Publications related to Understanding

Financing Biomedical Ventures - Myths and Realities

Angel funding is an important source of capital for startup ventures (J. Sohl 2019), providing a similar level of capital as institutional venture capital (OECD 2011). But angel funding is challenging to study due to the informal nature of the activity. A common paradigm for new venture funding argues that new ventures initially fund their activities with angel investment and then, as they show success, make progress to commercialization and de-risk core venture propositions, ventures transition to more professional institutional (venture capital) funding. A belief in this paradigm can strongly influence early venture creation activities, and assumptions about the later availability of capital from institutional venture capital underpin many startup business plans. However, the literature exploring this phenomenon is very sparse, and the question of the relationship of angel to venture funding transition has rarely been studied. By analyzing a large and robust dataset, this thesis advances the understanding of the actual behavior of investors and the impact this early behavior, and the funding choices involved, have on company outcomes. This thesis also explores a novel form of venture investing and places it into a broader context of new venture funding that may help explain some of the key observations discussed. These fundamentally empirical studies examine the nature/reality of important entrepreneurial phenomena of interactions between angel and venture funding in novel ways, pose questions, and identify a set results that point to a potential market failure. Attempts are made to understand these results and place them into the contexts of both research theory and a broader understanding of entrepreneurial behavior; there certainly remain a set of unanswered questions and potential fruitful directions for future research.

EPFL2020

Genetic selection for low glucocorticoid responsiveness recapitulates PTSD-related phenotypes: a behavioral, neuroimaging and sleep-physiology study

Silvia Monari

Humans show inter-individual differences in vulnerability to develop post-traumatic stress disorder (PTSD) following exposure to trauma. Several critical biobehavioral features have been consistently described in PTSD patients, including blunted cortisol levels, smaller hippocampal size, sleep disturbances. However, because of the delay between trauma exposure and the onset of symptoms characteristic of PTSD, only a few longitudinal studies have tried to dissect whether these features constitute pre-trauma risk factors or consequences of the trauma. Enormous effort in animal and human studies has been dedicated to understanding mechanisms of conditioned fear and fear extinction, processes that are at the core of PTSD. However, the same progress has not been translated into psychiatric practice for PTSD. Deepening our understanding of the contribution of key factors to PTSD-related alterations can serve to develop effective treatments.In particular, with regard to low cortisol levels in PTSD pathophysiology, a causative role for blunted glucocorticoid responsiveness in PTSD has not been demonstrated yet.Here, we have addressed this question in lines of Wistar rats genetically-selected for their differential habituation of glucocorticoid responses to stress (LOW-, INTER-, HIGH-CORT Responder rats) and focused on fear extinction, a hallmark of PTSD symptomology, as one of the key features. As a first step, we looked whether divergent trajectories of glucocorticoid responsiveness were associated with brain volume abnormalities, prompted by the influential role of glucocorticoid in brain development. Notably, rats with low or high corticosterone responsiveness exhibit smaller hippocampi, regardless of trauma exposure, compared to rats with normative corticosterone levels. Similarly, the distribution of corticosteroid receptors in the hippocampus presented similarities between the LOW-CR and the HIGH-CR rats with higher mineralocorticoid receptors (MR) and less glucocorticoid receptors (GR). Although LOW- and HIGH-CR rats displayed a similar hippocampal profile at the structural and molecular levels, only LOW-CR male rats exhibited strong deficits in extinction consolidation compared to rats with 'normative' glucocorticoid responses (INTER-CR rats), and showed higher fear response both at few days and at several weeks after trauma exposure. We next tested the causal involvement of corticosterone in the fear extinction consolidation, and found that post-extinction corticosterone treatment markedly prevented the deficits in extinction memory and attenuated fear relapse. In addition, pharmacological inhibition of corticosterone levels during extinction memory consolidation, but not during training, in the INTER-CR rats led to extinction deficits at retrieval one day later. These results indicate that blunted corticosterone levels contribute to confer major vulnerability than having a small hippocampus, and that consolidation processes following extinction are mainly affected by low corticosterone levels.It is well known that glucocorticoids play an important role in memory consolidation processes and that sleep disturbances are a diagnostic criterion of PTSD. Therefore, we investigated in greater detail the sleep architecture in undisturbed condition and during the consolidation period of the extinction phase, which is known to be supported by sleep-dependent processes. In polysomnographic recordings, we found that rats with blunted corticos

EPFL2022

Computational Methods for Audio-Visual Analysis of Emergent Leadership in Teams

Dairazalia Sanchez Cortes

Face-to-face interactions are part of everyday life, ranging from family to working in teams and to global communities. Social psychologists have long studied these interactions with the aim of understanding behavior, motivations, and emergence of interaction patterns. An organization is environment rich in daily interactions including structured periodic meetings, planning, brainstorming, negotiations, decision-making and informal gatherings and leaders play a key role in many of them. Leader face problems, propose solutions, make decisions, and often are the main source of inspiration of the employees. Identifying emergent leaders at early stages in organizations is a key issue in organizational behavioral research, and a new problem in social computing. The study of this phenomenon requires sensing of natural face-to-face interactions, automatic extraction of behavioral cues and reliable machine learning algorithms to identify emergent leaders. In this thesis we present a computational approach to analyze emergence of leadership in small groups using multimodal audio and visual features. In the computational framework, we first present an analysis on how an emergent leader is perceived in newly formed, small groups. We present the ELEA (Emergent LEadership Analysis) corpus collected with the aim of analyzing emergence of leaders. We propose to analyze emergent leaders, using a variety of nonverbal cues studied in social psychology and automatically extracted from audio and video streams. Our analysis address how the emergent leader is perceived by his/her peers in terms of speaking and visual active, and its relation with the most dominant person (including external observers’ perception). We then propose to investigate which individual nonverbal channel (or combination of features from different channels) provides better inferences of the emergent leader and related concepts using unsupervised and supervised methods. We use a supervised collective approach which adds relational information to the nonverbal cues and compare its performance, with the performance of supervised (non-collective) and unsupervised methods. We also propose to capture the social visual attention patterns from automatically extracted features from video, in order to analyze who receives or gives the largest amount of visual attention in the group. Finally, with the aim of understanding who receives the largest amount of visual attention while speaking and who has the highest dominance ratio (i.e., many occurrences of looking at others while speaking and few occurrences of looking at others while not speaking). We synchronize the audio and video streams to capture the speaking and attention activity patterns. We end our analysis exploring the impact of the verbal content (language style) in the interactions and its influence in the perception of emergent leaders. For the language style analysis, we propose to compute word categories extracted from manual transcriptions of the discussions as well as from automatically detected keywords. We propose to use a supervised method to obtain the relevant features, and to use only the top word categories to predict the emergent leader and related concepts in each group. We then propose to differentiate word categories, between highly context-related and context-free, to explore the feasibility to infer the emergent leader in a fully automatic approach from the context-free language style. This dissertation address an audio and visual analysis of the ubiquitous phenomenon of emergent leadership in a fully automatic computational approach from face-to-face interactions. The nonverbal behavioral analysis is inspired in previous works on social psychology in the context of emergent leadership and related concepts. The automatically extracted nonverbal features are modeled to feed state-of-the-art machine learning techniques in order to infer emergent leaders.

EPFL2013

Electrophoretic deposition of multi-scale structured TiO2 surfaces

The long term fixation of biomedical implants constitutes an issue in the clinical praxis. Implant fixation can be improved by functionalizing its surface. In fact, the tissue response around an implant is conditioned by its surface morphological and chemical properties. Coatings for implants (orthopedic and dental) function at the bone-implant fixation interface. As proved by research activities in the biomedical field, coatings with topographic features in the nano- and micro-range are promising in terms of enhanced osteointegration, thus improved implant fixation. As for surface chemistry, titanium dioxide (TiO2) is an estabilished material for biomedical implants thanks to its outstanding physical and chemical properties such as high corrosion resistance and good biocompatibility. Electrophoretic deposition (EPD) is a simple and versatile coating technique. According to literature, EPD is an emerging potential coating technique for biomedical implants. In this work, the use of EPD in the preparation of TiO2 coatings characterized by a controlled multi-scale structured surface was addressed. For this aim, EPD was combined with a new procedure of particle functionalization and with the use of a fugitive spacer (polystyrene, PS) for the sintering treatment. A control and better understanding of the EPD process were achieved through a preliminary parametric study on EPD of TiO2 nanoparticles and PS microbeads. Particle concentration was found to play a key role in the EPD deposit formation of TiO2 nanoparticles (cathodic) and PS microbeads (anodic). A threshold value of particle concentration was identified, below which no deposit growth occurred. An interpretation of this finding was provided on the base of a new formulation of the EPD deposition mechanism. The results of the particle concentration study contributed to the preparation of suspensions with TiO2-PS composite particles, which could be used for cathodic EPD. Composite TiO2-PS particles with TiO2 nanoparticles covering PS microbeads were obtained in a newly developed wet colloidal process based on heterocoagulation and the use of polyelectrolytes. The resulting TiO2-PS particles were cathodically deposited on Ti6Al4V substrates. A sintering post-treatment caused the burning out of the PS beads and the densification of the TiO2 nanoparticles. The desired coatings with controlled micro- and nano-topography were achieved. The investigation on the role of particle concentration in EPD and the new interpretation of the deposition mechanism bring a deeper understanding of the EPD process. The achievement of TiO2 coatings with controlled morphology in the micro- and nano-range prepared by cathodic EPD on Ti6Al4V substrates is a contribution to the ongoing research on biomedical implants. Mechanical tests and surface analysis evaluating wettability and in vitro cell behavior with the achieved coatings are relevant topics for further research.

EPFL2009

Understanding the performance gap: a machine learning approach on residential buildings in Turin, Italy

Roberto Boghetti, Jérôme Henri Kämpf

Buildings account for the highest share of primary energy usage and greenhouse gas emission in the E.U. and U.S. [1], and most of this energy is used for space and water heating. Being able to gain a broader understanding of the gap between predicted and in situ measured thermal performance of buildings may, in a lot of cases, help reducing the energy consumption and, therefore, alleviating our pressure on the environment [2]. The aim of this research is to further investigate this performance gap and to evaluate the possibility of using machine learning algorithms to effectively predict the energy demand of buildings. For this purpose, a group of residential buildings in the city of Turin, Italy, is taken as case study: an estimation of their yearly heating demand is made using different machine learning algorithms, and their results are evaluated and discussed. The research showed that the use of machine learning resulted in a performance gap in line, if not lower, with the current literature. The reasons for this outcome, as well as possible future research directions are finally discussed.

IOP Publishing Ltd2019

An Atomistic Simulation Method for Oxygen Impurities in Aluminium Based on Variable Charge Molecular Dynamics

Andreas Elsener

Impurities are known to have a significant impact on materials properties. In particular, the presence of impurities can change mechanical properties and stabilize the microstructure by reducing grain growth and recrystallization processes. In the past atomistic simulations, in particular molecular dynamics, have contributed a lot to the understanding of deformation mechanisms in nanocrystalline metals. Especially, insights into details of dislocation/GB interactions have been gained. Additionally, simulations on coupled grain boundary migration in bicrystalline samples have played an important role in understanding stress assisted grain growth in nanocrystalline metals. However, all these simulations have been performed on monatomic systems. This means that the role of impurities has not yet been considered in these simulations. Some of the important difference between experiments and simulations could be removed by introducing dilute O distributions to computational Al samples. For this purpose, a simulation method is required which can deal with the oxidation of Al atoms around the O impurities and which can simulate the ionic and metallic nature of bonding simultaneously. Here, a method is suggested which fulfills the requirements by modifying the variable charge method of Streitz and Mintmire [Phys. Rev. B 50, 11996 (1994)]. A local chemical potential approach which optimizes the charge on only those atoms expected to be ionic is developed. Additionally the EAM potential for the non-electrostatic interaction given in the publication of Streitz and Mintmire is substituted by empirical potentials which treat the Al-Al interactions with a well-known Al potential. The Al-O and O-O interactions in these EAM potentials are fitted for the simulation of dilute O impurities in Al and additionally for the simulation of corundum in case of a second potential. The aforementioned developments are applied to study the effect of O impurities on the deformation of nc Al. A fully three-dimensional nc sample containing 15 grains of 12 nm grain-size is deformed with a dilute O content in the triple junction lines. The impact of O impurities on dislocation propagation is also considered in a sample which consists of a single grain extracted from a large molecular dynamics simulation. This simulation geometry contains a perfect dislocation, which is pinned at the surrounding grain boundary network. Therefore it allows the study of pinning strength and after unpinning the propagation behavior of the dislocation under various O impurity distributions. Additionally, the role of O impurities on coupled GB migration is investigated by studying two bicrystalline samples with different O distributions in both of them. In the discussion, the emphasis is on the simulation method. Especially, the significance of the samples, simulation conditions and the performance of the method in the different applications are discussed. Additionally, the different developments (local chemical potential approach and EAM potentials) are critically analyzed and improvements for future simulations of impurities are suggested.

EPFL2010

There are 377 Krüppel-associated box (KRAB) domain-containing zinc finger proteins (KZFPs) in the human genome, making them the largest family of transcription factors. KZFPs are defined by a N-terminal KRAB domain and several zinc-finger domains arranged in an array at the C-terminus of the proteins. The zinc-finger domains each form sequence specific interactions with double stranded DNA, allowing the zinc-finger array to target specific genomic sequences. The KRAB domain, through its interaction with the protein TRIM28 (also known as KAP1) allows for the stable silencing of transcription in a genomic region. Together these two domains allow KZFPs to bind specific regions of the genome and generally lead to the formation of heterochromatin and silencing of transcription allthough other functions for some KZFPs have been recently reported. KZFPs usually target transposable elements (TEs), mobile genomic elements that can move through the genome either by cut-and-paste or copy-paste mechanisms and make up almost half of the human genome. Different KZFPs bind to specific regions of TEs, limiting their expression and thus mitigating some of the threat they pose to human development, allowing both the TE and its host to survive. In recent years it became apparent that both certain TEs and KZFPs have roles beyond the previously described threat and mitigation of that threat. TEs harbor gene regulatory regions allowing, through their spread, for a dissemination of those regions through the genome and for new gene regulatory networks to form. KZFPs can affect the transcription of genes located in proximity to their binding sites leading to changes in gene regulation as well. A multitude of regulatory roles involving KZFPs and TEs have been described in recent years making them an exciting field of study. A major hurdle in understanding both KZFPs and TEs is to identify the binding sites of KZFPs, as they reveal both the targets of the KZFP and how, if at all, a TE is regulated by KZFPs. To do so, we expanded on previous efforts and aimed to perform chromatin immunoprecipitation followed by massively parallel sequencing (ChIP-seq) on every member of the human KZFP family. Here we present ChIP-seq experiments for 110 new KZFPs, which together with previously published data, allow us to study the binding of almost all human KZFPs (95%). The entirety of the data was analysed together to generate a coherent dataset and results for each KZFP are made available to the public on our web portal (https://tronoapps.epfl.ch/web/krabopedia/). The identified binding sites allowed us to witness the adaptation of the KZFP family to new TEs and showed how targeted sequences shift after segmental gene duplication events. Furthermore, we could corroborate that several KZFPs target the same TE subfamilies in a seemingly redundant fashion and show that unexpectedly these KZFPs arose independently in different genomic locations. These results represent a valuable tool for anyone studying KZFPs and should aid in the pursuit of both understanding KZFPs and TEs.

EPFL2022

Construire à distance

Habib Sayah

Through a case study, this research aims at contributing to the historic understanding of the international architecture after the Second World War. It is based on the monographic analysis of the projects realised by the Geneva agency Addor & Julliard in Lebanon during the years 1950 to 1960. The general theme of "constructing at distance" embraces and problematizes two types of considerations: on the one hand, the challenges that international architecture of the years 1950-1960 had to face when the operations of conception and execution where realised in different contexts (i.e. functional and technical challenges due to climatic imperatives; logistical challenges linked to the characteristics of the local culture of construction ; strategic challenges in relation to the specific political and economic situation in the developing countries) ; on the other hand, the specific creative opportunities that the internationally active agencies were able to seize abroad and of which also their local production took advantage (treatment of prestige programs and ambitious operations with partners open to avant-garde experimentations). The operations realised at distance by the Geneva agency Addor & Julliard in Lebanon constitute an architectural corpus of approximately ten buildings in the urban and suburban zone. These realisations, which are not well known in the circles of researchers and architects, both locally and internationally, deserve to be analysed in detail, as they are very representative for the atmosphere of experimentation during the years 1950-1960 in Lebanon and generally in the other contexts of north-south collaboration. The work of the agency Addor & Julliard is still not well known in Geneva, with the exception of some publications on important projects like the Cayla campaign, or the Budé and Lignon blocks. Especially, the importance of the profitable interactions that the agency was able to establish between its two fields of activities in Geneva and Lebanon, and its significance for the development of this big agency, have not been stressed enough. The introductory part of our work situates the actuality of the problematic, in relation to the specific stakes of the protection of architectural and urban heritage in Lebanon. Still today, the heritage of the 1950-1960's is insufficiently understood in its cultural significance. It is also very much threatened. When it is not destroyed, it suffers from a camouflage that makes it totally unrecognisable. We then present the abundant documentation that we have gathered. This work on source material is necessary to counteract the superficial prejudice with which this architectural corpus is confronted. This part is then followed by a historical chapter on the agency Addor & Julliard before the opening of its Lebanese branch, as well as an overview of the Lebanese context between the beginning of the XXth century and 1960. These elements allow us to assert that the decisive factor allowing the agency to develop its foreign activity is to be found in the profile of particular competencies that it displayed by closely associating the architectural project and the real estate management. The apartment- and office-building realised in 1954 in Geneva the Zschokke enterprise, with its easily adaptable spatial organisation, played the trigger role : it encouraged the first Lebanese clients, the Beydoun family who had financial relations in Geneva, to mandate the agency for a project involving a multifunctional building in Lebanon. The Lebanese context of this period is characterised by a strong economic boom and a political stability conducive to investments. The real estate sector was in full growth and asked for innovative typologies and modern architectural images. This allowed the agency Addor & Julliard to emancipate itself from the still quite regionalist references that it was entertaining in Geneva and to direct itself resolutely towards the international tendencies. These elements of historic information are then followed by the detailed survey of the agency's Lebanese production. Several buildings were realised in Lebanon, Syria and Iraq, but it is in Lebanon that the principal operations are concentrated, which explains that the survey limits itself to this country. The inventory concerns the ten buildings that have been spared from the destruction of the Lebanese War (1975-1991) and of which the archive documents have been preserved. The description of each object includes the history of the commission, the urban situation, the legal and regulatory situation, as well as the project variants when they exist. Then, the realised variant is analysed in detail by paying attention to the distributive, constructive and stylistic aspects. This survey then leads to a more interpretative reading that aims at evaluating the impact of these constructions on the urban development of Beirut. Addor & Julliard never had real town-planning mandates in Lebanon. But even though their realisations limited themselves to the architectural scale, they nevertheless contributed to the concretisation of a resolutely modern representation of the city, especially because they succeeded in treating orders of a considerable symbolic importance. The theme of "constructing at distance" is addressed via a comparative method that integrates the Lebanese, Geneva and international projects of the same period. This chapter also deals with the contribution of the buildings of Addor & Julliard to the local Lebanese construction culture on both the technical and expressive level. The demonstration is based on the curtain-wall that Addor & Julliard used twice in two very different buildings: the STARCO centre (1954-1962) and the Lebanese Bank (1962-1963). The in-depth analysis of the conception and the realisation of the curtain-wall, emblem of the "international style", allows to discover that in Beirut its use resulted much less from the importation of generic and abstract solutions than from a skilled synthesis between technical resources, which were locally available, and the aimed-at iconic effect. We thus perceive that "constructing at distance" is more complex than a simple knowledge transfer from one environment to another. The local differentiation of constructive elements of the international repertoire between 1950 and 1960, such as the curtain-wall, prompts us to question and complement the analysis of Hitchcock et Johnson on these phenomena in their famous publication "The International Style" of 1932, which seems too superficial. Our study finishes with an advocacy for the protection of the projects of Addor & Julliard in Lebanon. Without being exhaustive, this advocacy is based on the examination of the transformations touching these projects until today and establishes a series of recommendations for their protection. It is said that in Lebanon modern architecture of the years 1950 to 1960 constitutes the witness of the efforts undertaken in this period by the local actors in order to emancipate their country from a certain marginality in international relations. For this reason, the modern heritage fully belongs to the Lebanese history. The annexes especially contain the data bases, which we have constituted during the inventory of the projects and the archives, as well as some particularly important documents: The contract established between the architects and their first client represents the start of their work in Lebanon, whereas the minutes of the press conference of 21 March 1963, during which the Society of engineers and architects of Beirut criticizes the work of Addor & Julliard in Lebanon, symbolises the end of their Lebanese collaboration. Finally, an album exposes the photographs of the buildings of Addor & Julliard at the time and in their present state. ------------------------------ 3 Imm. Zschokke à Genève. In Werk, Bauen & Wohnen, 1957: pp. 367-368. 4 Lambert, S., STARCO Center, Beirut, Lebanon. UK, in Architectural Design, Mars 1963: pp. 138-140.

EPFL2007

Epigenetic memory aids: Synaptic and molecular effects of HDAC inhibition that support memory formation

Allison Marie Burns

Learning and memory rely on synaptic communication in which intracellular signals are transported to the nucleus to stimulate transcriptional activation. Memory induced transcriptional increases are accompanied by alterations to the epigenetic landscape and can be pharmacologically mimicked to ameliorate memory in both healthy and cognitively impaired animals. Of particular interest in this regard is histone acetylation, as this epigenetic modification is enriched during memory formation and is readily amenable to pharmacological manipulation by means of histone deacetylase inhibitors (HDACis). Although multiple studies have shown that systemic HDACi administration can improve memory formation, their mode of action is not yet fully understood. In this study, we tested whether HDACis â given systemically â augment epigenetic, transcriptional and electrophysiological responses that are induced by learning, thus amplifying naturally occurring responses via cognitive epigenetic priming. To do this, we combined a system-wide HDACi treatment with a sub-threshold contextual fear conditioning (CFC) paradigm, a weakened Pavlovian modal that, alone, does not lead to long term memory formation. We found that, in combination, HDACi and CFC improve recent contextual memory that is accompanied by enhanced long-term potentiation in the hippocampus. Conversely, combined HDACi-CFC treatment induced no such synaptic strengthening in the striatum, a brain region that is not directly activated by fear conditioning. We then used bulk and single nuclear RNA-sequencing to show that HDACi activates unique transcriptional pathways, both between the two brain regions and between cell types within the hippocampus, indicating that HDACi does not act indiscriminatingly, but instead supports cellular processes that are already occurring in response to the conditioning. Finally, we show that HDACi treatment paired with contextual fear conditioning enriches H3K27ac at enhancers of known memory-related genes within the hippocampus but that not all these genes are necessarily more transcriptionally active at the same time point. These results indicate that systemic HDACi administration acts as a cognitive enhancer by amplifying brain-region specific processes that are naturally induced during memory formation but that these results may not be a direct effect of enhancer histone acetylation. These findings shed light on the mechanisms of HDACi-mediated cognitive epigenetic priming and help to pave the way for potential new therapies for memory-related disorders.

EPFL2022

Comparison of the functional properties of trimeric and monomeric CaiT of Escherichia coli

Kamila Krystyna Guérin

Secondary transporters exist as monomers, dimers or higher state oligomers. The significance of the oligomeric state is only partially understood. Here, the significance of the trimeric state of the L-carnitine/gamma-butyrobetaine antiporter CaiT of Escherichia coli was investigated. Amino acids important for trimer stability were identified and experimentally verified. Among others, CaiT-D288A and -D288R proved to be mostly monomeric in detergent solution and after reconstitution into proteoliposomes, as shown by blue native gel electrophoresis, gel filtration, and determination of intermolecular distances. CaiT-D288A was fully functional with kinetic parameters similar to the trimeric wild-type. Significant differences in amount and stability in the cell membrane between monomeric and trimeric CaiT were not observed. Contrary to trimeric CaiT, addition of substrate had no or only a minor effect on the tryptophan fluorescence of monomeric CaiT. The results suggest that physical contacts between protomers are important for the substrate-induced changes in protein fluorescence and the underlying conformational alterations.

2019