The rise of techno-geopolitical uncertainty: Implications of the United States CHIPS and Science Act.

Growing techno-geopolitical uncertainty affects international business in many ways, calling for more scholarly attention to its causes and multinational enterprise (MNE) responses. The United States CHIPS and Science Act epitomizes the country's recent embrace of techno-nationalism in its economic rivalry with China, which has major implications for IB scholarship and management practice. The Act exhibits two features that fly against America's traditional liberal policy stance of championing an open and rules-based multilateral system. First, its reliance on subsidies, export control, and investment screening signifies departure from free trade and from market-based industrial policies. Second, its use of guardrail provisions pursues the weaponization of global value chains for geopolitical and geo-economic purposes. We view the Act as a showcase of a paradigm shift from market-oriented liberalism to intervention-oriented techno-nationalism, heralding a new era of zero-sum thinking and geopolitical prioritization. By examining the broader trend of techno-nationalism, we explore the distinct features of the Act and analyze the geo-strategies that MNEs need to adopt in response to the resulting techno-geopolitical uncertainty. Our analysis highlights the paradigm shift in policymaking, identifies the root causes of this shift, and examines the potential pitfalls it may create. To navigate this uncertain landscape, we suggest four strategic responses for MNEs: geo-strategies, reconfiguration, resilience, and corporate diplomacy.

L'incertitude techno-géopolitique croissante influence de multiples façons les affaires internationales. Ceci appelle une attention accrue de la part des chercheurs sur ses causes et des réponses des entreprises multinationales. La loi américaine sur les puces et la science (The United States CHIPS and Science Act) illustre parfaitement l'adhésion récente du pays au techno-nationalisme dans le cadre de sa rivalité économique avec la Chine, ce qui a des implications majeures pour la recherche en affaires internationales et les pratiques de gestion. Cette loi présente deux caractéristiques qui vont à l'encontre de la politique libérale traditionnelle des États-Unis prônant un système multilatéral ouvert et fondé sur des règles. Premièrement, son recours aux subventions, au contrôle des exportations et au filtrage des investissements signifie que le pays s'écarte du libre-échange et des politiques industrielles basées sur le marché. Deuxièmement, son utilisation des dispositions de garde-fous poursuit la militarisation des chaînes de valeur globales à des fins géopolitiques et géoéconomiques. Nous considérons cette loi comme la vitrine d'un changement de paradigme, passant d'un libéralisme axé sur le marché à un techno-nationalisme axé sur l'intervention, annonçant une nouvelle ère de pensée à somme nulle et de priorisation géopolitique. En examinant la tendance plus large du techno-nationalisme, nous explorons les caractéristiques distinctes de cette loi, et analysons les géostratégies que les entreprises multinationales doivent adopter en réponse à l'incertitude techno-géopolitique qui en résulte. Notre analyse met en évidence le changement de paradigme dans l'élaboration des politiques, identifie les causes profondes de ce changement, et examine également les pièges potentiels qu'il peut créer. Pour naviguer dans ce paysage incertain, nous suggérons quatre réponses stratégiques aux entreprises multinationales : géostratégies, reconfiguration, résilience et diplomatie d'entreprise.

La creciente incertidumbre tecno-geopolítica afecta a los negocios internacionales de muchas maneras, lo que convoca a una mayor atención académica a sus causas y a las respuestas de las empresas multinacionales (EMN). La Ley CHIPS y Ciencia de Estados Unidos ejemplifica la reciente adopción por parte del país del tecno-nacionalismo en su rivalidad económica con China, lo que tiene importantes implicaciones para los estudios de negocios internacionales y la práctica gerencial. La Ley presenta dos características que van en contra de la postura política liberal tradicional de Estados Unidos, que defiende un sistema multilateral abierto y basado en normas. En primer lugar, su dependencia de las subvenciones, el control de las exportaciones y el control de las inversiones supone un alejamiento del libre comercio y de las políticas industriales basadas en el mercado. En segundo lugar, su uso de disposiciones de protección persigue la militarización de las cadenas de valor mundiales con fines geopolíticos y geoeconómicos. En nuestra opinión, la Ley es una exhibición de un cambio de paradigma, del liberalismo orientado al mercado al tecno-nacionalismo orientado a la intervención, que anuncia una nueva era de pensamiento de suma cero y priorización geopolítica. Al examinar la tendencia más amplia del tecno-nacionalismo, exploramos las características distintivas de la Ley y analizamos las geoestrategias que las EMN deben adoptar en respuesta a la incertidumbre tecno-geopolítica resultante. Nuestro análisis destaca el cambio de paradigma en la formulación de políticas, identifica las causas fundamentales de este cambio y examina los posibles atolladeros que puede crear. Para navegar por este panorama incierto, sugerimos cuatro respuestas estratégicas para las EMN: geoestrategias, reconfiguración, resiliencia y diplomacia corporativa.

Crescente incerteza tecnogeopolítica afeta os negócios internacionais de várias maneiras, exigindo mais atenção acadêmica para suas causas e respostas de empresas multinacionais (MNE). A Lei de CHIPS e Ciência dos Estados Unidos simboliza a recente adoção do nacionalismo tecnológico em sua rivalidade econômica com a China, que tem grandes implicações para a pesquisa em IB e práticas gerenciais. A Lei exibe duas características que vão contra a tradicional postura política liberal dos Estados Unidos de defender um sistema multilateral aberto e baseado em regras. Primeiro, sua dependência em subsídios, controle de exportação e triagem de investimentos significa afastamento do livre comércio e de políticas industriais baseadas no mercado. Em segundo lugar, o uso de provisões de proteção busca o uso de cadeias de valor globais como armas para fins geopolíticos e geoeconômicos. Enxergamos a Lei como uma vitrine de uma mudança de paradigma do liberalismo orientado para o mercado para o tecnonacionalismo orientado para a intervenção, anunciando uma nova era de pensamento de soma zero e priorização geopolítica. Ao examinar a ampla tendência do tecnonacionalismo, exploramos as características distintas da Lei e analisamos as geoestratégias que MNEs precisam adotar em resposta à incerteza tecnogeopolítica resultante. Nossa análise destaca a mudança de paradigma na formulação de políticas, identifica as causas originais dessa mudança e examina as possíveis armadilhas que ela pode criar. Para navegar nesse cenário incerto, sugerimos quatro respostas estratégicas para MNEs: geoestratégias, reconfiguração, resiliência e diplomacia corporativa.

Industry 4.0 in international business research.

The advent of Industry 4.0 promises to transform the global business landscape, the nature of markets and industries, and the way multinationals organize their operations as well as how and where they compete. These changes will have important - indeed profound - implications for IB scholarship. In this article, we explain Industry 4.0 and its distinguishing characteristics; discuss its organizational and strategic implications for multinationals; and outline the fundamental questions it raises for future IB research. To spur future analysis, we also present a conceptual foundation that articulates the new features, processes, and capabilities that support MNEs' pursuit of Industry 4.0-related opportunities surrounding digitalization, intelligence, technology, and innovation. We also discuss what Industry 4.0 means for IB research concerning social engagement, environmental sustainability, and international entrepreneurship. We elucidate how this new landscape shapes the extant IB literature and how future research can push it further along.

L'avènement de l'Industrie 4.0 promet de transformer le paysage commercial mondial, la nature des marchés et des industries, la façon d'organiser des opérations des multinationales ainsi que la manière dont et le lieu où ces dernières rivalisent. Ces changements auront des implications importantes, voire profondes, pour la recherche en affaires internationales (International Business ­ IB). Dans cet article, nous expliquons l'Industrie 4.0 et ses caractéristiques distinctives ­ discutons ses implications organisationnelles et stratégiques pour les multinationales ­ et exposons les questions fondamentales qu'elle soulève pour de futures recherches en IB. Afin de stimuler de futures analyses, nous présentons également un fondement conceptuel articulé autour des caractéristiques, capacités et processus nouveaux qui permettent aux multinationales de saisir les opportunités liées à l'Industrie 4.0 en matière de numérisation, d'intelligence, de technologie et d'innovation. Nous examinons également ce que l'Industrie 4.0 signifie pour la recherche en IB en matière d'engagement social, de durabilité environnementale et d'entrepreneuriat international. Nous mettons en lumière comment ce nouveau paysage façonne la littérature existante de l'IB et comment de futures recherches peuvent la faire progresser.

La llegada de la Industria 4.0 promete transformar el panorama empresarial global, la naturaleza de los mercados y las industrias, y el modo en que las multinacionales organizan sus operaciones, así como el modo y el lugar en que compiten. Estos cambios tendrán importantes implicaciones ­ de hecho, profundas ­ para los académicos de negocios internacionales. En este artículo, explicamos la Industria 4.0 y sus características distintivas, analizamos sus implicaciones organizacionales y estratégicas para las multinacionales y esbozamos las cuestiones fundamentales que plantea para la futura investigación sobre negocios internacionales. Para estimular futuros análisis, también presentamos una base conceptual que articula las nuevas características, procesos y capacidades que apoyan la búsqueda de oportunidades relacionadas con la Industria 4.0 por parte de las empresas multinacionales en torno a la digitalización, la inteligencia, la tecnología y la innovación. También analizamos lo que significa la Industria 4.0 para la investigación en negocios internacionales en lo que respecta al compromiso social, la sostenibilidad medioambiental y el emprendimiento internacional. Esclarecemos cómo este nuevo panorama da forma a la literatura existente de negocios internacionales y cómo la investigación futura puede hacerla avanzar.

O advento da Indústria 4.0 promete transformar o cenário global de negócios, a natureza de mercados e indústrias e a forma pela qual multinacionais organizam suas operações, e como e onde competem. Essas mudanças terão implicações importantes ­ realmente profundas ­ para a pesquisa em IB. Neste artigo, explicamos a Indústria 4.0 e suas características distintivas; discutimos suas implicações organizacionais e estratégicas para multinacionais; e delineamos as questões fundamentais que ela levanta para futuras pesquisas em IB. Para estimular futuras análises, também apresentamos uma base conceitual que articula as novas características, processos e capacidades que apoiam a busca de oportunidades relacionadas à Indústria 4.0 por MNEs em torno da digitalização, inteligência, tecnologia e inovação. Também discutimos o que a Indústria 4.0 significa para a pesquisa em IB no que tange ao engajamento social, sustentabilidade ambiental e empreendedorismo internacional. Elucidamos como esse novo cenário molda a literatura existente em IB e como pesquisas futuras podem avançá-la ainda mais.

Corporate social performance in international business.

We examine the 2022 JIBS Decade Award article by Ioannou and Serafeim (J Int Bus Stud 43(9):834-864, 2012) and review the literature since 2012 to clarify research developments in corporate social responsibility and corporate social performance (CSP) in the multinational enterprise, articulating key themes, findings and antecedents. We present a general framework that highlights unique traits and processes of CSP for MNEs. To advance scholarly progress, we delineate how new theoretical perspectives, such as organizational identity and strategic choice, can be blended with the IB literature to deepen theorization of the topic. We also discuss how new global dynamics, such as geopolitics, digitization, and activism, may shape CSP strategies and activities for MNEs and how future research can tackle these issues.

Nous examinons l'article d'Ioannou et Serafeim (2012) ­ lauréat du 2022 JIBS Decade Award ­ et passons en revue la littérature depuis 2012 afin de clarifier les développements de la recherche sur la responsabilité sociale des entreprises (Corporate Social Responsibility ­ CSR) et la performance sociale des entreprises (Corporate Social Performance ­ CSP) dans l'entreprise multinationale, et ce en articulant les thèmes clés, les résultats et les antécédents. Nous présentons un cadre général mettant en évidence les processus et les caractéristiques uniques de la CSP pour les entreprises multinationales. Dans le but de faire progresser la recherche, nous décrivons comment de nouvelles perspectives théoriques, telles que l'identité organisationnelle et le choix stratégique, peuvent être combinées à la littérature des affaires internationales en vue d'approfondir la théorisation du thème de recherche. Nous discutons également comment les nouvelles dynamiques mondiales, telles que la géopolitique, la numérisation et l'activisme, peuvent façonner les activités et les stratégies de CSP des multinationales, et comment de futures recherches peuvent aborder ces questions.

Examinamos el artículo galardonado con el Premio JIBS de la Década de 2022 de Ioannou y Serafeim (2012) y revisamos la bibliografía desde 2012 para aclarar la evolución de la investigación sobre la responsabilidad social de las empresas (RSE) y el desempeño social de las empresas (CSP por sus iniciales en inglés) en la empresa multinacional, articulando los temas clave, las conclusiones y los antecedentes. Presentamos un marco general que pone de relieve los rasgos y procesos únicos del desempeño social de las empresas en las empresas multinacionales. Para avanzar en el progreso académico, delineamos cómo las nuevas perspectivas teóricas, como la identidad organizacional y la elección estratégica, pueden combinarse con la literatura de la empresa multinacional para profundizar en la teorización del tema. También discutimos cómo las nuevas dinámicas globales, como la geopolítica, la digitalización y el activismo, pueden dar forma a las estrategias y actividades de desempeño social de las empresas de las empresas multinacionales y cómo la investigación futura puede abordar estas cuestiones.

Examinamos o artigo de Ioannou e Serafeim (2012) vencedor do 2022 JIBS Decade Award e revisamos a literatura desde 2012 para esclarecer desenvolvimentos da pesquisa em responsabilidade social corporativa (CSR) e desempenho social corporativo (CSP) na empresa multinacional, articulando temas-chave, conclusões e antecedentes. Apresentamos um modelo geral que destaca características e processos únicos de CSP para MNEs. Para avançar progresso acadêmico, delineamos como novas perspectivas teóricas, tais como identidade organizacional e escolha estratégica, podem ser combinadas com a literatura de IB para aprofundar a teorização do tópico. Também discutimos como novas dinâmicas globais, como geopolítica, digitalização e ativismo, podem moldar estratégias e atividades de CSP para MNEs e como pesquisas futuras podem abordar essas questões.

Scavenging ROS and inflammation produced during treatment to enhance the wound repair efficacy of photothermal injectable hydrogel.

Injectable hydrogels with near infrared (NIR) photothermal ability show attractive application prospects in the treatment of wound infection and promoting skin defect repair. Nevertheless, excess reactive oxygen species (ROS) and inflammatory responses caused by bacterial infection and photothermal therapy (PTT) would delay tissue regeneration and wound healing. In this study, a novel NIR photothermal injectable hydrogel with anti-oxidation and anti-inflammation by incorporating α-lipoic acid modified palladium nanoparticles into calcium ions crosslinked sodium alginate hydrogel was developed. The resulting hydrogel facilitated to fill perfectly various irregular wounds, and could convert NIR light into local high-heat to kill >80 % of Escherichia coli and Staphylococcus aureus. Remarkably, the hydrogel exhibited excellent anti-oxidant and anti-inflammatory activity, which could scavenge >60 % of ROS in cells and decrease the relative expression level of tumor necrosis factor-alpha and interleukin-1ß genes by 52.9 % and 53.3 % respectively. It was found that the NIR photothermal injectable hydrogel with anti-oxidation and anti-inflammation could effectively reduce ROS and inflammation caused by bacterial infection and PPT. Additionally, it could also enhance wound repair efficiency. The hydrogel is expected to be a potential wound dressing for the treatment of clinical skin defects.

New connectivity in the fragmented world.

We are entering a significantly fragmented world that is full of extreme disruptions and adversities. New connectivity in digital form proves the essential characteristic to help international businesses better cope with these disruptions. This connectivity signifies a dominant feature of the new era of international business and a critical catalyst to address new uncertainties in today's fragmented world. However, this new normal raises a series of complex issues that extend the IB research agenda. This article illustrates this connectivity's conceptual components, theoretical framework, and broad implications for IB research. We further show how MNEs leverage new connectivity to bolster competitive vitality and organizational adaptability when facing unprecedented uncertainties in a fractured and fragile world. This study also offers insights into digital ways of improving cross-border resilience. We conclude with suggested avenues for future research and potential steps.

Nous entrons dans un monde considérablement fragmenté, plein de perturbations et d'adversités extrêmes. La nouvelle connectivité sous forme numérique s'avère la caractéristique essentielle pour aider les entreprises internationales à mieux faire face à ces perturbations. Cette connectivité représente non seulement une caractéristique dominante de la nouvelle ère des affaires internationales (International Business ­ IB), mais aussi un catalyseur essentiel pour dissiper de nouvelles incertitudes du monde fragmenté d'aujourd'hui. Mais cette nouvelle normalité soulève une série de questions complexes qui élargissent le programme de recherche en IB. Cet article éclaire les composantes conceptuelles et le cadre théorique de cette connectivité ainsi que ses vastes implications pour la recherche en IB. Nous montrons également comment les entreprises multinationales, confrontées à des incertitudes sans précédent dans un monde fracturé et fragile, tirent parti de cette nouvelle connectivité afin de renforcer leur vitalité concurrentielle et leur adaptabilité organisationnelle. Cette recherche apporte également des renseignements sur des moyens numériques susceptibles d'améliorer la résilience transfrontalière. Nous concluons en suggérant des pistes de futures recherches et des étapes potentielles.

Estamos entrando en un mundo significativamente fragmentado que está lleno de disrupciones y adversidades extremas. La nueva conectividad en forma digital demuestra la característica esencial para ayudar a los negocios internacionales a conllevar con estas disrupciones. Esta conectividad significa un rasgo dominante en la nueva era de los negocios internacionales y un catalizador crítico para encarar las nuevas incertidumbres en el mundo fragmentado de hoy. Pero este nuevo normal suscita una serie de asuntos complejos que extienden la agenda de investigación en negocios internacionales. Este artículo ilustra estos componentes conceptuales, marco teórico y amplias implicaciones de la conectividad para la investigación en negocios internacionales. Además, mostramos cómo las empresas multinacionales apalancan la nueva conectividad para reforzar la vitalidad competitividad y la adaptabilidad organizacional cuando se enfrentan a incertidumbres en un mundo fracturado y frágil. Este estudio también ofrece pistas sobre las formas digitales para mejorar la resiliencia transfronteriza. Concluimos con avenidas sugeridas para la investigación futura y los pasos potenciales.

Estamos entrando em um mundo significativamente fragmentado, cheio de extremas rupturas e adversidades. Nova conectividade em formato digital demonstra a característica essencial para ajudar empresas internacionais a lidar melhor com essas disrupções. Essa conectividade significa uma característica dominante da nova era dos negócios internacionais e um catalisador crítico para lidar com novas incertezas no mundo fragmentado de hoje. Mas esse novo normal levanta uma série de questões complexas que ampliam a agenda de pesquisa em IB. Este artigo ilustra os componentes conceituais, modelo teórico e amplas implicações para a pesquisa em IB dessa conectividade. Mostramos ainda como MNEs alavancam a nova conectividade para reforçar a vitalidade competitiva e a adaptabilidade organizacional ao enfrentar incertezas sem precedentes em um mundo fraturado e frágil. Este estudo também oferece insights sobre formas digitais de melhorar a resiliência transfronteiriça. Concluímos com sugestões de caminhos para pesquisas futuras e possíveis etapas.

Learning from inbound foreign acquisitions for outbound expansion by emerging market MNEs.

Although cross-border acquisitions (CBAs) are prevalent, many such acquisitions fail to complete. This challenge is even more profound for emerging market MNEs (EMNEs). Drawing upon the vicarious learning theory, we argue that EMNEs can learn from inbound foreign acquirers through the latter's demonstration, professional services firms, and employees. This learning mechanism enables EMNEs to better deal with the complexity and uncertainty in various stages of acquiring foreign firms, thus increasing the completion rate of their outbound CBAs. We also suggest that the effectiveness of vicarious learning is further enhanced by the relatedness between inbound and outbound CBAs. Our analysis of 3599 outbound CBAs from 27 emerging economies during 2000-2018 shows that prior inbound CBAs completed in an emerging economy have a positive effect on the completion likelihood of outbound CBAs conducted by EMNEs from this economy. This positive effect becomes even stronger when the percentage of (1) inbound CBAs served by the EMNE's financial advisors, (2) inbound foreign acquirers that are in the same industry as the EMNE, and (3) inbound foreign acquirers that are from the same country as a focal outbound CBA's target country, is larger. These findings offer new insights into the inbound-outbound acquisition links and the internationalization process of EMNEs. Supplementary Information: The online version contains supplementary material available at 10.1057/s41267-022-00583-x.

Bien que les acquisitions transfrontalières (Cross-Border Acquisitions ­ CBAs) soient répandues, nombre d'entre elles ne sont pas menées à bien. Ce défi est encore plus grand pour les multinationales des marchés émergents (Emerging Market MNEs ­ EMNEs). Nous appuyant sur la théorie de l'apprentissage vicariant, nous argumentons que les EMNEs peuvent apprendre des acquéreurs étrangers entrants par le biais des démonstrations de ces derniers, des entreprises de services professionnels et des employés. Ce mécanisme d'apprentissage permet aux EMNEs de mieux gérer la complexité et l'incertitude des différentes étapes de l'acquisition d'entreprises étrangères, augmentant ainsi le taux d'achèvement de leurs CBAs sortantes. Nous suggérons également que l'efficacité de l'apprentissage vicariant est renforcée par la relation entre les CBAs entrantes et sortantes. Notre analyse de 3599 CBAs sortantes de 27 économies émergentes entre 2000 et 2018 montre que les CBAs entrantes antérieures réalisées dans une économie émergente ont un impact positif sur la probabilité d'achèvement des CBAs sortantes réalisées par les EMNEs de cette économie. Cet impact positif devient encore plus fort lorsque le pourcentage (1) de CBAs entrantes servies par les conseillers financiers de l'EMNE, (2) d'acquéreurs étrangers entrants appartenant au même secteur d'activité que l'EMNE, et (3) d'acquéreurs étrangers entrants provenant du même pays que le pays cible d'une CBA sortante focale, est plus élevé. Ces résultats apportent de nouveaux renseignements sur les liens entre les acquisitions entrantes et sortantes, ainsi que sur le processus d'internationalisation des EMNEs.

Aunque las adquisiciones transfronterizas (CBAs por sus iniciales en inglés) son frecuentes, muchas de ellas no consiguen completarse. Este reto es aún más profundo para las empresas multinacionales de mercados emergentes (EMNE por sus iniciales en inglés). Basándonos en la teoría del aprendizaje vicario, argumentamos que las empresas multinacionales de mercados emergentes pueden aprender de los adquirentes extranjeros entrantes a través de la demostración de estos últimos, de las empresas de servicios profesionales y de los empleados. Este mecanismo de aprendizaje permite a las empresas multinacionales de mercados emergentes afrontar mejor la complejidad y la incertidumbre en varias etapas de la adquisición de empresas extranjeras, aumentando así la tasa de finalización de sus adquisiciones transfronterizas salientes. También sugerimos que la eficacia del aprendizaje vicario se ve reforzada por la relación entre las adquisiciones transfronterizas entrantes y salientes. Nuestro análisis de 3.599 adquisiciones transfronterizas salientes de 27 economías emergentes durante 2000­2018 muestra que las adquisiciones transfronterizas entrantes anteriores completados en una economía emergente tienen un efecto positivo en la probabilidad de finalización de las adquisiciones transfronterizas salientes realizados por las empresas multinacionales de mercados emergentes de esta economía. Este efecto positivo se hace aún más fuerte cuando el porcentaje de (1) las adquisiciones transfronterizas entrantes atendidos por los asesores financieros de la empresa multinacional de mercados emergentes, (2) adquirentes extranjeros entrantes que están en la misma industria que la empresa multinacional de mercados emergentes, y (3) adquirentes extranjeros entrantes que son del mismo país que el país objetivo de una adquisición transfronteriza saliente focal, es mayor. Estos resultados ofrecen nuevas perspectivas sobre los vínculos de adquisición entrante-saliente y el proceso de internacionalización de las empresas multinacionales de mercados emergentes.

Embora as aquisições transfronteiriças (CBAs) sejam predominantes, muitas dessas aquisições não têm sucesso na sua conclusão. Esse desafio é ainda mais profundo para MNEs de mercados emergentes (EMNEs). Com base na teoria da aprendizagem vicária, argumentamos que EMNEs podem aprender com compradores estrangeiros entrantes por meio de sua demonstração, empresas de serviços profissionais e funcionários. Esse mecanismo de aprendizagem permite que EMNEs lidem melhor com a complexidade e a incerteza em vários estágios de aquisição de empresas estrangeiras, dessa forma aumentando a taxa de conclusão de suas CBAs. Também sugerimos que a eficácia da aprendizagem vicária é ainda mais reforçada pela relação entre CBAs de entrada e saída. Nossa análise de 3.599 CBAs de saída de 27 economias emergentes durante 2000­2018 mostra que CBAs de entrada anteriores concluídas em uma economia emergente têm um efeito positivo na probabilidade de conclusão de CBAs de saída conduzidas por EMNEs dessa economia. Este efeito positivo torna-se ainda mais pronunciado quando é maior o percentual de (1) CBAs de entrada atendidos por consultores financeiros da EMNE, (2) adquirentes estrangeiros de entrada que são da mesma indústria que a EMNE e (3) adquirentes estrangeiros de entrada que são do mesmo país do destino de uma CBA de saída. Essas descobertas oferecem novos insights sobre as conexões de aquisição de entrada e saída e o processo de internacionalização de EMNEs.

Illusions of techno-nationalism.

Current techno-nationalism presents new risks in international business, amplifying volatility, uncertainty, and complexity for multinational enterprises (MNEs). This study explains how today's techno-nationalism differs from its traditional form, the underlying theoretic logic, the damage it may cause to MNEs, and what MNEs can do to contain the potential harm. We elaborate on several points: (1) new techno-nationalism combines geopolitical, economic, national security, and ideological considerations, and is thus more complex and disruptive to international business than the traditional standpoint; (2) new techno-nationalism is underpinned by the realism doctrine, which portrays the world as zero-sum competition in which states leverage their power of economic coercion, and does not recognize the importance of technological interconnectivity, resource complementarity, open innovation, and positive-sum co-opetition; (3) techno-nationalism obstructs MNEs, especially those dependent on the global technology supply chain and on target country market contribution; and (4) MNEs can respond to techno-nationalism, defensively or offensively, contingent upon their exposure and ability to manage the risks associated with related policies.

Le techno-nationalisme actuel présente de nouveaux risques dans les affaires internationales, amplifiant la volatilité, l'incertitude et la complexité pour les entreprises multinationales (Multinational enterprises - MNEs). Cette recherche explique en quoi le techno-nationalisme actuel diffère de sa forme traditionnelle. Elle explique également la logique théorique sous-jacente, les dommages qu'il peut causer aux MNEs ainsi que ce que celles-ci peuvent faire afin de maîtriser les dommages potentiels. Nous développons plusieurs points : (1) le nouveau techno-nationalisme combine des considérations géopolitiques, économiques, idéologiques et de sécurité nationale, et est donc plus complexe et disruptif pour les affaires internationales que la perspective traditionnelle ; (2) le nouveau techno-nationalisme s'appuie sur la doctrine du réalisme qui décrit le monde comme une concurrence à somme nulle dans laquelle les États tirent parti de leur pouvoir de coercition économique et ne reconnaissent pas l'importance de l'interconnectivité technologique, de la complémentarité des ressources, de l'innovation ouverte et de la coopétition à somme positive ; (3) le techno-nationalisme entrave les MNEs, plus spécifiquement, celles qui dépendent de la chaîne d'approvisionnement technologique globale et de la contribution des pays marchés cibles ; et (4) les MNEs peuvent réagir, de manière défensive ou offensive, au techno-nationalisme, et ce en fonction de leur exposition et de leur capacité à gérer les risques liés aux politiques associées.

El tecno-nacionalismo actual presenta nuevos riesgos en negocios internacionales, amplificación de la volatilidad, incertidumbre, y complejidad de las empresas multinacionales (EMNs). Este estudio explica como el tecno-nacionalismo de hoy difiere de su forma tradicional, la lógica teórica subyacente, el daño que puede causar a las empresas multinacionales, y que pueden hacer las empresas multinacionales para contener el daño potencial. Detallamos en varios puntos: (1) el tecno-nacionalismo combina consideraciones geopolíticas, económicos, de seguridad nacional e ideológicas, y por lo tanto más complejos y disruptivos negocios internacionales que lo que era el punto de vista tradicional; (2) el nuevo tecno-nacionalismo está sustentado en la doctrina del realismo, que presenta el mundo como una competencia de suma cero en la que los estados apalancan su poder de coerción económica, y no reconoce la importancia de la interconectividad tecnológica, complementariedad de recursos, innovación abierta, y coopetición de suma positiva; (3) el tecno-nacionalismo obstaculiza a las empresas multinacionales, especialmente a aquellas que dependen de la cadena de suministro de tecnología global y de la contribución del mercado del país de destino; y (4) las empresas multinacionales puede responder al tecno-nacionalismo, defensivamente o ofensivamente, supeditado a su exposición y habilidad para gestionar los riesgos asociados con a las políticas relacionadas.

O tecnonacionalismo atual apresenta novos riscos nos negócios internacionais, ampliando volatilidade, incerteza e complexidade para empresas multinacionais (MNEs). Este estudo explica como o tecnonacionalismo de hoje difere de sua forma tradicional, a lógica teórica subjacente, o dano que pode causar a MNEs e o que MNEs podem fazer para conter o potencial dano. Elaboramos vários pontos: (1) o novo tecnonacionalismo combina considerações geopolíticas, econômicas, de segurança nacional e ideológicas e, portanto, é mais complexo e perturbador para os negócios internacionais do que o ponto de vista tradicional; (2) o novo tecnonacionalismo é sustentado pela doutrina do realismo, que retrata o mundo como uma competição de soma zero na qual estados alavancam seu poder de coerção econômica e não reconhece a importância da interconectividade tecnológica, complementaridade de recursos, inovação aberta e coopetição de soma positiva; (3) o tecnonacionalismo obstrui MNEs, especialmente aquelas que dependem da cadeia de suprimento de tecnologia global e da contribuição do mercado do país-alvo; e (4) MNEs podem responder ao tecnonacionalismo, defensiva ou ofensivamente, dependendo de sua exposição e capacidade de gerenciar os riscos associados às políticas relacionadas.

A general framework of digitization risks in international business.

Digital global connectivity offers multinational enterprises new opportunities, but it also brings unique risks, an area not yet well examined in international business. This article presents an organizational information-processing framework, which elucidates what (risk types and sources), how (risk assessing and managing), and whom (vulnerable firms) these risks relate to, in a dialectical manner that seeks to combine theoretical insights and managerial actions. We focus on three types of risks (digital interdependence, information security, and regulatory complexity) that MNEs uniquely face, and explain within-country and cross-country risk drivers. We document variances among MNEs in exposure to these risks, proposing that information flow intensity, geographic diversity, international strategy, and global platform participation carry strong implications on the firm's risk exposure and response. Finally, this framework offers actions essential for MNEs, individually and collectively, to manage digital risks, emphasizing processes of building and deploying digital intelligence in pursuit of transnational resilience for cross-border activities that become increasingly digitally connected.

La connectivité numérique globale offre de nouvelles opportunités aux entreprises multinationales (MNEs - Multinational Enterprises), mais comporte également des risques uniques, un domaine qui n'est pas encore suffisamment examiné en profondeur dans les affaires internationales. Cet article présente un cadre de traitement de l'informaction organizational, sequel allocate à quai (types et sources de risques), à quelle manière (d'évaluation et de gestion des risques) et à qui (entreprises vulnérables) se rapportent ces risques. Et ce, d'une manière dialectique visant à combiner des connaissances théoriques et des actions managériales. Nous nous focalisons sur trois types de risques (interdépendance numérique, sécurité de l'information et complexité de la réglementation) auxquels s'exposent particulièrement les MNEs, et expliquons les déterminants des risques entre les pays et à l'intérieur de chaque pays. Observant les variations d'exposition à ces risques entre les MNEs, nous proposons que l'intensité du flux d'informations, la diversité géographique, la stratégie internationale et la participation à une plate-forme globale apportent d'importantes implications pour l'exposition et la réponse aux risques de l'entreprise. Enfin, ce cadre propose aux MNEs des actions essentielles pour gérer, individuellement et collectivement, les risques numériques, en mettant l'accent sur les processus de construction et de déploiement de l'intelligence numérique dans la poursuite de la résilience transnationale pour les activités transfrontalières de plus en plus numériquement connectées.

La conectividad global ofrece a las empresas multinacionales nuevas oportunidades, pero también trajo retos únicos, un área que no ha sido aún bien examinada en negocios internacionales. Este artículo presenta un marco de procesamiento de información organizacional, la cual esclarece qué (tipos y fuentes de riesgo), cómo (evaluación y gestión de riesgos), y a quiénes (empresas vulnerables) se relacionan estos riegos, de una manera dialéctica que busca combinar los conocimientos teóricos y las acciones gerenciales. Nos enfocamos en tres tipos de riesgos (interdependencia digital, seguridad de la información, y complejidad regulatoria) que enfrentan las empresas multinacionales de manera exclusiva y explicamos las causas del riesgo dentro y entre los países. Documentamos las variaciones entre las empresas multinacionales en cuanto a la exposición a estos riesgos, proponiendo que la intensidad de los flujos de información, la diversidad geográfica, la estrategia internacional, y la participación en plataformas globales acarrea fuertes implicaciones en la exposición y en la respuesta al riesgo de las empresas. Finalmente, este marco brinda acciones esenciales para las empresas multinacionales, individualmente y colectivamente, para gestionar los riesgos digitales, enfatizando en los procesos de construcción y despliegue de inteligencia digital en búsqueda de la resiliencia transnacional de las actividades transfronterizas que están cada vez más conectadas digitalmente.

A conectividade digital global oferece novas oportunidades a empresas multinacionais, mas também traz riscos únicos, uma área ainda não bem examinada em negócios internacionais. Este artigo apresenta um modelo de processamento de informações organizacionais, que elucida o quê (tipos e fontes de risco), como (avaliação e gerenciamento de risco) e com quem (empresas vulneráveis) esses riscos se relacionam, de uma forma dialética que busca combinar insights teóricos e ações gerenciais. Nós nos concentramos em três tipos de riscos (interdependência digital, segurança de informação e complexidade regulatória) que MNEs enfrentam de forma única e explicamos fatores de risco dentro do país e entre países. Documentamos variâncias entre as MNEs na exposição a esses riscos, propondo que a intensidade do fluxo de informações, a diversidade geográfica, a estratégia internacional e a participação na plataforma global têm fortes implicações na exposição da empresa ao risco e sua resposta. Por fim, este modelo oferece ações essenciais para MNEs, individual e coletivamente, para gerenciar riscos digitais, enfatizando processos de construção e implantação de inteligência digital em busca de resiliência transnacional para atividades internacionais que cada vez mais se tornam digitalmente conectadas.

One-pot, self-catalyzed synthesis of self-adherent hydrogels for photo-thermal, antimicrobial wound treatment.

Self-adhering hydrogels are promising materials to be employed as wound dressings, because they can be used for wound healing without the necessity of additional stitching. However, micro-organisms can easily adhere to these hydrogels as well, which usually causes wound infections. Therefore, adhesive hydrogels are often combined with antibiotics. However, this introduces a risk of drug resistance, cytotoxicity and poor cell affinity. Consequently, recently, there has been great interest in developing non-antibiotic, antibacterial adhesive hydrogels. In this article, we present a simple one-pot synthesis procedure to prepare self-adhesive hydrogels composed of poly(acrylamide) (PAM), naturally derived chitosan (CS) and tannic acid/ferric ion chelates (TA@Fe3+). TA@Fe3+ enables self-catalysis of the polymerization reaction. In addition, due to its near infrared (NIR) photothermal responsiveness, TA@Fe3+ allows for eliminating the bacterial activity with up to 91.6% and 94.7% effectivity against Escherichia coli and Staphylococcus aureus, respectively. Mechanical and adhesion testing shows that the hydrogels are tough as well as flexible and will adhere repeatedly to many types of biological tissues, which can be attributed to the combination of physical and chemical bonding between TA@Fe3+ and PAM and CS, respectively. Moreover, in vitro and in vivo tests indicate that the NIR photothermally active hydrogel can effectively prevent bacterial infection and accelerate tissue regeneration, which demonstrates that these hydrogels are promising functional materials for wound healing applications.

MicroRNA-503-3p affects osteogenic differentiation of human adipose-derived stem cells by regulation of Wnt2 and Wnt7b under cyclic strain.

BACKGROUND: MicroRNAs (miRNAs) play a role in regulating osteogenic differentiation (OD) of mesenchymal stem cells by inhibiting mRNAs translation under cyclic strain. miR-503-3p was downregulated in OD of human adipose-derived stem cells (hASCs) in vivo under cyclic strain in our previous study, while it might target the Wnt/ß-catenin (W-ß) pathway. In this study, we explored miR-503-3p's role in OD of hASCs under cyclic strain. METHODS: OD of hASCs was induced by cyclic strain. Bioinformatic and dual luciferase analyses were used to confirm the relationship between Wnt2/Wnt7b and miR-503-3p. Immunofluorescence was used to detect the effect of miR-503-3p on Wnt2/Wnt7b and ß-catenin in hASCs transfected with miR-503-3p mimic and inhibitor. Mimic, inhibitor, and small interfering RNA (siRNA) transfected in hASCs to against Wnt2 and Wnt7b. Quantitative real-time PCR (RT-PCR) and western blot were used to examine the OD and W-ß pathway at the mRNA and protein levels, respectively. Immunofluorescence was performed to locate ß-catenin. ALP activity and calcium were detected by colorimetric assay. RESULTS: Results of immunophenotypes by flow cytometry and multi-lineage potential confirmed that the cultured cells were hASCs. Results of luciferase reporter assay indicated that miR-503-3p could regulate the expression levels of Wnt2 and Wnt7b by targeting their respective 3'-untranslated region (UTR). Under cyclic strain, gain- or loss-function of miR-503-3p studies by mimic and inhibitor revealed that decreasing expression of miR-503-3p could significantly bring about promotion of OD of hASCs, whereas increased expression of miR-503-3p inhibited OD. Furthermore, miR-503-3p high-expression reduced the activity of the W-ß pathway, as indicated by lowering expression of Wnt2 and Wnt7b, inactive ß-catenin in miR-503-3p-treated hASCs. By contrast, miR-503-3p inhibition activated the W-ß pathway. CONCLUSIONS: Collectively, our findings indicate that miR-503-3p is a negative factor in regulating W-ß pathway by Wnt2 and Wnt7b, which inhibit the OD of hASCs under cyclic strain.

miR-26b-5p/TCF-4 Controls the Adipogenic Differentiation of Human Adipose-derived Mesenchymal Stem Cells.

In this study, we assessed the ability of miR-26b-5p to regulate T cell factor 4 (TCF-4) expression and thereby control human adipose-derived mesenchymal stem cell (hADMSC) adipogenic differentiation. Adipogenic medium was used to induce hADMSC differentiation over a 6-d period. The ability of miR-26b-5p to interact with the TCF-4 mRNA was confirmed through both predictive bioinformatics analyses and luciferase reporter assays. Immunofluorescent staining was used to visualize the impact of miR-26b-5p inhibition or overexpression on TCF-4 and ß-catenin levels in hADMSCs. Further functional analyses were conducted by transfecting these cells with siRNAs specific for TCF-4 and ß-catenin. Adipogenic marker and Wnt/ß-catenin pathway gene expression levels were assessed via real-time polymerase chain reaction and western blotting. ß-catenin localization was assessed via immunofluorescent staining. As expected, our adipogenic media induced the adipocytic differentiation of hADMSCs. In addition, we confirmed that TCF-4 is an miR-26b-5p target gene in these cells, and that protein levels of both TCF-4 and ß-catenin were reduced when these cells were transfected with miR-26b-5p mimics. Overexpression of this microRNA also enhanced hADMSC adipogenesis, whereas TCF-4 and ß-catenin overexpression inhibited this process. The enhanced hADMSC adipogenic differentiation that was observed following TCF-4 or ß-catenin knockdown was partially reversed when miR-26b-5p expression was inhibited. We found that miR-26b-5p serves as a direct negative regulator of TCF-4 expression within hADMSCs, leading to inactivation of the Wnt/ß-catenin pathway and thereby promoting the adipogenic differentiation of these cells in vitro.

The osteogenic differentiation of human adipose-derived stem cells is regulated through the let-7i-3p/LEF1/ß-catenin axis under cyclic strain.

BACKGROUND: The Wnt/ß-catenin pathway is involved in the osteogenic differentiation of human adipose-derived stem cells (hASCs) under cyclic strain. Very little is known about the role of microRNAs in these events. METHODS: Cells were obtained using enzyme digestion methods, and proliferation was detected using Cell Counting Kit 8. Cell cycles and immunophenotypes were detected by flow cytometry. The multilineage potential of hASCs was induced by induction media. Cyclic strain was applied to hASCs (0.5 Hz, 2 h/day, 6 days) to induce osteogenic differentiation and miRNA changes. Bioinformatic and dual-luciferase analyses confirmed lymphoid enhancer factor 1 (LEF1) as a potential target of let-7i-3p. The effect of let-7i-3p on LEF1 in hASCs transfected with a let-7i-3p mimic and inhibitor was analyzed by immunofluorescence. hASCs were transfected with a let-7i-3p mimic, inhibitor, or small interfering RNA (siRNA) against LEF1 and ß-catenin. Quantitative real-time PCR (qPCR) and western blotting were performed to examine the osteogenic markers and Wnt/ß-catenin pathway at the mRNA and protein levels, respectively. Immunofluorescence and western blotting were performed to confirm the activation of the Wnt/ß-catenin pathway. RESULTS: Flow cytometry showed that 82.12% ± 5.83% of the cells were in G1 phase and 17.88% ± 2.59% of the cells were in S/G2 phase; hASCs were positive for CD29, CD90, and CD105. hASCs could have the potential for osteogenic, chondrogenic, and adipogenic differentiation. MicroRNA screening via microarray showed that let-7i-3p expression was decreased under cyclic strain. Bioinformatic and dual-luciferase analyses confirmed that LEF1 in the Wnt/ß-catenin pathway was the target of let-7i-3p. Under cyclic strain, the osteogenic differentiation of hASCs was promoted by overexpression of LEF1and ß-catenin and inhibited by overexpression of let-7i-3p. hASCs were transfected with let-7i-3p mimics and inhibitor. Gain- or loss-of-function analyses of let-7i-3p showed that the osteogenic differentiation of hASCs was promoted by decreased let-7i-3p expression and inhibited by increased let-7i-3p expression. Furthermore, high LEF1 expression inactivated the Wnt/ß-catenin pathway in let-7i-3p-enhanced hASCs. In contrast, let-7i-3p inhibition activated the Wnt/ß-catenin pathway. CONCLUSIONS: Let-7i-3p, acting as a negative regulator of the Wnt/ß-catenin pathway by targeting LEF1, inhibits the osteogenic differentiation of hASCs under cyclic strain in vitro.

Novel Gold Nanorod-Based HR1 Peptide Inhibitor for Middle East Respiratory Syndrome Coronavirus.

Middle East respiratory syndrome coronavirus (MERS-CoV) causes a severe acute respiratory syndrome-like illness with high pathogenicity and mortality due to the lack of effective therapeutics. Currently, only few antiviral agents are available for the treatment of MERS, but their effects have been greatly impaired by low antiviral activity, poor metabolic stability, and serious adverse effects. Therefore, the development of effective treatment for MERS is urgently needed. In this study, a series of heptad repeat 1 (HR1) peptide inhibitors have been developed to inhibit HR1/HR2-mediated membrane fusion between MERS-CoV and host cells, which is the major pathway of MERS-CoV-induced host infections. Particularly, peptide pregnancy-induced hypertension (PIH) exhibits potent inhibitory activity with IC50 of 1.171 µM, and its inhibitory effects can be further increased to 10-fold by forming a gold nanorod complex (PIH-AuNRs). In addition, PIH-AuNRs display enhanced metabolic stability and biocompatibility in vitro and in vivo and, therefore, effectively prevent MERS-CoV-associated membrane fusion. In summary, PIH-AuNRs represent a novel class of antiviral agents and have a great potential in treating MERS in the clinic.

Synergistic Amplification of Oxidative Stress-Mediated Antitumor Activity via Liposomal Dichloroacetic Acid and MOF-Fe2.

Cancer cells are susceptible to oxidative stress; therefore, selective elevation of intracellular reactive oxygen species (ROS) is considered as an effective antitumor treatment. Here, a liposomal formulation of dichloroacetic acid (DCA) and metal-organic framework (MOF)-Fe2+ (MD@Lip) has been developed, which can efficiently stimulate ROS-mediated cancer cell apoptosis in vitro and in vivo. MD@Lip can not only improve aqueous solubility of octahedral MOF-Fe2+ , but also generate an acidic microenvironment to activate a MOF-Fe2+ -based Fenton reaction. Importantly, MD@Lip promotes DCA-mediated mitochondrial aerobic oxidation to increase intracellular hydrogen peroxide (H2 O2 ), which can be consequently converted to highly cytotoxic hydroxyl radicals (•OH) via MOF-Fe2+ , leading to amplification of cancer cell apoptosis. Particularly, MD@Lip can selectively accumulate in tumors, and efficiently inhibit tumor growth with minimal systemic adverse effects. Therefore, liposome-based combination therapy of DCA and MOF-Fe2+ provides a promising oxidative stress-associated antitumor strategy for the management of malignant tumors.

FOXM1 is a novel predictor of recurrence in patients with oral squamous cell carcinoma associated with an increase in epithelial­mesenchymal transition.

Although forkhead box protein M1 (FOXM1) is markedly upregulated in human premalignant and oral squamous cell carcinoma (OSCC) tissues and cultured cells, the association of FOXM1 expression with OSCC prognosis is not well understood. The present study investigated the possible association of FOXM1 expression in patients with OSCC with their clinicopathological characteristics and clinical outcomes. The expression of FOXM1 protein in OSCC tissues from 119 patients was evaluated by immunohistochemistry, and the results demonstrated that FOXM1 overexpression in patients with OSCC was associated with tumour recurrence and poor prognosis. To study the in vitro effects of FOXM1, its expression was decreased by small interfering RNA (siRNA) in OSCC cell lines, and FOXM1 knockdown decreased the proliferative, migratory and invasive capacities of cells. FOXM1 inhibition by siRNA gave rise to reduced expression of vimentin and increased expression of E­cadherin. The present study reported FOXM1 as a novel predictor of tumour recurrence in patients with OSCC and its potential involvement in epithelial­mesenchymal transition in OSCC cells.

Assessing the Efficacy of Lopinavir/Ritonavir-Based Preferred and Alternative Second-Line Regimens in HIV-Infected Patients: A Meta-Analysis of Key Evidence to Support WHO Recommendations.

Background: Nucleoside reverse transcriptase inhibitors (NRTIs) and non-NRTIs (NNRTIs) with boosted protease inhibitors are included in standardized first-line and second-line regimens. Recent World Health Organization (WHO) guidelines recommend a boosted protease inhibitor (PI) combined with 2 NRTIs or raltegravir as a second-line regimen. Objective: Ritonavir-boosted lopinavir (LPV/r) is known as a key second-line antiretroviral therapy (ART) in resource-limited settings. We carried out a meta-analysis to analyze virologic suppression and effectiveness of LPV/r-based second-line therapy in HIV-infected patients. Methods: In this meta-analysis, we searched randomized controlled trials and observational cohort studies to evaluate outcomes of second-line ART for patients with HIV who failed first-line therapy. A systematic search was conducted in Pubmed, Cochrane Library, and Embase from inception to January 2018. Outcomes included viral suppression, CD4 cell counts, drug resistance, adverse events, and self-reported adherence. We assessed comparative efficacy and safety in a meta-analysis. Data analysis was performed using RevMan 5.3 and Stata12.0. Results: Nine studies comprising 3,923 patients were included in the meta-analysis. The overall successful virologic suppression rate of the second-line regimen was 77% (ITT) and 87% (PP) at 48 weeks with a plasma HIV RNA load of <400 copies/mL. No statistical significance was found in CD4 cell count recoveries between LPV/r plus 2-3 NRTIs and simplified regimens (LPV/r plus raltegravir) at 48 weeks (P = 0.09), 96 weeks (P = 0.05), and 144 weeks (P = 0.73). Four studies indicated that the virus had low-level resistance to LPV/r, and the most common clinically significant PI-resistance mutations were 46I, 54V, 82A/82F, and 76V; however, no virologic failure due to LPV/r resistance was detected. In addition, no statistical significance was found between the two groups in self-reported adherence [relative risks (RR) = 1.03,95% confidence interval (CI) 1.00, 1.07, P = 0.06], grade 3 or 4 adverse events (RR = 0.84, 95% CI 0.64, 1.10, P = 0.20) or serious events (RR = 0.85, 95% CI 0.77, 1.17, P = 0.62). Conclusions: These results suggest that the LPV/r-based regimen demonstrates efficacious and low resistance as second-line antiretroviral therapy.Both LPV/r plus 2-3 NRTIs and LPV/r plus RAL regimens improved CD4 cell counts. There was no evidence of superiority of simplified regimens over LPV/r plus 2-3 NRTIs.

Deficiency of autoimmune regulator impairs the immune tolerance effect of bone marrow-derived dendritic cells in mice.

As a transcription factor, autoimmune regulator (Aire) participates in thymic negative selection and maintains immune tolerance mainly by regulating the ectopic expression of tissue-restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs). Aire is also expressed in dendritic cells (DCs). DCs are professional antigen-presenting cells (APCs) that affect the differentiation of T cells toward distinct subpopulations and participate in the immune response and tolerance, thereby playing an important role in maintaining homeostasis. To determine the role of Aire in maintaining immune tolerance by bone marrow-derived dendritic cells (BMDCs), in the present study we utilized Aire-knockout mice to examine the changes of maturation status and TRAs expression on BMDCs, additionally investigate the differentiation of CD4+ T cells. The results showed that expression of costimulatory molecule and major histocompatibility complex class II (MHC-II) molecule was increased and expression of various TRAs was decreased in BMDCs from Aire-knockout mice. Aire deficiency reduced the differentiation of naïve CD4+ T cells into type 2T helper (Th2) cells and regulatory T cells (Tregs) but enhanced the differentiation of naïve CD4+ T cells into Th1 cells, Th17 cells, and follicular helper T (Tfh) cells. The results demonstrate that Aire expressed by BMDCs plays an important role in the maintenance of homeostasis by regulating TRA expression and the differentiation of T cell subsets.

Transplantation of Aire-overexpressing bone marrow-derived dendritic cells delays the onset of type 1 diabetes.

Autoimmune regulator (Aire) plays an indispensable role in maintaining central immune tolerance by promoting the ectopic expression of tissue-restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs) and dendritic cells (DCs), which lead to the deletion of autoreactive T cells or the induction of Tregs and consequently prevent autoimmune disease development. Curing autoimmune diseases has always been a challenge. DC-based immunotherapy represents a new and effective method to establish tolerance. We attempted to transplant Aire-overexpressing bone marrow-derived DCs (Aire-BMDCs) to treat type 1 diabetes (T1D) and to explore a new strategy for autoimmune disease treatment. We observed that the onset of T1D in recipient mice was delayed; insulin autoantibody (IAA) production was significantly decreased; the structure of islets was protected; and the degree of inflammatory infiltration was lower. Furthermore, we found that Aire-BMDCs can promote apoptosis and induce autoreactive CD4+ T cell clonal anergy, inhibit Th1 and Th17 production, and induce Treg production. These results suggest that transplantation of Aire-BMDCs will be a manipulation and effective method for preventing or treating T1D.

Follicular CXCR5- expressing CD8(+) T cells curtail chronic viral infection.

During chronic viral infection, virus-specific CD8(+) T cells become exhausted, exhibit poor effector function and lose memory potential. However, exhausted CD8(+) T cells can still contain viral replication in chronic infections, although the mechanism of this containment is largely unknown. Here we show that a subset of exhausted CD8(+) T cells expressing the chemokine receptor CXCR5 has a critical role in the control of viral replication in mice that were chronically infected with lymphocytic choriomeningitis virus (LCMV). These CXCR5(+) CD8(+) T cells were able to migrate into B-cell follicles, expressed lower levels of inhibitory receptors and exhibited more potent cytotoxicity than the CXCR5(-) [corrected] subset. Furthermore, we identified the Id2-E2A signalling axis as an important regulator of the generation of this subset. In patients with HIV, we also identified a virus-specific CXCR5(+) CD8(+) T-cell subset, and its number was inversely correlated with viral load. The CXCR5(+) subset showed greater therapeutic potential than the CXCR5(-) [corrected] subset when adoptively transferred to chronically infected mice, and exhibited synergistic reduction of viral load when combined with anti-PD-L1 treatment. This study defines a unique subset of exhausted CD8(+) T cells that has a pivotal role in the control of viral replication during chronic viral infection.