Diethyl 2-{[2-(trifluoro­meth­yl)anil­ino]methyl­idene}propane­dioate

The title compound, C15H16F3NO4, is an N-substituted derivative of ortho-trifluoro­methyl­aniline featuring a twofold Michael system. The least-squares planes defined by the atoms of the phenyl ring and the atoms of the Michael system enclose an angle of 15.52 (5)°. Apart from classical intra­molecular N—H⋯O and N—H⋯F hydrogen bonds, inter­molecular C—H⋯O contacts are observed, the latter connecting the mol­ecules into chains along [110]. The shortest inter­centroid distance between two aromatic systems is 3.6875 (9) Å

Establishment of an ES Cell-Derived Murine Megakaryocytic Cell Line, MKD1, with Features of Primary Megakaryocyte Progenitors

Because of the scarcity of megakaryocytes in hematopoietic tissues, studying megakaryopoiesis heavily relies on the availability of appropriate cellular models. Here, we report the establishment of a new mouse embryonic stem (ES) cell-derived megakaryocytic cell line, MKD1. The cells are factor-dependent, their cell surface immunophenotype and gene expression profile closely resemble that of primary megakaryocyte progenitors (MkPs) and they further differentiate along the megakaryocyte lineage upon valproic acid treatment. At a functional level, we show that ablation of SCL expression, a transcription factor critical for MkP maturation, leads to gene expression alterations similar to that observed in primary, Scl-excised MkPs. Moreover, the cell line is amenable to biochemical and transcriptional analyses, as we report for GpVI, a direct target of SCL. Thus, the MKD1 cell line offers a pertinent experimental model to study the cellular and molecular mechanisms underlying MkP biology and more broadly megakaryopoiesis

'The debatable territory where geology and archaeology meet': reassessing the early archaeobotanical work of Clement Reid and Arthur Lyell at Roman Silchester

The first large-scale archaeobotanical study in Britain, conducted from 1899 to 1909 by Clement Reid and Arthur Lyell at Silchester, provided the first evidence for the introduction of Roman plant foods to Britain, yet the findings have thus far remained unverified. This paper presents a reassessment of these archaeobotanical remains, now stored as part of the Silchester Collection in Reading Museum. The documentary evidence for the Silchester study is summarised, before the results are presented for over a 1000 plant remains including an assessment of preservation, identification and modern contamination. The dataset includes both evidence for the presence of nationally rare plant foods, such as medlar, and several archaeophytes. The methodologies and original interpretations of Reid and Lyell’s study are reassessed in light of current archaeobotanical knowledge. Spatial and contextual patterns in the distribution of plant foods and ornamental taxa are also explored. Finally, the legacy of the study for the development of archaeobotany in the 20th century is evaluated

Neural Circuits Underlying Rodent Sociality: A Comparative Approach

All mammals begin life in social groups, but for some species, social relationships persist and develop throughout the course of an individual’s life. Research in multiple rodent species provides evidence of relatively conserved circuitry underlying social behaviors and processes such as social recognition and memory, social reward, and social approach/avoidance. Species exhibiting different complex social behaviors and social systems (such as social monogamy or familiarity preferences) can be characterized in part by when and how they display specific social behaviors. Prairie and meadow voles are closely related species that exhibit similarly selective peer preferences but different mating systems, aiding direct comparison of the mechanisms underlying affiliative behavior. This chapter draws on research in voles as well as other rodents to explore the mechanisms involved in individual social behavior processes, as well as specific complex social patterns. Contrasts between vole species exemplify how the laboratory study of diverse species improves our understanding of the mechanisms underlying social behavior. We identify several additional rodent species whose interesting social structures and available ecological and behavioral field data make them good candidates for study. New techniques and integration across laboratory and field settings will provide exciting opportunities for future mechanistic work in non-model species

Critical evaluation of key evidence on the human health hazards of exposure to bisphenol A

Despite the fact that more than 5000 safety-related studies have been published on bisphenol A (BPA), there seems to be no resolution of the apparently deadlocked controversy as to whether exposure of the general population to BPA causes adverse effects due to its estrogenicity. Therefore, the Advisory Committee of the German Society of Toxicology reviewed the background and cutting-edge topics of this BPA controversy. The current tolerable daily intake value (TDI) of 0.05 mg/kg body weight [bw]/day, derived by the European Food Safety Authority (EFSA), is mainly based on body weight changes in two- and three-generation studies in mice and rats. Recently, these studies and the derivation of the TDI have been criticized. After having carefully considered all arguments, the Committee had to conclude that the criticism was scientifically not justified; moreover, recently published additional data further support the reliability of the two-and three-generation studies demonstrating a lack of estrogen-dependent effects at and below doses on which the current TDI is based. A frequently discussed topic is whether doses below 5 mg/ kg bw/day may cause adverse health effects in laboratory animals. Meanwhile, it has become clear that positive results from some explorative studies have not been confirmed in subsequent studies with higher numbers of animals or a priori defined hypotheses. Particularly relevant are some recent studies with negative outcomes that addressed effects of BPA on the brain, behavior, and the prostate in rodents for extrapolation to the human situation. The Committee came to the conclusion that rodent data can well be used as a basis for human risk evaluation. Currently published conjectures that rats are insensitive to estrogens compared to humans can be refuted. Data from toxicokinetics studies show that the half-life of BPA in adult human subjects is less than 2 hours and BPA is completely recovered in urine as BPA-conjugates. Tissue deconjugation of BPA-glucuronide and -sulfate may occur. Because of the extremely low quantities, it is only of minor relevance for BPA toxicity. Biomonitoring studies have been used to estimate human BPA exposure and show that the daily intake of BPA is far below the TDI for the general population. Further topics addressed in this article include reasons why some studies on BPA are not reproducible; the relevance of oral versus non-oral exposure routes; the degree to which newborns are at higher systemic BPA exposure; increased BPA exposure by infusions in intensive care units; mechanisms of action other than estrogen receptor activation; and the current regulatory status in Europe, as well as in the USA, Canada, Japan, New Zealand, and Australia. Overall, the Committee concluded that the current TDI for BPA is adequately justified and that the available evidence indicates that BPA exposure represents no noteworthy risk to the health of the human population, including newborns and babies

Genome-wide association meta-analysis identifies five novel loci for age-related hearing impairment

Previous research has shown that genes play a substantial role in determining a person's susceptibility to age-related hearing impairment. The existing studies on this subject have different results, which may be caused by difficulties in determining the phenotype or the limited number of participants involved. Here, we have gathered the largest sample to date (discovery n = 9,675; replication n = 10,963; validation n = 356,141), and examined phenotypes that represented low/mid and high frequency hearing loss on the pure tone audiogram. We identified 7 loci that were either replicated and/or validated, of which 5 loci are novel in hearing. Especially the ILDR1 gene is a high profile candidate, as it contains our top SNP, is a known hearing loss gene, has been linked to age-related hearing impairment before, and in addition is preferentially expressed within hair cells of the inner ear. By verifying all previously published SNPs, we can present a paper that combines all new and existing findings to date, giving a complete overview of the genetic architecture of age-related hearing impairment. This is of importance as age-related hearing impairment is highly prevalent in our ageing society and represents a large socio-economic burden

Do female Norway rats form social bonds?

This study was funded by the SNF-grant 31003A_156152 provided to MT.Social bonds reflect specific and enduring relationships among conspecifics. In some group-living animals, they have been found to generate immediate and long-term fitness benefits. It is currently unclear how important and how widespread social bonds are in animals other than primates. It has been hypothesized that social bonds may help in establishing stable levels of reciprocal cooperation. Norway rats (Rattus norvegicus) reciprocate received help to an unrelated social partner. It is hitherto unknown, however, whether this cooperative behaviour is based on the establishment of social bonds among involved individuals. Norway rats live in social groups that can be very large; hence, without bonds, it may be difficult to keep track of other individuals and their previous behaviour, which is a precondition for generating evolutionarily stable levels of cooperation based on direct reciprocity. Here we tested whether wild-type female rats form bonds among each other, which are stable both over time and across different contexts. In addition, we scrutinized the potential influence of social rank on the establishment of bonds. Despite the fact that the hierarchy structure within groups remained stable over the study period, no stable social bonds were formed between group members. Apparently, social information from consecutive encounters with the same social partner is not accumulated. The lack of long-term social bonds might explain why rats base their decisions to cooperate primarily on the last encounter with a social partner, which may differ from other animals where cooperation is based on the existence of long-term social bonds.PostprintPeer reviewe

Assessing Physical Activity in People With Mental Illness: 23-country Reliability and Validity of the Simple Physical Activity Questionnaire (SIMPAQ)

Background: Physical inactivity is a key contributor to the global burden of disease and disproportionately impacts the wellbeing of people experiencing mental illness. Increases in physical activity are associated with improvements in symptoms of mental illness and reduction in cardiometabolic risk. Reliable and valid clinical tools that assess physical activity would improve evaluation of intervention studies that aim to increase physical activity and reduce sedentary behaviour in people living with mental illness. Methods: The five-item Simple Physical Activity Questionnaire (SIMPAQ) was developed by a multidisciplinary, international working group as a clinical tool to assess physical activity and sedentary behaviour in people living with mental illness. Patients with a DSM or ICD mental illness diagnoses were recruited and completed the SIMPAQ on two occasions, one week apart. Participants wore an Actigraph accelerometer and completed brief cognitive and clinical assessments. Results: Evidence of SIMPAQ validity was assessed against accelerometer-derived measures of physical activity. Data were obtained from 1010 participants. The SIMPAQ had good test-retest reliability. Correlations for moderate-vigorous physical activity was comparable to studies conducted in general population samples. Evidence of validity for the sedentary behaviour item was poor. An alternative method to calculate sedentary behaviour had stronger evidence of validity. This alternative method is recommended for use in future studies employing the SIMPAQ. Conclusions: The SIMPAQ is a brief measure of physical activity and sedentary behaviour that can be reliably and validly administered by health professionals.Universidad Pablo de Olavide de Sevilla. Departamento de Deporte e Informátic

Modulation of the activity of N-methyl-D-aspartate receptors as a novel treatment option for depression: current clinical evidence and therapeutic potential of rapastinel (GLYX-13)

Andrei-Nicolae Vasilescu,1,* Nina Schweinfurth,2,* Stefan Borgwardt,2,* Peter Gass,1 Undine E Lang,2,* Dragos Inta,1,2,* Sarah Eckart2,* 1Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany; 2Department of Psychiatry (Universitäre Psychiatrische Kliniken), University of Basel, Basel, Switzerland *These authors contributed equally to this work Abstract: Classical monoaminergic antidepressants show several disadvantages, such as protracted onset of therapeutic action. Conversely, the fast and sustained antidepressant effect of the N-methyl-d-aspartate receptor (NMDAR) antagonist ketamine raises vast interest in understanding the role of the glutamate system in mood disorders. Indeed, numerous data support the existence of glutamatergic dysfunction in major depressive disorder (MDD). Drawback to this short-latency therapy is its side effect profile, especially the psychotomimetic action, which seriously hampers the common and widespread clinical use of ketamine. Therefore, there is a substantial need for alternative glutamatergic antidepressants with milder side effects. In this article, we review evidence that implicates NMDARs in the prospective treatment of MDD with focus on rapastinel (formerly known as GLYX-13), a novel synthetic NMDAR modulator with fast antidepressant effect, which acts by enhancing NMDAR function as opposed to blocking it. We summarize and discuss current clinical and animal studies regarding the therapeutic potential of rapastinel not only in MDD but also in other psychiatric disorders, such as obsessive–compulsive disorder and posttraumatic stress disorder. Additionally, we discuss current data concerning the molecular mechanisms underlying the antidepressant effect of rapastinel, highlighting common aspects as well as differences to ketamine. In 2016, rapastinel received the Breakthrough Therapy designation for the treatment of MDD from the US Food and Drug Administration, representing one of the most promising alternative antidepressants under current investigation. Keywords: depression, glutamate, NMDARs, rapastinel, ketamin