Investigating the 8.2 ka event in northwestern Madagascar: Insight from data–model comparisons

The 8.2 ka event is a well-known cooling event in the Northern Hemisphere, but is poorly understood in Madagascar. Here, we compare paleoclimate data and outputs from paleoclimate simulations to better understand it. Records from Madagascar suggest two distinct sub-events (8.3 ka and 8.2 ka), that seem to correlate with records from northern high latitude. This could indicate causal relationships via changes in the Atlantic Meridional Overturning Circulation (AMOC) with changes in moisture source's δ18O, and changes in the mean position of the Inter-Tropical Convergence Zone (ITCZ), as climate modelling suggests. These two sub-events are also apparent in other terrestrial records, but the climatic signals are different. The prominent 8.2 ka sub-event records a clear antiphase relationship between the northern and southern hemisphere monsoons, whereas such relationship is less evident during the first 8.3 ka sub-event. Data–model comparison have also shown a mismatch between the paleoclimate data and the model outputs, the causes of which are more or less understood and may lie in the proxies, in the model, or in both data and model. Knowing that paleoclimate proxies and climate models produce different sets of variables, further research is needed to improve the data–model comparison approach, so that both paleoclimate data and paleoclimate models will better predict the likely climate status of a region during a specified time in the past with minimal uncertainties

Deregulated splicing is a major mechanism of RNA-induced toxicity in Huntington's disease

Huntington's disease (HD) is caused by an expanded CAG repeat in the huntingtin (HTT) gene, translating into an elongated polyglutamine stretch. In addition to the neurotoxic mutant HTT protein, the mutant CAG repeat RNA can exert toxic functions by trapping RNA-binding proteins. While few examples of proteins that aberrantly bind to mutant HTT RNA and execute abnormal function in conjunction with the CAG repeat RNA have been described, an unbiased approach to identify the interactome of mutant HTT RNA is missing. Here, we describe the analysis of proteins that preferentially bind mutant HTT RNA using a mass spectrometry approach. We show that (I) the majority of proteins captured by mutant HTT RNA belong to the spliceosome pathway, (II) expression of mutant CAG repeat RNA induces mis-splicing in a HD cell model, (III) overexpression of one of the splice factors trapped by mutant HTT ameliorates the HD phenotype in a fly model and (VI) deregulated splicing occurs in human HD brain. Our data suggest that deregulated splicing is a prominent mechanism of RNA-induced toxicity in HD

A phase I dose escalation study of BIBW 2992, an irreversible dual inhibitor of epidermal growth factor receptor 1 (EGFR) and 2 (HER2) tyrosine kinase in a 2-week on, 2-week off schedule in patients with advanced solid tumours

To assess tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and clinical activity of the dual epidermal growth factor receptor (EGFR) 1 and 2 (HER2) tyrosine kinase inhibitor BIBW 2992. An escalating schedule of once-daily (OD) BIBW 2992 for 14 days followed by 14 days off medication was explored. Thirty-eight patients were enrolled. Dose levels were 10, 20, 30, 45, 70, 85, and 100 mg. At 100 mg dose-limiting toxicity (DLT) (common toxicity criteria grade 3 skin rash and grade 3 diarrhoea despite treatment with loperamide) occurred in two patients. In the next-lower dose of 70 mg, DLT (grade 3 fatigue and ALAT elevation) occurred in one of six patients. An intermediate dose level of 85 mg was studied. Here DLT occurred in two patients (grade 3 diarrhoea despite treatment and grade 2 diarrhoea lasting more than 7 days despite treatment). An additional 12 patients were treated at 70 mg. BIBW 2992 PK after single and multiple doses revealed moderately fast absorption, and no deviation from dose proportionality. Pharmacodynamics analysis in skin biopsies did not show significant changes in EGFR-associated biomarkers. However, a significant inhibitory effect on the proliferation index of epidermal keratinocytes was observed. No partial or complete responses were observed, stable disease lasting more than four cycles was seen in seven patients. The recommended dose for studies with BIBW 2992 for 14 days followed by 14 days off medication is 70 mg OD

User-made immobilities: a transitions perspective

In this paper we aim to conceptualize the role of users in creating, expanding and stabilizing the automobility system. Drawing on transition studies we offer a typology of user roles including user-producers, user-legitimators, user-intermediaries, user-citizens and user-consumers, and explore it on the historical transition to the automobile regime in the USA. We find that users play an important role during the entire transition process, but some roles are more salient than others in particular phases. Another finding is that the success of the transition depends on the stabilization of the emerging regime that will trigger upscaling in terms of the numbers of adopters. The findings are used to reflect on potential crossovers between transitions and mobilities research

Huntingtin gene repeat size variations affect risk of lifetime depression

Huntington disease (HD) is a severe neuropsychiatric disorder caused by a cytosine-adenine-guanine (CAG) repeat expansion in the HTT gene. Although HD is frequently complicated by depression, it is still unknown to what extent common HTT CAG repeat size variations in the normal range could affect depression risk in the general population. Using binary logistic regression, we assessed the association between HTT CAG repeat size and depression risk in two well-characterized Dutch cohorts─the Netherlands Study of Depression and Anxiety and the Netherlands Study of Depression in Older Persons─including 2165 depressed and 1058 non-depressed persons. In both cohorts, separately as well as combined, there was a significant non-linear association between the risk of lifetime depression and HTT CAG repeat size in which both relatively short and relatively large alleles were associated with an increased risk of depression (β = −0.292 and β = 0.006 for the linear and the quadratic term, respectively; both P < 0.01 after adjustment for the effects of sex, age, and education level). The odds of lifetime depression were lowest in persons with a HTT CAG repeat size of 21 (odds ratio: 0.71, 95% confidence interval: 0.52 to 0.98) compared to the average odds in the total cohort. In conclusion, lifetime depression risk was higher with both relatively short and relatively large HTT CAG repeat sizes in the normal range. Our study provides important proof-of-principle that repeat polymorphisms can act as hitherto unappreciated but complex genetic modifiers of depression

Combined scanning probe microscopy and x-ray scattering instrument for in situ catalysis investigations

Catalysis and Surface Chemistr

Operando Structure Activity Stability Relationship of Iridium Oxides during the Oxygen Evolution Reaction

Creating active and stable electrodes is an essential step toward efficient and durable electrolyzers. To achieve this goal, understanding what aspects of the electrode structure dictate activity and catalyst dissolution is key. Here, we investigate these aspects by studying trends in the activity, stability, and operando structure of iridium oxides during the oxygen evolution reaction. Using operando X-ray photoelectron and X-ray absorption spectroscopy, we determined the near-surface structure of oxides ranging from amorphous to crystalline during the reaction. We show that applying oxygen evolution potentials universally yields deprotonated μ2-O moieties and a μ1-O/μ1-OH mixture, with universal deprotonation energetics but in different amounts. This quantitative difference mainly results from variations in deprotonation depth: surface deprotonation for crystalline IrO2 versus near-surface deprotonation for semicrystalline and amorphous IrOx. We argue that both surface deprotonation and subsurface deprotonation modify the barrier for the oxygen evolution and Ir dissolution reactions, thus playing an important role in catalyst performance

Understanding the positioning of 'the electric vehicle consumer':variations in interdisciplinary discourses and their implications for sustainable mobility systems

The discursive category of ‘the consumer’ has multiple characterisations, connected to varied accounts of social action, relations and change. This paper is interested in the implications of these varied characterisations for understanding the interdisciplinary knowledge about mobility systems being marshalled in the pursuit of social change. It focuses upon the case of electric vehicles (EVs), examining the varied representations of consumers in three fields – psychological and economic, consumer culture, and transitions management research. It identifies that the EV consumer is positioned within these fields as a purchaser of an inferior ‘car’, a user of multiple materialities, and as one among many important social actors. In order to further consider the implications of these strategically contrasting cases, it considers two questions about how ‘the EV consumer’ is discursively positioned in each: How does this imagined consumer shape what the EV needs to be in order to be widely adopted? What action is required to steer change towards a future of EVs? Doing so highlights how assumptions about ‘the EV consumer’ can establish problematic comparisons between EVs and internal combustion vehicles (ICVs) and exclude the analysis of how EVs and electricity are simultaneously consumed. The usage of ‘the consumer’ as a floating signifier within transitions management literature is argued to provide both risks for interdisciplinary dialogue and potential opportunities for both EV research and steering change towards sustainable mobility systems