Loss of DPP6 in neurodegenerative dementia : a genetic player in the dysfunction of neuronal excitability

Emerging evidence suggested a converging mechanism in neurodegenerative brain diseases (NBD) involving early neuronal network dysfunctions and alterations in the homeostasis of neuronal firing as culprits of neurodegeneration. In this study, we used paired-end short-read and direct long-read whole genome sequencing to investigate an unresolved autosomal dominant dementia family significantly linked to 7q36. We identified and validated a chromosomal inversion of ca. 4Mb, segregating on the disease haplotype and disrupting the coding sequence of dipeptidyl-peptidase 6 gene (DPP6). DPP6 resequencing identified significantly more rare variants-nonsense, frame-shift, and missense-in early-onset Alzheimer's disease (EOAD, p value = 0.03, OR = 2.21 95% CI 1.05-4.82) and frontotemporal dementia (FTD, p = 0.006, OR = 2.59, 95% CI 1.28-5.49) patient cohorts. DPP6 is a type II transmembrane protein with a highly structured extracellular domain and is mainly expressed in brain, where it binds to the potassium channel K(v)4.2 enhancing its expression, regulating its gating properties and controlling the dendritic excitability of hippocampal neurons. Using in vitro modeling, we showed that the missense variants found in patients destabilize DPP6 and reduce its membrane expression (p < 0.001 and p < 0.0001) leading to a loss of protein. Reduced DPP6 and/or K(v)4.2 expression was also detected in brain tissue of missense variant carriers. Loss of DPP6 is known to cause neuronal hyperexcitability and behavioral alterations in Dpp6-KO mice. Taken together, the results of our genomic, genetic, expression and modeling analyses, provided direct evidence supporting the involvement of DPP6 loss in dementia. We propose that loss of function variants have a higher penetrance and disease impact, whereas the missense variants have a variable risk contribution to disease that can vary from high to low penetrance. Our findings of DPP6, as novel gene in dementia, strengthen the involvement of neuronal hyperexcitability and alteration in the homeostasis of neuronal firing as a disease mechanism to further investigate

An Evolutionary Trade-Off between Protein Turnover Rate and Protein Aggregation Favors a Higher Aggregation Propensity in Fast Degrading Proteins

We previously showed the existence of selective pressure against protein aggregation by the enrichment of aggregation-opposing ‘gatekeeper’ residues at strategic places along the sequence of proteins. Here we analyzed the relationship between protein lifetime and protein aggregation by combining experimentally determined turnover rates, expression data, structural data and chaperone interaction data on a set of more than 500 proteins. We find that selective pressure on protein sequences against aggregation is not homogeneous but that short-living proteins on average have a higher aggregation propensity and fewer chaperone interactions than long-living proteins. We also find that short-living proteins are more often associated to deposition diseases. These findings suggest that the efficient degradation of high-turnover proteins is sufficient to preclude aggregation, but also that factors that inhibit proteasomal activity, such as physiological ageing, will primarily affect the aggregation of short-living proteins

An analysis of structural and evolutionary mechanisms against protein aggregation

Proteins are essential cell components and correct folding is crucial for their biological activity. Folding however is an error prone process,often producing misfolded protein conformations, which in turn can result in protein aggregation. The aggregation process is driven by exposureof short aggregation-prone regions (APRs) within protein sequences thatcan self-associate to form intermolecular β-structured assemblies. Under native conditions, these APRs are buried inside the protein core. As aggregation is a detrimental process, cellular organisms have developed an efficient protein quality control machinery consisting of chaperones and various proteases to minimize the risk of misfolding and ensure protein homeostasis. In addition, strategically placed aggregation-opposing gatekeeper residues - usually charged amino acids - have evolved along the sequence.In my thesis, I investigated in more detail the selective forces on protein sequences to avoid protein aggregation and in addition the impact of non-synonymous mutations on protein stability and aggregation.I demonstrated that short-living proteins have a lower tendency to aggregate. This suggests that the short lifetime of these proteins is sufficient to preclude protein aggregation. As the efficiency of protein degradation wanes with aging, this would explainwhy we observe a higher association of high turnover proteins with age-dependent aggregation-related diseases.Because the strategic placement of gatekeeper residues at the flanks of APRs is crucial in keeping the aggregation tendency limited, it would not be surprising to find them highly conserved within a species. Although gatekeeper residues are thermodynamically unfavorable for protein structure, my research showed they are indeed mutational cold spots, thereby confirming their important role for protein solubility. Consequently, mutations of gatekeeper residues in human proteins are often found to be disease-associated. Protein destabilization due to mutation can result in exposure of APRs. Thus, it would be useful to have a way to estimate the prevalence of protein aggregation upon non-synonymous mutation. To accomplish this, I first redesigned the SNPeffect webserver. This online prediction tool returns themolecular and structural effect of protein coding variants using TANGO,WALTZ, and FoldX. It allowed me to analyze in an automated way a representative dataset of variants, which revealed that 34% of disease mutations could result in protein aggregation by being destabilizing and occurring in a domain with a strong aggregating stretch. This basic finding indicates that protein aggregation could be a major disease modifier, not only in neurodegeneration, but also in cancer.status: publishe

Harmony and common ground: Aikido principles for intercultural training

This paper investigates the added value of aikido, a martial art, as an embodied pedagogy for intercultural communication training: what is the potential of bringing the physical practice of aikido into the intercultural communication classroom, emphasizing experiential discovery instead of traditional didactic explanations? To this end, we conducted a benchmarking study identifying the core principles of aikido. We interviewed twenty aikido experts worldwide and performed a qualitative content analysis of the transcribed interview data relying on NVivo software. First, and foremost, our findings show fundamental similarities between aikido interaction and intercultural interaction. They reveal a shared significance of focused interaction by consciously seeking harmony and co-creating common ground. Second, we demonstrate that the aikido pedagogy teaches harmony and common ground through (i) multisensory learning practice and (ii) somatic discovery by training physiological and mental tranquility. Our conclusion is that aikido has potential as an embodied pedagogy for intercultural communication training

Interviewing aikido experts all over the world : towards a framework for intercultural training

Aikido (aikidō) is a primarily weaponless, noncompetitive martial art characterized by circular movements and throws as well as locks applied to the joints [grappling techniques involving manipulation of an opponent's joints]. Today it is practiced globally as self-defense, as a recreational activity, as a meditative technique, as a social activity, and indeed as a ritual act (Niehaus, 2019). Moreover, it is based on a philosophy of peace and non-violence (Brawdy, 2001). Aikido aims to turn opponents into partners, to build bridges even when the odds are against harmony (Ueshiba & Stevens, 1993). This presentation explores the effectiveness and efficiency of aikido as a somatic, multisensory and embodied learning method to benefit intercultural intelligence. It focuses on the principles of aikido to become a practical and useful framework. To identify the core principles of aikido, we performed a benchmark study. Semi-structured interviews with twenty key aikido experts from all over the world revealed their current views. All informants were recruited through purposive sampling. The sample was homogeneous in knowledge and expertise, heterogeneous in geographical spread (Etikan, 2016). It contained at least one expert from each continent, which was an attempt to add to the Japanese view on aikido, to avoid a Eurocentric view and to decolonize the research method. Relying on NVivo software, we performed a qualitative content analysis of the interview data, coding the data into categories to make the main inferences. The preliminary results of the study found two main categories of aikido principles. One category focuses on the interaction with the opponent such as entering into the situation (irimi), unification with the other (musubi), soft counterattacks (atemi), respect and a win-win outcome. The second category focuses on personal principles such as breath power (kokyu), balance, posture and openness. Aikido integrates the two categories into one whole. To validate and triangulate the interview findings, a large-scale survey will address different communities of aikido practitioners all over the world. The results will then feed an aikido framework for a longitudinal comparative experiment between aikido-based and non-aikido-based intercultural training

Intercultural business communication competence: applying the aikido principle of oneness in a culture-general approach

Culture-general understanding provides the foundation for the complex cultural interactions we experience. Numerous twenty-first-century scholars identified the need for culture-general approaches, counterbalancing culture-specific approaches which are traditionally characterized by a dichotomous perspective, an anthropocentric worldview and binary thinking in terms of otherness and difference (Jia and Jia, 2016). This paper explores the added value of aikido’s oneness principle in martial art for culture-general intercultural training for business people. Practiced worldwide, aikido is characterized by an anthropocosmic worldview (Jia & Jia, 2016): it sees humanity as being one with self, society, nature and heaven, not being the center of the universe. Many aikido practitioners share this anthropocosmic view and believe it is why aikido is called the martial art of harmony. Aikido teaches an understanding of human movements to induce unity and agreement between the practitioner, the attacker and their surroundings (Soltoggio et al., 2016). A successful aikido interaction fosters oneness and ends in a noble outcome for all parties involved. We compared Deardorff’s (2006) pyramid model of intercultural competence with the findings of a qualitative content analysis of twenty aikido expert interviews. Several intercultural study scholars considered Deardorff’s model to be quite a complete model. The comparison between the pyramid model and the aikido principles from the data-set showed a significant overlap. However, one cluster of aikido principles did not have an equivalent in the pyramid model: oneness. Oneness relates to the anthropocosmic worldview: if you see yourself as one with the other person in an interaction, it is natural to pursue a noble outcome instead of doing harm. Aikido practitioners learn how to achieve oneness in aikido interaction. Therefore, applying aikido’s principle of oneness to intercultural business interaction contributes to an anthropocosmic culture-general training approach

The potential of aikido as a means to improve intercultural encounters and communication

In today’s deeply divided times, intercultural understanding is suffering: “unscrupulous media and politicians stoke ethnic and racial fear for their personal gain” and “ever more barriers between people […] are being put up and fortified” (Piller, 2017: 202). To contribute to bridging cultures, some communication training methods have used the Japanese martial art of aikido as a model. This paper reports on a benchmarking study to identify how aikido generates principles for intercultural training that tackle the importance of non-violent communication (Rosenberg, 2015). The goal is to obtain a blend of inside (emic) and outside (etic) views (Keesing, 1991) on aikido’s self-defence technique and aikido’s philosophy of peace and non-violence (Brawdy, 2001). The benchmarking study takes a two-pronged approach, integrating a qualitative and a quantitative methodology. Firstly, it relies on semi-structured interviews with key aikido experts. All informants are recruited by means of purposive and convenience sampling. The sample is homogeneous in knowledge and expertise, heterogeneous in geographical spread (Etikan, 2016). Relying on Nvivo software, we perform a content analysis of the interview data, coding the data into categories to make the main inferences. Secondly, we validate the key findings from the qualitative analysis by means of a large-scale survey of communities of aikido practitioners

Harmony and common ground : aikido principles for intercultural training

Aikido, a martial art, is practised globally and aims to turn opponents into partners, even when the odds are against harmony. Typically, aikido stands for seeking harmony, common ground and non-violence instead of the combat in most other martial arts. In many parts of the world, it is also applied as a metaphor or an embodiment method in fields such as therapy and communication training. In the field of intercultural business communication training, for instance, it may be argued that aikido meets a need for experimental training approaches with experiential discovery rather than conventional didactic expository (Waxin & Panaccio, 2005; Treven, 2003; Graf, 2004; Díaz & Moore, 2018). In this paper we investigate how and to what extent aikido may be beneficial to intercultural business communication training: we report on a benchmarking study in which we identify what interviewed aikido experts consider to be core principles of aikido on and off the mat. Relying on NVivo software, we performed a qualitative content analysis of the interview data. The findings showed that the way people learn, teach, understand and perceive aikido has fundamental similarities. The respondents referred to aikido principles with the same core meaning, however, with some local or individual nuances: building common ground in interactions and discovering the power of harmony through self-development. The curriculum of aikido consists of movement practice that illustrates and teaches common ground and harmony in challenging interactions: unification and circulation based on an attitude of tranquillity, openness and curiosity. Because aikido movements are not meant to react to an attack but to create a win-win outcome, neither the attacker nor the attacked is a victim. This is similar to interculturality, the communicative process in intercultural interaction which emerges from the situation (Kecskés, 2020). We conclude that aikido has potential in an embodied learning process of intercultural communication skills. The hands-on style of learning involves aikido movements simulating intercultural interactions followed by feedback and discussions. In this way, learners discover insights into the other person’s sensitivities and an emergent common ground framework to add to their intercultural competence repertoires. This embodied approach aims to be an example of experiential discovery that strives to equip employees with a broad range of skills that will help them act appropriately in different international business contexts (Graf, 2005). In the panel organized by Istvan Kecskes: Common ground in intercultural interaction

Benchmarking aikido principles: today’s meaning in the world

In many parts of the world, aikido is applied as a metaphor or an embodiment method in other domains such as therapy and communication training (Faggianelli & Lukoff, 2006; Brawdy, 2001). Aikido often stands for seeking harmony, common ground and non-violence instead of the combat in many other martial arts. Ueshiba Morihei (1883-1969) founded aikido and gave form to his martial art in the 1920s. The traditional literature on aikido and aikido principles, in English and Japanese, is mainly written from "within"; by Ueshiba’s followers, aikido practitioners and by family members (Niehaus, 2019). A benchmarking study identified what current aikido experts consider to be principles of aikido on and off the mat in order to determine to what extent the principles of aikido serve other domains today. Twenty aikido experts from each continent gave their views in a semi-structured interview. Relying on NVivo software, we performed a qualitative content analysis of the interview data. All informants were recruited through purposive sampling. The sample was homogeneous in knowledge and expertise, heterogeneous in geographical spread (Etikan, 2016). The study found that the informants referred to aikido principles with the same core meaning, however, with local or individual nuances. Differences were based on the reality the informants live in and on the aikido style they practise. The similarities are fundamental and show that many principles are universal. They showed a pattern in which aikido undergirds principles for interaction (openness, cooperation and other-awareness) and for self-development (tranquillity and self-awareness). Because the findings showed significant similarities, aikido has the potential to be a model for embodied pedagogy in other domains

Interviewing aikido experts : aikido as an embodied pedagogy for recipient design in intercultural business communication

Aikido is one of the martial arts practised globally. Most martial arts stand for combat and self-defence. However, aikido typically stands for seeking harmony by turning opponents into partners (Shimizu, 1994; Ueshiba & Stevens, 1993). Because of this, it is applied as a metaphor or an embodiment method (a combination of cognitive and physical experience) in fields such as therapy, conflict resolution and communication training (Brawdy, 2001; Faggianelli & Lukoff, 2006; Lukoff & Strozzi-Heckler, 2017). In the field of intercultural business communication training, for instance, it may be argued that aikido meets a need for training approaches using experiential discovery rather than conventional didactic expository (Waxin & Panaccio, 2005; Treven, 2003; Graf, 2004; Díaz & Moore, 2018). However, few scholars have investigated aikido as a training approach for intercultural communication or business communication. As a first step in exploring the possible effectiveness and efficiency of aikido as an embodied pedagogy for intercultural business communication training, we identified the core principles of aikido. We performed a global benchmarking study with semi-structured interviews: twenty aikido experts from all over the world reflected on the principles of aikido. Relying on NVivo software, we performed a qualitative content analysis of the interview data (Gibbs & Flick, 2018). Preliminary findings show at least four core principles which focus on the careful attention to the other in aikido interaction: adaptability, other-relative view, safety and win-win attitude. Firstly, in an aikido interaction, an aikido practitioner adapts to the moves, the speed, the direction, the power and the physiology of the training partner. Secondly, an aikido practitioner practises an other-relative view to see the other in relation to one self and to understand any inequality in the interaction. Thirdly, an aikido practitioner behaves safely, i.e. effectively and efficiently without doing harm to all the people involved in the interaction. Fourthly, an aikido practitioner aims for a win-win outcome. These four principles could be interpreted as recipient-design principles, with recipient design referring to the capacity and sensitivity for tuning communicative behaviour to conversation partners (Blokpoel et al., 2012; Kecskés, 2018; Sacks et al., 1974). Kecskés developed the notion of 'conscious recipient design' in the context of intercultural interaction. As successful aikido interaction matches recipient-design principles, it may indicate that intercultural business communication training could teach conscious recipient design relying on the embodied pedagogy of aikido, thus potentially increasing the effectiveness and efficiency of intercultural business training. Although the interview findings still need to be triangulated with a large-scale survey for aikido practitioners all over the world, we can already propose a first version of two models. Firstly, the aikido principles inspired a model that shows the steps, the flow and the intention of intercultural interaction. It includes the conscious recipient design. Secondly, this paper proposes an aikido-based version of Deardorff’s pyramid model of intercultural competence (Deardorff, 2006). Scholars referred to Deardorff’s model for being rather complete (Nadeem et al., 2018; Szőke, 2018; Tong et al., 2018; Tran & Seepho, 2016). On the one hand, the model shows attitudes, knowledge and skills that are comparable to aikido principles. On the other hand, some aikido principles add to the model and thus create a new version, an aikido-based pyramid model of intercultural competence. The two models (intercultural interaction and intercultural competence) and the results of both the interview study and the survey study will feed a pedagogical framework for teaching intercultural business communication. The framework will use the body as a learning tool, called embodied pedagogy. It will focus on experiencing the aikido motions rather than cognitively understanding the aikido principles, i.e. more on inductive than on deductive learning. In the next step in exploring the possible effectiveness and efficiency of applying aikido in intercultural communication, we will conduct a longitudinal comparative experiment between aikido-based and non-aikido-based intercultural business communication training