Novel endosomolytic compounds enable highly potent delivery of antisense oligonucleotides

The therapeutic and research potentials of oligonucleotides (ONs) have been hampered in part by their inability to effectively escape endosomal compartments to reach their cytosolic and nuclear targets. Splice-switching ONs (SSOs) can be used with endosomolytic small molecule compounds to increase functional delivery. So far, development of these compounds has been hindered by a lack of high-resolution methods that can correlate SSO trafficking with SSO activity. Here we present in-depth characterization of two novel endosomolytic compounds by using a combination of microscopic and functional assays with high spatiotemporal resolution. This system allows the visualization of SSO trafficking, evaluation of endosomal membrane rupture, and quantitates SSO functional activity on a protein level in the presence of endosomolytic compounds. We confirm that the leakage of SSO into the cytosol occurs in parallel with the physical engorgement of LAMP1-positive late endosomes and lysosomes. We conclude that the new compounds interfere with SSO trafficking to the LAMP1-positive endosomal compartments while inducing endosomal membrane rupture and concurrent ON escape into the cytosol. The efficacy of these compounds advocates their use as novel, potent, and quick-acting transfection reagents for antisense ONs

Exploring the underlying dynamics of buyer-seller interaction in project afterlife

Abstract The marketing view of a business relationship that follows the handover of a project reflects an era before services became common in the industry. At that time, business relationships were assumed to end after project handover, especially in commercial terms. Since then, services have become an integral part of project business, enabling the emergence of a post-project business relationship. It can be validly argued that the literature has not sufficiently recognized the changing practices of project-based companies. Obviously, a business exchange can outlive a project handover, but the consequences for buyer-seller interaction remain unexplored. This study describes and explains the underlying dynamics of buyer-seller interaction in project afterlife. Interaction is considered to be an inherently dynamic process that is dependent on a continuous yet variable exchange of services. The theoretical foundation of this study builds on the literature on interaction and networks as well as the literature on project marketing and management. The empirical part of the study is conducted as a combination of single and multiple qualitative case studies in five different project contexts: content management systems, windmills, mining, engineered wood solutions, and paper machines. Eighty-two personal interviews provide the primary data. This study comprises an overview and four individual papers that contribute to a process-based understanding of post-project interaction. The study primarily contributes to the project marketing research. First, the results indicate that buyer-seller interaction varies between three extreme orientations, making the development of a post-project business relationship inherently dynamic and challenging to manage. Second, the study expands theory regarding post-project interaction by describing four typical relationships in service-intensive projects. Third, the study extends the theoretical lens of project marketing and provides analytical tools to examine post-project interaction. Fourth, the study clarifies the role of key individuals in mediating change in post-project nets. Fifth, the study identifies several intergroup tensions that restrain interaction and proposes methods to overcome these tensions.Tiivistelmä Markkinoinnin näkemys projektitoimituksen jälkeisestä liikesuhteesta perustuu pääosin aikaan ennen teollisuusyritysten palveluliiketoiminnan yleistymistä, jolloin liikesuhteen uskottiin päättyvän varsinkin taloudellisessa mielessä. Palveluliiketoiminta on kehittynyt osaksi projektiyritysten liiketoimintaa, mikä mahdollistaa liikesuhteen jatkumisen projektitoimituksen jälkeen. Voi perustellusti väittää, että alan kirjallisuus ei ole riittävästi tunnistanut yritysten muuttuneita käytäntöjä. Tästä syystä tarvitaan lisää tutkimusta palveluintensiivisten projektiyritysten liikesuhteista projektien jälkeisissä vaiheissa. Yritysten liikesuhteet muuttuvat dynaamisesti ja vaikka palveluvaihdanta on jatkuvaa, sen sisältö vaihtelee ajan kuluessa. Tämän tutkimuksen lähtökohta on kuvata ja selittää erilaisten yhteistoimintojen ja sidosten jatkumista yritysten välillä. Tutkimuksen teoreettinen tausta koostuu projektimarkkinoinnin ja projektijohtamisen kirjallisuudesta, joiden taustat ovat pääosin teollisten liikesuhteiden tutkimuksessa. Laadullisen tapaustutkimuksen empiirinen osio on toteutettu viidessä eri projektikontekstissa, joita ovat tuulivoima, kaivosala, paperikone, sisällönhallintajärjestelmä ja jalostettu puuteollisuus. Pääaineisto koostuu 82 haastattelusta. Tämä tutkimus koostuu johdanto-osiosta ja neljästä tutkimuspaperista, joiden tuloksena on prosessipohjainen viitekehys liikesuhteen kehityksestä. Tulokset ovat merkittäviä erityisesti projektimarkkinoinnin näkökulmasta, sillä ne osoittavat asiakkaan ja myyjän välisen vuorovaikutuksen vaihtelevan kolmen äärityypin välillä tehden liikesuhteen kehityksestä dynaamisen ja vaikeasti johdettavan. Tutkimus laajentaa näkemystä projektitoimituksen jälkeisestä vaihdannasta tunnistamalla neljä palveluvaihdantaan pohjautuvaa suhdetyyppiä. Lisäksi tutkimus kehittää työkaluja projektitoimitusten jälkeisten liikesuhteiden analyysiin ja laajentaa projektimarkkinoinnin teoreettista pohjaa. Tutkimus selventää myös avainhenkilöiden toimintaa projektitoimituksen jälkeisissä lähiverkoissa ja tunnistaa keinoja, joilla liikesuhdetta rasittavia henkilöiden välisiä jännitteitä voidaan välttää

The development of post-project buyer-seller interaction in service-intensive projects

The purpose of this research is to enhance the understanding of post-project buyer-seller interaction, a topic previously studied mainly from the perspective of social exchange or sleeping relationships. With the advent of service-intensive projects, however, the dynamics of post-project interaction has changed, demanding a broader theorization. This research extends the scope of project marketing, by proposing a research framework illustrating interaction development in a longitudinal setting. We utilize the framework to analyze three projects, two of which continued for more than a decade, through a qualitative case study. The research provides empirical insight into the interaction orientations and development patterns arising in the post-project stage. It suggests that post-project interaction develops through three main orientations (cooperative development, buyer-led development, and seller-led maintenance) that vary over time, thus creating unique development patterns. The study concludes with five practical recommendations for managers to deal with evolving post-project interaction

At the temporary-permanent interface:overcoming knowledge boundaries with boundary objects

Abstract There is no shortage of literature on managing complex projects. However, we lack an understanding of projects in which the complexity goes beyond technical, financial and time-related challenges. We report on two Nordic business school accreditation projects, where the major management challenge is the knowledge boundaries institutionalized deep into the ethos of the schools. We focus on the project team’s use of boundary objects — a communication device across social groups — to expose and overcome knowledge boundaries materializing at temporary-permanent interface. We identify three progressively more challenging boundary object uses: informative, interactive and integrative. Consequently, we suggest a dynamic approach to boundary objects wherein their use evolves throughout the project life span as a consequence of the lived “in situ” experiences

Using a ‘lens’ to re-search business markets, relationships and networks:tensions, challenges and possibilities

Abstract In this research, we wish to address the tension tucked away in scholarly work: the simultaneous need to break in and break out of academic communities and their ways of thinking. More precisely, we are interested in social re-search (i.e., searching again) processes and how scholars authenticate their research within an established cultural convention. For that purpose, we focus on the use of the term ‘lens’, which is omnipresent in research texts but rarely defined. Upon completing an integrative literature review and considering the embeddedness of a lens in culture, language, research communities and our ontological assumptions, we define a ‘research lens’ as a sociocultural representation and tool that helps to negotiate our scientific interpretation of the world. Our contribution to industrial marketing stems from surfacing and discussing four uses of a lens evident in the industrial marketing literature, introducing a metaphorical lens as a way to reform knowledge, and finally exemplifying how our lens tends to either mirror, reflect, symbolize or mirage the contours of our world without our full awareness of it