Germline mutations in mitochondrial complex I reveal genetic and targetable vulnerability in IDH1-mutant acute myeloid leukaemia

The interaction of germline variation and somatic cancer driver mutations is underinvestigated. Here we describe the genomic mitochondrial landscape in adult acute myeloid leukaemia (AML) and show that rare variants affecting the nuclear- and mitochondriallyencoded complex I genes show near-mutual exclusivity with somatic driver mutations affecting isocitrate dehydrogenase 1 (IDH1), but not IDH2 suggesting a unique epistatic relationship. Whereas AML cells with rare complex I variants or mutations in IDH1 or IDH2 all display attenuated mitochondrial respiration, heightened sensitivity to complex I inhibitors including the clinical-grade inhibitor, IACS-010759, is observed only for IDH1-mutant AML. Furthermore, IDH1 mutant blasts that are resistant to the IDH1-mutant inhibitor, ivosidenib, retain sensitivity to complex I inhibition. We propose that the IDH1 mutation limits the flexibility for citrate utilization in the presence of impaired complex I activity to a degree that is not apparent in IDH2 mutant cells, exposing a mutation-specific metabolic vulnerability. This reduced metabolic plasticity explains the epistatic relationship between the germline complex I variants and oncogenic IDH1 mutation underscoring the utility of genomic data in revealing metabolic vulnerabilities with implications for therapy.Mahmoud A. Bassal, Saumya E. Samaraweera, Kelly Lim, Brooks A. Bernard, Sheree Bailey, Satinder Kaur, Paul Leo, John Toubia, Chloe Thompson-Peach, Tran Nguyen, Kyaw Ze Ya Maung, Debora A. Casolari, Diana G. Iarossi, Ilaria S. Pagani, Jason Powell, Stuart Pitson, Siria Natera, Ute Roessner, Ian D. Lewis, Anna L. Brown, Daniel G. Tenen, Nirmal Robinson, David M. Ross, Ravindra Majeti, Thomas J. Gonda, Daniel Thomas, Richard J. D, Andre

Pain relief in labour: a qualitative study to determine how to support women to make decisions about pain relief in labour

Background Engagement in decision making is a key priority of modern healthcare. Women are encouraged to make decisions about pain relief in labour in the ante-natal period based upon their expectations of what labour pain will be like. Many women find this planning difficult. The aim of this qualitative study was to explore how women can be better supported in preparing for, and making, decisions during pregnancy and labour regarding pain management. Methods Semi-structured interviews were conducted with 13 primiparous and 10 multiparous women at 36 weeks of pregnancy and again within six weeks postnatally. Data collection and analysis occurred concurrently to identify key themes. Results Three main themes emerged from the data. Firstly, during pregnancy women expressed a degree of uncertainty about the level of pain they would experience in labour and the effect of different methods of pain relief. Secondly, women reflected on how decisions had been made regarding pain management in labour and the degree to which they had felt comfortable making these decisions. Finally, women discussed their perceived levels of control, both desired and experienced, over both their bodies and the decisions they were making. Conclusion This study suggests that the current approach of antenatal preparation in the NHS, of asking women to make decisions antenatally for pain relief in labour, needs reviewing. It would be more beneficial to concentrate efforts on better informing women and on engaging them in discussions around their values, expectations and preferences and how these affect each specific choice rather than expecting them to make to make firm decisions in advance of such an unpredictable event as labour

Velocity-space sensitivity of the time-of-flight neutron spectrometer at JET

The velocity-space sensitivities of fast-ion diagnostics are often described by so-called weight functions. Recently, we formulated weight functions showing the velocity-space sensitivity of the often dominant beam-target part of neutron energy spectra. These weight functions for neutron emission spectrometry (NES) are independent of the particular NES diagnostic. Here we apply these NES weight functions to the time-of-flight spectrometer TOFOR at JET. By taking the instrumental response function of TOFOR into account, we calculate time-of-flight NES weight functions that enable us to directly determine the velocity-space sensitivity of a given part of a measured time-of-flight spectrum from TOFOR

Relationship of edge localized mode burst times with divertor flux loop signal phase in JET

A phase relationship is identified between sequential edge localized modes (ELMs) occurrence times in a set of H-mode tokamak plasmas to the voltage measured in full flux azimuthal loops in the divertor region. We focus on plasmas in the Joint European Torus where a steady H-mode is sustained over several seconds, during which ELMs are observed in the Be II emission at the divertor. The ELMs analysed arise from intrinsic ELMing, in that there is no deliberate intent to control the ELMing process by external means. We use ELM timings derived from the Be II signal to perform direct time domain analysis of the full flux loop VLD2 and VLD3 signals, which provide a high cadence global measurement proportional to the voltage induced by changes in poloidal magnetic flux. Specifically, we examine how the time interval between pairs of successive ELMs is linked to the time-evolving phase of the full flux loop signals. Each ELM produces a clear early pulse in the full flux loop signals, whose peak time is used to condition our analysis. The arrival time of the following ELM, relative to this pulse, is found to fall into one of two categories: (i) prompt ELMs, which are directly paced by the initial response seen in the flux loop signals; and (ii) all other ELMs, which occur after the initial response of the full flux loop signals has decayed in amplitude. The times at which ELMs in category (ii) occur, relative to the first ELM of the pair, are clustered at times when the instantaneous phase of the full flux loop signal is close to its value at the time of the first ELM

Marriage and Social Boundaries among British Pakistanis

A cosmopolitan environment offers challenges for cultural groups that seek to reproduce themselves in the next generation. British Pakistanis have not seen the kind of breakdown in marriage boundaries that characterizes other post-war migrants to Britain. The article examines how this pattern is linked to commitments to transnational marriage, which promise a source of future remittances to Pakistan. However, the need to maintain these links has exaggerated the importance of religious and moral display for British Pakistanis, and these have wider effects in the policing of social contact with outsiders and the negative portrayal of the sexual morality of non-Pakistanis