Reverse-translational biomarker validation of Abnormal Repetitive Behaviors in mice: an illustration of the 4P's modeling approach

The NIMH's new strategic plan, with its emphasis on the "4P's" (Prediction, Pre-emption, Personalization, and Populations) and biomarker-based medicine requires a radical shift in animal modeling methodology. In particular 4P's models will be non-determinant (i.e. disease severity will depend on secondary environmental and genetic factors); and validated by reverse-translation of animal homologues to human biomarkers. A powerful consequence of the biomarker approach is that different closely related disorders have a unique fingerprint of biomarkers. Animals can be validated as a highly specific model of a single disorder by matching this 'fingerprint'; or as a model of a symptom seen in multiple disorders by matching common biomarkers. Here we illustrate this approach with two Abnormal Repetitive Behaviors (ARBs) in mice: stereotypies and barbering (hair pulling). We developed animal versions of the neuropsychological biomarkers that distinguish human ARBs, and tested the fingerprint of the different mouse ARBs. As predicted, the two mouse ARBs were associated with different biomarkers. Both barbering and stereotypy could be discounted as models of OCD (even though they are widely used as such), due to the absence of limbic biomarkers which are characteristic of OCD and hence are necessary for a valid model. Conversely barbering matched the fingerprint of trichotillomania (i.e. selective deficits in set-shifting), suggesting it may be a highly specific model of this disorder. In contrast stereotypies were correlated only with a biomarker (deficits in response shifting) correlated with stereotypies in multiple disorders, suggesting that animal stereotypies model stereotypies in multiple disorders.

Drivers of collaboration to mitigate climate change: An illustration of Swiss climate policy over 15 years

Climate change mitigation policy is driven by scientific knowledge and involves actors from the international, national and local decision-making levels. This multi-level and cross-sectoral context requires collaborative management when designing mitigation solutions over time and space. But collaboration in general policymaking settings, and particularly in the complex domain of climate mitigation, is not an easy task. This paper addresses the question of what drives collaboration among collective actors involved in climate mitigation policy. We wish to investigate whether common beliefs or power structures influence collaboration among actors. We adopt a longitudinal approach to grasp differences between the early and more advanced stages of mitigation policy design. We use survey data to investigate actors’ collaboration, beliefs and power, and apply a Stochastic Actor-oriented Model for network dynamics to three subsequent networks in Swiss climate policy between 1995 and 2012. Results show that common beliefs among actors, as well as formal power structures, have a higher impact on collaboration relations than perceived power structures. Furthermore, those effects hold true for decision-making about initial mitigation strategies, but less so for the implementation of those measures.

Experimental Evaluation of Immediate Recanalization Effect and Recanalization Efficacy of a New Thrombus Retriever for Acute Stroke Treatment In Vivo

BACKGROUND AND PURPOSE: Currently, several new stent retriever devices for acute stroke treatment are under development and early clinical evaluation. Preclinical testing under standardized conditions is an important first step to evaluate the technical performance and potential of these devices. The aim of this study was to evaluate the immediate recanalization effect, recanalization efficacy, thrombus-device interaction, and safety of a new stent retriever intended for thrombectomy in patients with acute stroke. MATERIAL AND METHODS: The pREset thrombectomy device (4 × 20 mm) was evaluated in 16 vessel occlusions in an established swine model. Radiopaque thrombi (10-mm length) were used for visualization of thrombus-device interaction during application and retrieval. Flow-restoration effect immediately after deployment and after 5-minute embedding time before retrieval, recanalization rate after retrieval, thromboembolic events, and complications were assessed. High-resolution FPCT was performed to illustrate thrombus-device interaction during the embedding time. RESULTS: Immediate flow restoration was achieved in 75% of occlusions. An increase or stable percentage of recanalizations during embedding time before retrieval was seen in 56.3%; a decrease, in 12.5%; reocclusion of a previously recanalized vessel, in 18.8%; and no recanalization effect at all, in 12.5%. Complete recanalization (TICI 3) after retrieval was achieved in 93.8%; partial recanalization (TICI 2b), in 6.2%. No distal thromboembolic events were observed. High-resolution FPCT illustrated entrapment of the thrombus between the stent struts and compression against the contralateral vessel wall, leading to partial flow restoration. During retrieval, the thrombus was retained in a straight position within the stent struts. CONCLUSIONS: In this experimental study, the pREset thrombus retriever showed a high recanalization rate in vivo. High-resolution FPCT allows detailed illustration of the thrombus-device interaction during embedding time and is advocated as an add-on tool to the animal model used in this study.

Alternative splicing of pre-mRNA in cancer: focus on G protein-coupled peptide hormone receptors

Through alternative splicing, multiple different transcripts can be generated from a single gene. Alternative splicing represents an important molecular mechanism of gene regulation in physiological processes such as developmental programming as well as in disease. In cancer, splicing is significantly altered. Tumors express a different collection of alternative spliceoforms than normal tissues. Many tumor-associated splice variants arise from genes with an established role in carcinogenesis or tumor progression, and their functions can be oncogenic. This raises the possibility that products of alternative splicing play a pathogenic role in cancer. Moreover, cancer-associated spliceoforms represent potential diagnostic biomarkers and therapeutic targets. G protein-coupled peptide hormone receptors provide a good illustration of alternative splicing in cancer. The wild-type forms of these receptors have long been known to be expressed in cancer and to modulate tumor cell functions. They are also recognized as attractive clinical targets. Recently, splice variants of these receptors have been increasingly identified in various types of cancer. In particular, alternative cholecystokinin type 2, secretin, and growth hormone-releasing hormone receptor spliceoforms are expressed in tumors. Peptide hormone receptor splice variants can fundamentally differ from their wild-type receptor counterparts in pharmacological and functional characteristics, in their distribution in normal and malignant tissues, and in their potential use for clinical applications.

On the Limits of Greenwich Mean Time, or The Failure of a Modernist Revolution

On the Limits of Greenwich Mean Time, or The Failure of a Modernist Revolution From the introduction of World Standard Time in 1884 to Einstein’s theory of relativity, the nature and regulation of time was a highly contested issue in modernism, with profound political, social and epistemological consequences. Modernist aesthetic sensibilities widely revolted against the increasingly strict rule of the clock, which, as Georg Simmel observed in “The Metropolis and Mental Life,” was established as the necessary basis of a capitalist, urban life. This paper will focus on the contending conceptions of time arising in key modernist texts by authors like Joyce, Woolf and Conrad. I will argue that the uniformity and regularity of time necessary to a rising capitalist society came under attack in a similar way by both modernist literary aesthetics and new scientific discoveries. However, while Einstein’s theory of relativity may have led to a subsequent change of paradigm in scientific thought, it has failed to significantly alter social and popular conceptions of time. Although alternative ways of thinking and living with time are proposed by modernist authors, they remain isolated aesthetic experiments, ineffectual against the regulatory pressure of economic and social structures. In this struggle about the nature of time, so I suggest, science and literature join force against a society that is increasingly governed by economic reason. The fact that they lost this struggle can serve as a striking illustration of an increasing shift of social influence from science and art towards economy.

Three-dimensional printing for perioperative planning of complex aortic arch surgery

Purpose In this study, we show the use of three-dimensional printing models for preoperative planning of surgery for patients with complex aortic arch anomalies. Description A 70-year-old man with an extensively arteriosclerotic aneurysm reaching from the ascending aorta to the descending aorta was referred to our center for complete aortic arch replacement. We visualized and reconstructed computed tomography data of the patient and fabricated a flexible three-dimensional model of the aortic arch including the aneurysm. Evaluation This model was very helpful for the preoperative decision making and planning of the frozen elephant trunk procedure owing to the exact and lifelike illustration of the native aortic arch. Conclusions Three-dimensional models are helpful in preoperative planning and postoperative evaluation of frozen elephant trunk procedures in patients with complex aortic anatomy.

Capital interplays and the self-rated health of young men: results from a cross-sectional study in Switzerland.

INTRODUCTION We apply capital interplay theory to health inequalities in Switzerland by investigating the interconnected effects of parental cultural, economic and social capitals and personal educational stream on the self-rated health of young Swiss men who live with their parents. METHODS We apply logistic regression modelling to self-rated health in original cross-sectional survey data collected during mandatory conscription of Swiss male citizens in 2010 and 2011 (n = 23,975). RESULTS In comparison with sons whose parents completed mandatory schooling only, sons with parents who completed technical college or university were significantly more likely to report very good or excellent self-rated health. Parental economic capital was an important mediating factor in this regard. Number of books in the home (parental cultural capital), family economic circumstances (parental economic capital) and parental ties to influential people (parental social capital) were also independently associated with the self-rated health of the sons. Although sons in the highest educational stream tended to report better health than those in the lowest, we found little evidence for a health-producing intergenerational transmission of capitals via the education stream of the sons. Finally, the positive association between personal education and self-rated health was stronger among sons with relatively poorly educated parents and stronger among sons with parents who were relatively low in social capital. CONCLUSIONS Our study provides empirical support for the role of capital interplays, social processes in which capitals interpenetrate or co-constitute one another, in the intergenerational production of the health of young men in Switzerland.

How gender fair are German schoolbooks in the twenty-first century? An analysis of language and illustrations in schoolbooks for mathematics and German

Schoolbooks convey not only school-relevant knowledge; they also influence the development of stereotypes about different social groups. Particularly during the 1970s and 1980s, many studies analysed schoolbooks and criticised the overall predominance of male persons and of traditional role allocations. Since that time, women’s and men’s occupations and social functions have changed considerably. The present research investigated gender portrayals in schoolbooks for German and mathematics that were recently published in Germany. We examined the proportions of female and male persons in pictures and texts and categorized their activities, occupational and parental roles. Going beyond previous studies, we added two criteria: the use of gender-fair language and the spatial arrangements of persons in pictures. Our results show that schoolbooks for German contained almost balanced depictions of girls and boys, whereas women were less frequently shown than men. In mathematics books, males outnumbered females in general. Across both types of books, female and male persons were engaged in many different activities, not only gendertyped ones; however, male persons were more often described via their profession than females. Use of gender-fair language has found its way into schoolbooks but is not used consistently. Books for German were more gender fair in terms of linguistic forms than books for mathematics. For spatial arrangements, we found no indication for gender biases. The results are discussed with a focus on how schoolbooks can be optimized to contribute to gender equality.

Surface-patterned micromechanical elements by polymer injection molding with hybrid molds

Hybrid molds enable the fabrication of polymeric parts with features of different length scales by injection molding. The resulting polymer microelements combine optical or biological functionalities with designed mechanical properties. Two applications are chosen for illustration of this concept: As a first example, microelements for optical communication via fiber-to-fiber coupling are manufactured by combining two molds to a small mold insert. Both molds are fabricated using lithography and electroplating. As a second example, microcantilevers (μCs) for chemical sensing are surface patterned using a modular mold composed of a laser-machined cavity defining the geometry of the μCs, and an opposite flat tool side which is covered by a patterned polymer foil. Injection molding results in an array of 35 μm-thick μCs with microscale surface topographies. In both cases, when the mold is assembled and closed, reliefs are transferred onto one surface of the molded element whose outlines are defined by the micromold cavity. The main advantage of these hybrid methods lies in the simple integration of optical surface structures and gratings onto the surface of microcomponents with different sizes and orientations. This allows for independent development of functional properties and combinations thereof.