, G; Stamelou, M; Walker, M; Kullmann, D; Warner, T; Jarman, P; Hanna, M; Kurian, MA; Bhatia, KP; Houlden, H
Paroxysmal dyskinesia can be subdivided into three clinical syndromes: paroxysmal kinesigenic dyskinesia or choreoathetosis, paroxysmal exercise-induced dyskinesia, and paroxysmal non-kinesigenic dyskinesia. Each subtype is associated with the known causative genes PRRT2, SLC2A1 and PNKD, respectively. Although separate screening studies have been carried out on each of the paroxysmal dyskinesia genes, to date there has been no large study across all genes in these disorders and little is known about the pathogenic mechanisms. We analysed all three genes (the whole coding regions of SLC2A1 and PRRT2 and exons one and two of PNKD) in a series of 145 families with paroxysmal...
Epidemiology of Mycoplasma genitalium in British men and women aged 16-44 years: evidence from the third National Survey of Sexual Attitudes and Lifestyles (Natsal-3) - Sonnenberg, P; Ison, CA; Clifton, S; Field, N; Tanton, C; Soldan, K; Beddows, S; Alexander, S; Khanom, R; Saunders, P; Copas, AJ; Wellings, K; Mercer, CH; Johnson, AM
BACKGROUND: There are currently no large general population epidemiological studies of Mycoplasma genitalium (MG), which include prevalence, risk factors, symptoms and co-infection in men and women across a broad age range. METHODS: In 2010--12, we conducted the third National Survey of Sexual Attitudes and Lifestyles (Natsal-3), a probability sample survey in Britain. Urine from 4507 sexually-experienced participants, aged 16-44 years, was tested for MG. RESULTS: MG prevalence was 1.2% [95% confidence interval (CI): 0.7-1.8%] in men and 1.3% (0.9-1.9%) in women. There were no positive MG tests in men aged 16-19, and prevalence peaked at 2.1% (1.2-3.7%) in men aged...
Neuropilins 1 and 2 mediate neointimal hyperplasia and re-endothelialization following arterial injury - Pellet-Many, C; Mehta, V; Fields, L; Mahmoud, M; Lowe, V; Evans, I; Ruivo, J; Zachary, I
AIMS: Neuropilins 1 and 2 (NRP1 and NRP2) play crucial roles in endothelial cell migration contributing to angiogenesis and vascular development. Both NRPs are also expressed by cultured vascular smooth muscle cells (VSMCs) and are implicated in VSMC migration stimulated by PDGF-BB, but it is unknown whether NRPs are relevant for VSMC function in vivo. We investigated the role of NRPs in the rat carotid balloon injury model, in which endothelial denudation and arterial stretch induce neointimal hyperplasia involving VSMC migration and proliferation. METHODS AND RESULTS: NRP1 and NRP2 mRNAs and proteins increased significantly following arterial injury, and immunofluorescent staining...
Inhibition of NAADP signalling on reperfusion protects the heart by preventing lethal calcium oscillations via two-pore channel 1 and opening of the mitochondrial permeability transition pore - Davidson, SM; Foote, K; Kunuthur, S; Gosain, R; Tan, N; Tyser, R; Zhao, YJ; Graeff, R; Ganesan, A; Duchen, MR; Patel, S; Yellon, DM
AIMS: In the heart, a period of ischaemia followed by reperfusion evokes powerful cytosolic Ca(2+) oscillations that can cause lethal cell injury. These signals represent attractive cardioprotective targets, but the underlying mechanisms of genesis are ill-defined. Here, we investigated the role of the second messenger nicotinic acid adenine dinucleotide phosphate (NAADP), which is known in several cell types to induce Ca(2+) oscillations that initiate from acidic stores such as lysosomes, likely via two-pore channels (TPCs, TPC1 and 2). METHODS AND RESULTS: An NAADP antagonist called Ned-K was developed by rational design based on a previously existing scaffold. Ned-K suppressed Ca(2+)...
A systematic screening to identify de novo mutations causing sporadic early-onset Parkinson's disease - Kun-Rodrigues, C; Ganos, C; Guerreiro, R; Schneider, SA; Schulte, C; Lesage, S; Darwent, L; Holmans, P; Singleton, A; International Parkinson's Disease Genomics Consortium (IPDGC),; Bhatia, K; Bras, J
Despite the many advances in our understanding of the genetic basis of Mendelian forms of Parkinson's disease (PD), a large number of early-onset cases still remain to be explained. Many of these cases, present with a form of disease that is identical to that underlined by genetic causes, but do not have mutations in any of the currently known disease-causing genes. Here, we hypothesized that de novo mutations may account for a proportion of these early-onset, sporadic cases. We performed exome sequencing in full parent-child trios where the proband presents with typical PD to unequivocally identify de novo mutations. This...
Pain and temperature processing in dementia: a clinical and neuroanatomical analysis - Fletcher, PD; Downey, LE; Golden, HL; Clark, CN; Slattery, CF; Paterson, RW; Rohrer, JD; Schott, JM; Rossor, MN; Warren, JD
Symptoms suggesting altered processing of pain and temperature have been described in dementia diseases and may contribute importantly to clinical phenotypes, particularly in the frontotemporal lobar degeneration spectrum, but the basis for these symptoms has not been characterized in detail. Here we analysed pain and temperature symptoms using a semi-structured caregiver questionnaire recording altered behavioural responsiveness to pain or temperature for a cohort of patients with frontotemporal lobar degeneration (n = 58, 25 female, aged 52-84 years, representing the major clinical syndromes and representative pathogenic mutations in the C9orf72 and MAPT genes) and a comparison cohort of patients with amnestic...
Utopian urbanism and representational city-ness: On the Dholera before Dholera smart city - Jazeel, T
This commentary responds to Ayona Datta’s critique of India’s smart city agenda by emphasizing the representational work that urban futures require. In the context of Dholera smart city, I draw attention to the discursive terrains – around city-ness and utopianism in particular – mobilized by the state in order to normalize the inevitability of exclusionary urban planning and imaginations. I suggest these representational fields are key battlegrounds for critical urban geography.
Dynamic risk control by human nucleus accumbens - Nachev, P; Lopez-Sosa, F; Gonzalez-Rosa, JJ; Galarza, A; Avecillas, J; Pineda-Pardo, JA; Lopez-Ibor, JJ; Reneses, B; Barcia, JA; Strange, B
Real-world decisions about reward often involve a complex counterbalance of risk and value. Although the nucleus accumbens has been implicated in the underlying neural substrate, its criticality to human behaviour remains an open question, best addressed with interventional methodology that probes the behavioural consequences of focal neural modulation. Combining a psychometric index of risky decision-making with transient electrical modulation of the nucleus accumbens, here we reveal profound, highly dynamic alteration of the relation between probability of reward and choice during therapeutic deep brain stimulation in four patients with treatment-resistant psychiatric disease. Short-lived phasic electrical stimulation of the region of the...
Social redistribution of pain and money - Story, GW; Vlaev, I; Metcalfe, RD; Crockett, MJ; Kurth-Nelson, Z; Darzi, A; Dolan, RJ
People show empathic responses to others' pain, yet how they choose to apportion pain between themselves and others is not well understood. To address this question, we observed choices to reapportion social allocations of painful stimuli and, for comparison, also elicited equivalent choices with money. On average people sought to equalize allocations of both pain and money, in a manner which indicated that inequality carried an increasing marginal cost. Preferences for pain were more altruistic than for money, with several participants assigning more than half the pain to themselves. Our data indicate that, given concern for others, the fundamental principle...
Cooperation is related to dispersal patterns in Sino-Tibetan populations - Wu, JJ; Ji, T; He, QQ; Du, J; Mace, R
There is growing recognition in both evolutionary biology and anthropology that dispersal is key to establishing patterns of cooperation. However, some models predict that cooperation is more likely to evolve in low dispersal (viscous) populations, while others predict that local competition for resources inhibits cooperation. Sex-biased dispersal and extra-pair mating may also have an effect. Using economic games in Sino-Tibetan populations with strikingly different dispersal patterns, we measure cooperation in 36 villages in southwestern China; we test whether social structure is associated with cooperative behaviour toward those in the neighbourhood. We find that social organization is associated with levels of...
An orphan gene is necessary for preaxial digit formation during salamander limb development - Kumar, A; Gates, PB; Czarkwiani, A; Brockes, JP
Limb development in salamanders differs from other tetrapods in that the first digits to form are the two most anterior (preaxial dominance). This has been proposed as a salamander novelty and its mechanistic basis is unknown. Salamanders are the only adult tetrapods able to regenerate the limb, and the contribution of preaxial dominance to limb regeneration is unclear. Here we show that during early outgrowth of the limb bud, a small cohort of cells express the orphan gene Prod1 together with Bmp2, a critical player in digit condensation in amniotes. Disruption of Prod1 with a gene-editing nuclease abrogates these cells,...