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In the phase 3 Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients (ENESTnd) study, nilotinib resulted in earlier and higher response rates and a lower risk of progression to accelerated phase/blast crisis (AP/BC) than imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). Here, patients’ long-term outcomes in ENESTnd are evaluated after a minimum follow-up of 5 years. By 5 years, more than half of all patients in each nilotinib arm (300 mg twice daily, 54%; 400 mg twice daily, 52%) achieved a molecular response 4.5 (MR 4.5 ; BCR-ABL ⩽0.0032% on the International Scale) compared with 31% of patients in the imatinib arm. A benefit of nilotinib was observed across all Sokal risk groups. Overall, safety results remained consistent with those from previous reports. Numerically more cardiovascular events (CVEs) occurred in patients receiving nilotinib vs imatinib, and elevations in blood cholesterol and glucose levels were also more frequent with nilotinib. In contrast to the high mortality rate associated with CML progression, few deaths in any arm were associated with CVEs, infections or pulmonary diseases. These long-term results support the positive benefit-risk profile of frontline nilotinib 300 mg twice daily in patients with CML-CP.

The role of Fat Mass and Obesity-associated protein （FTO） and its substrate N6-methyladenosine （m6A） in mRNA processing and adipogenesis remains largely unknown. We show that FTO expression and m6A levels are inversely correlated during adipogenesis. FTO depletion blocks differentiation and only catalytically active FTO restores adi- pogenesis. Transcriptome analyses in combination with m6A-seq revealed that gene expression and mRNA splicing of grouped genes are regulated by FTO. M6A is enriched in exonic regions flanking 5＇- and 3＇-splice sites, spatially over- lapping with mRNA splicing regulatory serine/arginine-rich （SR） protein exonic splicing enhancer binding regions. Enhanced levels of m6A in response to FTO depletion promotes the RNA binding ability of SRSF2 protein, leading to increased inclusion of target exons. FTO controls exonic splicing of adipogenie regulatory factor RUNX1T1 by regulating m6A levels around splice sites and thereby modulates differentiation. These findings provide compelling evidence that FTO-dependent m6A demethylation functions as a novel regulatory mechanism of RNA processing and plays a critical role in the regulation of adipogenesis.

Although the efficacy of racemate ketamine, a rapid onset and sustained antidepressant, for patients with treatment-resistant depression was a serendipitous finding, clinical use of ketamine is limited, due to psychotomimetic side effects and abuse liability. Behavioral and side-effect evaluation tests were applied to compare the two stereoisomers of ketamine. To elucidate their potential therapeutic mechanisms, we examined the effects of these stereoisomers on brain-derived neurotrophic factor (BDNF)–TrkB signaling, and synaptogenesis in selected brain regions. In the social defeat stress and learned helplessness models of depression, R -ketamine showed a greater potency and longer-lasting antidepressant effect than S -ketamine (esketamine). Furthermore, R -ketamine induced a more potent beneficial effect on decreased dendritic spine density, BDNF–TrkB signaling and synaptogenesis in the prefrontal cortex (PFC), CA3 and dentate gyrus (DG) of the hippocampus from depressed mice compared with S -ketamine. However, neither stereoisomer affected these alterations in the nucleus accumbens of depressed mice. In behavioral tests for side effects, S -ketamine, but not R -ketamine, precipitated behavioral abnormalities, such as hyperlocomotion, prepulse inhibition deficits and rewarding effects. In addition, a single dose of S -ketamine, but not R -ketamine, caused a loss of parvalbumin (PV)-positive cells in the prelimbic region of the medial PFC and DG. These findings suggest that, unlike S -ketamine, R -ketamine can elicit a sustained antidepressant effect, mediated by increased BDNF–TrkB signaling and synaptogenesis in the PFC, DG and CA3. R -ketamine appears to be a potent, long-lasting and safe antidepressant, relative to S -ketamine, as R -ketamine appears to be free of psychotomimetic side effects and abuse liability.

Background/Objectives: Insects have been the subject of recent attention as a potentially environmentally sustainable and nutritious alternative to traditional protein sources. The purpose of this paper is to test the hypothesis that insects are nutritionally preferable to meat, using two evaluative tools that are designed to combat over- and under-nutrition. Subjects/Methods: We selected 183 datalines of publicly available data on the nutrient composition of raw cuts and offal of three commonly consumed meats (beef, pork and chicken), and six commercially available insect species, for energy and 12 relevant nutrients. We applied two nutrient profiling tools to this data: The Ofcom model, which is used in the United Kingdom, and the Nutrient Value Score (NVS), which has been used in East Africa. We compared the median nutrient profile scores of different insect species and meat types using non-parametric tests and applied Bonferroni adjustments to assess for statistical significance in differences. Results: Insect nutritional composition showed high diversity between species. According to the Ofcom model, no insects were significantly ‘healthier’ than meat products. The NVS assigned crickets, palm weevil larvae and mealworm a significantly healthier score than beef ( P <0.001) and chicken ( P <0.001). No insects were statistically less healthy than meat. Conclusions: Insect nutritional composition is highly diverse in comparison with commonly consumed meats. The food category ‘insects’ contains some foods that could potentially exacerbate diet-related public health problems related to over-nutrition, but may be effective in combating under-nutrition.

Subcortical structures, which include the basal ganglia and parts of the limbic system, have key roles in learning, motor control and emotion, but also contribute to higher-order executive functions. Prior studies have reported volumetric alterations in subcortical regions in schizophrenia. Reported results have sometimes been heterogeneous, and few large-scale investigations have been conducted. Moreover, few large-scale studies have assessed asymmetries of subcortical volumes in schizophrenia. Here, as a work completely independent of a study performed by the ENIGMA consortium, we conducted a large-scale multisite study of subcortical volumetric differences between patients with schizophrenia and controls. We also explored the laterality of subcortical regions to identify characteristic similarities and differences between them. T1-weighted images from 1680 healthy individuals and 884 patients with schizophrenia, obtained with 15 imaging protocols at 11 sites, were processed with FreeSurfer. Group differences were calculated for each protocol and meta-analyzed. Compared with controls, patients with schizophrenia demonstrated smaller bilateral hippocampus, amygdala, thalamus and accumbens volumes as well as intracranial volume, but larger bilateral caudate, putamen, pallidum and lateral ventricle volumes. We replicated the rank order of effect sizes for subcortical volumetric changes in schizophrenia reported by the ENIGMA consortium. Further, we revealed leftward asymmetry for thalamus, lateral ventricle, caudate and putamen volumes, and rightward asymmetry for amygdala and hippocampal volumes in both controls and patients with schizophrenia. Also, we demonstrated a schizophrenia-specific leftward asymmetry for pallidum volume. These findings suggest the possibility of aberrant laterality in neural pathways and connectivity patterns related to the pallidum in schizophrenia.

Cet article propose deux arguments principaux. D’abord, que la théorie égalitariste de la justice en éducation non-seulement englobe, mais supporte la théorie suffisantiste, et donc que le débat égalitarisme/suffisantisme — du moins celui qui a cours entre Brighouse et Swift d’une part et Anderson et Satz d’autre part — n’a pas lieu d’être. Ensuite, que l’application qu’opèrent Brighouse et Swift de leur propre théorie est excessive — quant aux choix parentaux et quant à ce qu’ils considèrent comme étant des comportements partiaux illégitimes. This article makes two main arguments. First, egalitarianism in education allows for the suffisantist perspective, which means that the egalitarianism vs. sufficiency debate—at least the one between Brighouse and Swift on the one hand, and Anderson and Satz on the other——is, for the most part, irrelevant. Second, Brighouse and Swift’s application of their own theory is excessive in regard to the type of choices they consider to be partial and thus illegitimate for parents to make.

Dans une constellation de textes entourant Spectres de Marx, Derrida procède à un geste qui semble contraire à la «déconstruction» et qui paraît s’apparenter plutôt à la méthode phénoménologique. En érigeant la messianicité au statut de structure universelle indéconstructible, ces textes donnent lieu en effet à une radicalisation et une transcendantalisation de la temporalité propre aux messianismes historiques. Cet article entend d’abord mettre en évidence le caractère phénoménologique de cette approche et ensuite en questionner la légitimité et le sens à la lumière de textes ultérieurs, où Derrida analyse le rapport entre médias et christianisme. In a series of texts surrounding Specters of Marx, Derrida makes a gesture that seems in contradiction with “deconstruction” and that is apparently closer to a classical phenomenological method. By giving messianicity the status of an irreducible universal structure, these texts give rise to a radicalization and transcendentalization of the temporality of historical messianisms. This article, first, highlights the phenomenological character of this approach and, second, questions its legitimacy in the light of subsequent texts, in which Derrida analyzes the relationship between media and Christianity.

Nous effectuons dans cet article un survol des dangers liés à certaines représentations des phénomènes épigénétiques lors de la formulation de recommandations sociales et médicales. Après avoir exploré les représentations de l’épigénétique dans différents ouvrages de vulgarisation et discours médiatiques, nous critiquons certaines des conclusions susceptibles d’émerger de tels discours qui peuvent paraître prématurées. Nous insistons en particulier sur les enjeux relevant de la responsabilité parentale —notamment celle des femmes — quant à la transmission de marqueurs épigénétiques. Enfin, nous proposons quelques considérations épistémologiques concernant la biologie du développement qui viennent nuancer la portée des discours concernant une éventuelle responsabilité épigénétique. Une telle clarification est susceptible, selon nous, de lever plusieurs difficultés relatives à la compréhension des recherches en épigénétique ainsi qu’à leur application éventuelle hors du champ scientifique. This article offers an overview of the risks related to some representations of epigenetics in the process of making social and medical recommendations. After exploring different representations of epigenetics in popular literature and media discourses, I identify some of the premature conclusions that could emerge from such discourses, stressing issues related to parental responsibility—especially as they relate to women—regarding the transmission of epigenetic marks. I then propose some epistemological considerations regarding developmental biology in order to draw a more nuanced picture of epigenetic responsibility. I argue that such considerations are important to clarify our general understanding of epigenetic research as well as its potential translation outside the scientific area.

Le concept de banalité du mal, proposé par Hannah Arendt pour décrire le profil psychologique du criminel nazi dans Eichmann in Jerusalem, est intimement lié à ses lectures de Platon. Pour aborder la question du mal, elle a découvert des appuis chez Kant, mais le problème de la culpabilité sous le régime nazi renvoie ultimement au défaut de penser. Le deux-en-un, concept qui décrit la pensée, a été défini sur la base de l’œuvre platonicienne. L’examen de ces sources philosophiques permet de mieux comprendre les possibilités et les limites de la réflexion arendtienne sur le mal. The concept of the “banality of evil,” put forward by Hannah Arendt to describe the psychological profile of the Nazi criminal in Eichmann in Jerusalem, is intimately tied to her reading of Plato. In Arendt’s examination of the question of evil, she found some support in Kant’s philosophy. However, the problem of guilt under Nazism ultimately goes back to an inability to think. The two-in-one, a concept which describes the activity of thinking, is based on Plato’s dialogues. An examination of these philosophical sources contributes to the understanding of the possibilities and the limits of Arendt’s reflection on evil.

Optical fibre sensors based on Brillouin scattering have been vigorously studied in the context of structural health monitoring on account of their capacity for distributed strain and temperature measurements. However, real-time distributed strain measurement has been achieved only for two-end-access systems; such systems reduce the degree of freedom in embedding the sensors into structures, and furthermore render the measurement no longer feasible when extremely high loss or breakage occurs at a point along the sensing fibre. Here, we demonstrate real-time distributed measurement with an intrinsically one-end-access reflectometry configuration by using a correlation-domain technique. In this method, the Brillouin gain spectrum is obtained at high speed using a voltage-controlled oscillator, and the Brillouin frequency shift is converted into a phase delay of a synchronous sinusoidal waveform; the phase delay is subsequently converted into a voltage, which can be directly measured. When a single-point measurement is performed at an arbitrary position, a strain sampling rate of up to 100 kHz is experimentally verified by detecting locally applied dynamic strain at 1 kHz. When distributed measurements are performed at 100 points with 10 times averaging, a repetition rate of 100 Hz is verified by tracking a mechanical wave propagating along the fibre. Some drawbacks of this ultrahigh-speed configuration, including the reduced measurement accuracy, lowered spatial resolution and limited strain dynamic range, are also discussed. Fibre sensors: ultrafast sampling An optical fibre sensing scheme that measures strain with a high spatial resolution and a very high sampling rate has been developed. Optical fibre sensors based on Brillouin scattering are promising for monitoring structural health. The system built by Yosuke Mizuno of Tokyo Institute of Technology and colleagues measures the frequency shift induced in the fibre’s Brillouin gain spectrum on stretching the fibre. This frequency shift is converted into a phase delay of a sinusoidal waveform, which enables the direct detection of the frequency shift. The approach allows single-point strain measurements to be performed at a rate of up to 100 kilohertz at any point along the fibre. Distributed measurements at multiple points along the fibre are also possible, although at lower repetition rates. Importantly, the scheme only requires access from one end of the fibre.