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

Preparing n-of-1 antisense oligonucleotide treatments for rare neurological diseases in Europe: genetic, regulatory, and ethical perspectives

Antisense oligonucleotide (ASO) therapies present a promising disease-modifying treatment approach for rare neurological diseases (RNDs). However, the current focus is on "more common" RNDs, leaving a large share of RND patients still without prospect of disease-modifying treatments. In response to this gap, n-of-1 ASO treatment approaches are targeting ultrarare or even private variants. While highly attractive, this emerging, academia-driven field of ultimately individualized precision medicine is in need of systematic guidance and standards, which will allow global scaling of this approach. We provide here genetic, regulatory, and ethical perspectives for preparing n-of-1 ASO treatments and research programs, with a specific focus on the European context. By example of splice modulating ASOs, we outline genetic criteria for variant prioritization, chart the regulatory field of n-of-1 ASO treatment development in Europe, and propose an ethically informed classification for n-of-1 ASO treatment strategies and level of outcome assessments. To accommodate the ethical requirements of both individual patient benefit and knowledge gain, we propose a stronger integration of patient care and clinical research when developing novel n-of-1 ASO treatments: each single trial of therapy should inherently be driven to generate generalizable knowledge, be registered in a ASO treatment registry, and include assessment of generic outcomes, which allow aggregated analysis across n-of-1 trials of therapy.Genetics of disease, diagnosis and treatmen

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

A Social Sciences and Humanities research agenda for transport and mobility in Europe: key themes and 100 research questions

Transport and mobility systems need to be transformed to meet climate change goals and reduce negative environmental and social effects. Despite EU policies having targeted such problems for more than three decades, transitions have been slow and geographically uneven. For effective change to happen, transport and mobility research needs fresh perspectives and better integration of knowledge from the Social Sciences and Humanities. Based on a Horizon Scanning approach, which allowed for a great deal of openness and variety in scholarly viewpoints, this paper presents a novel research agenda consisting of 8 themes and 100 research questions that may contribute to achieving environmentally sustainable mobility transitions within Europe. This research agenda highlights the need to not only support technological solutions for low-carbon mobility, but the importance of transformative policies that include new processes of knowledge production, civic participation and epistemic justice. We contend that the agenda points to the need for further research on the dynamics of science-society interactions

Behavior in behavioral strategy : capturing, measuring, analyzing

Measuring behavior requires research methods that can capture observed outcomes and expose underlying processes and mechanisms. In this chapter, we present a toolbox of instruments and techniques we designed experimental tasks to simulate decision environments and capture behavior. We deployed protocol analysis and text analysis to examine the underlying cognitive processes. In combination, these can simultaneously grasp antecedents, outcomes, processes, and mechanisms. We applied them to collect rich behavioral data on two key topics in strategic management: the exploration–exploitation trade-off and strategic risk-taking. This mix of methods is particularly useful in describing actual behavior as it is, not as it should be, replacing assumptions with data and offering a finer-grained perspective of strategic decision-making