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Dengue is the most prevalent arthropod-borne viral disease, caused by dengue virus, a member of the Flaviviridae family. Its worldwide incidence is now a major health problem, with 2.5 billion people living in risk areas. In this review, we integrate the structural rearrangements of each viral protein and their functions in all the steps of virus entry into the host cells. We describe in detail the putative receptors and attachment factors in mammalian and mosquito cells, and the recognition of viral immunocomplexes via Fcγ receptor in immune cells. We also discuss that virus internalization might occur through distinct entry pathways, including clathrin-mediated or non-classical clathrin-independent endocytosis, depending on the host cell and virus serotype or strain. The implications of viral maturation in virus entry are also explored. Finally, we discuss the mechanisms of viral genome access to the cytoplasm. This includes the role of low pH-induced conformational changes in the envelope protein that mediate membrane fusion, and original insights raised by our recent work that supports the hypothesis that capsid protein would also be an active player in this process, acting on viral genome translocation into the cytoplasm. This review addresses the structural rearrangements of dengue virus proteins and their functions during virus entry into the host cells, exploring (a) the cellular elements involved in virus binding to mammalian and mosquito cells, (b) the internalization routes that ultimately lead to virus entry into the cell and (c) the mechanisms by which viral genome gain access to the cytoplasm, including original insights from our recent work that supports the hypothesis that the capsid protein has a role in this process.

In this paper, we suggest that internalization theory might be extended by incorporating complementary insights from GVC theory. More specifically, we argue that internalization theory can explain why lead firms might wish to externalize selected activities, but that it is largely silent on the mechanisms by which those lead firms might exercise control over the resultant externalized relationships with their GVC partners. We advance an explanation linking the choice of control mechanism to two factors: power asymmetries between the lead firms and their GVC partners, and the degree of codifiability of the information to be exchanged in the relationship.

An ongoing pandemic of coronavirus disease 2019 (COVID-19) is now the greatest threat to global public health. Herbal medicines and their derived natural products have drawn much attention in the treatment of COVID-19, but the detailed mechanisms by which natural products inhibit SARS-CoV-2 have not been elucidated. Here, we show that platycodin D (PD), a triterpenoid saponin abundant in Platycodon grandiflorum (PG), a dietary and medicinal herb commonly used in East Asia, effectively blocks the two main SARS-CoV-2 infection routes via lysosome- and transmembrane protease serine 2 (TMPRSS2)-driven entry. Mechanistically, PD prevents host entry of SARS-CoV-2 by redistributing membrane cholesterol to prevent membrane fusion, which can be reinstated by treatment with a PD-encapsulating agent. Furthermore, the inhibitory effects of PD are recapitulated by the pharmacological inhibition or gene silencing of NPC1 , which is mutated in patients with Niemann–Pick type C (NPC) displaying disrupted membrane cholesterol distribution. Finally, readily available local foods or herbal medicines containing PG root show similar inhibitory effects against SARS-CoV-2 infection. Our study proposes that PD is a potent natural product for preventing or treating COVID-19 and that briefly disrupting the distribution of membrane cholesterol is a potential novel therapeutic strategy for SARS-CoV-2 infection. COVID-19: Closing the cellular door on coronavirus A molecule derived from a traditional Korean herbal medicine can impede entry of SARS-CoV-2 into cultured cells. The coronavirus responsible for COVID-19 can enter the cell via direct fusion with the plasma membrane, or after internalization into organelles called lysosomes. South Korean researchers led by Seungtaek Kim of the Institut Pasteur Korea, Seongnam, and C. Justin Lee at the Institute for Basic Science, Daejon, have identified a compound that can thwart both modes of entry. They treated cultured human cells with platycodin D (PD), extracted from a plant used throughout East Asia as a remedy for respiratory disease. The researchers showed that PD inhibits SARS-CoV-2 fusion with the plasma membrane while also blocking lysosomal release. This mechanism appears to be mediated by PD’s influence on membrane cholesterol content, suggesting a novel strategy for treating COVID-19.

We study the internationalization of digital service multinational enterprises (SMNCs), focusing on how digitalization alters internalization theory’s assumptions about the nature of firm-specific assets (FSAs) and the theory’s predictions about governance choices in cross-border transactions. We invoke Simon’s (Proc Am Philos Soc 106(6):467–482, 1962) near-decomposability concept to explain how digitalization enables two distinct types of FSAs – technology and human capital. Applying the ideas of modularity and skill complexity, we further distinguish between core versus peripheral technology FSAs and between generic versus advanced human capital FSAs. Building on the transferability and appropriability of these strategic assets, we theorize on the FSAs’ internalization propensity in the digital age. We propose that with rising digitalization, the network plays a dual role–as a governance mode and as a strategic resource. Integrating insights from network economics, particularly increasing returns to scale, we propose that network advantages (On) emerge as a distinct strategic resource that merits separate investigation from the traditional asset-based (Oₐ) and transaction-based (Ot) advantages.

Global value chain (GVC) governance is an established field within international business research, yet the relational aspects of GVCs have, to date, garnered less scholarly attention than have efficiency considerations. This conceptual study’s objective is to explore the relational dynamics of GVC governance using an internalization theory perspective, and by linking GVC research with insights from the business network literature. GVCs are argued to be a distinct form of asymmetrical networks, associated with economizing and capability creation features, as well as costs. The orchestrating firm can thus enhance efficiency outcomes of the GVC using social mechanisms similar to those adopted by core actors in a business network. In the study, six such mechanisms were identified: (1) selectivity, (2) inclusion of non-business intermediaries, (3) joint strategizing, (4) relational capital, (5) multilateral feedback, and (6) rules for equitable value distribution. While safeguarding the GVC’s efficiency, the above social mechanisms are associated with challenges and limitations, and therefore do not guarantee international competitive success. However, deployed in an integrative fashion, these social mechanisms facilitate coordination (thus economizing on bounded rationality), reduce the hazards of imperfect effort by partners (thus economizing on bounded reliability), and foster innovation and new capability development.

The emerging digital context for international business along with rising deglobalization forces have accentuated multinational enterprises’ organizing challenges, particularly with regard to managing relationships with global platform and ecosystem partners. We propose that the loose coupling perspective, which suggests the coexistence of coupling (linkages) to maintain responsiveness and looseness (separateness) to retain distinctiveness, can provide valuable insights on addressing such external governance-related challenges in the context of global platforms and ecosystems. We draw on and integrate ideas from loose coupling theory and digitalization to inform on the key contingencies and mechanisms of MNEs’ external organizing. We show how these insights can be further integrated with other perspectives such as new internalization theory to inform combined internal and external governance in digital globalization.

Abstract The 2 hormones responsible for the amplification of insulin secretion after oral as opposed to intravenous nutrient administration are the gut peptides, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). However, whereas GLP-1 also inhibits appetite and food intake and improves glucose regulation in patients with type 2 diabetes (T2DM), GIP seems to be devoid of these activities, although the 2 hormones as well as their receptors are highly related. In fact, numerous studies have suggested that GIP may promote obesity. However, chimeric peptides, combining elements of both peptides and capable of activating both receptors, have recently been demonstrated to have remarkable weight-losing and glucose-lowering efficacy in obese individuals with T2DM. At the same time, antagonists of the GIP receptor have been reported to reduce weight gain/cause weight loss in experimental animals including nonhuman primates. This suggests that both agonists and antagonist of the GIP receptor should be useful, at least for weight-losing therapy. How is this possible? We here review recent experimental evidence that agonist-induced internalization of the two receptors differs markedly and that modifications of the ligand structures, as in co-agonists, profoundly influence these cellular processes and may explain that an antagonist may activate while an agonist may block receptor signaling.

Sodium taurocholate cotransporting polypeptide (NTCP) is a host cell receptor required for hepatitis B virus (HBV) entry. However, the susceptibility of NTCP-expressing cells to HBV is diverse depending on the culture condition. Stimulation with epidermal growth factor (EGF) was found to potentiate cell susceptibility to HBV infection. Here, we show that EGF receptor (EGFR) plays a critical role in HBV virion internalization. In EGFR-knockdown cells, HBV or its preS1-specific fluorescence peptide attached to the cell surface, but its internalization was attenuated. PreS1 internalization and HBV infection could be rescued by complementation with functional EGFR. Interestingly, the HBV/preS1–NTCP complex at the cell surface was internalized concomitant with the endocytotic relocalization of EGFR. Molecular interaction between NTCP and EGFR was documented by immunoprecipitation assay. Upon dissociation from functional EGFR, NTCP no longer functioned to support viral infection, as demonstrated by either (i) the introduction of NTCP pointmutation that disrupted its interaction with EGFR, (ii) the detrimental effect of decoy peptide interrupting the NTCP–EGFR interaction, or (iii) the pharmacological inactivation of EGFR. Together, these data support the crucial role of EGFR in mediating HBV–NTCP internalization into susceptible cells. EGFR thus provides a yet unidentified missing link from the cell-surface HBV–NTCP attachment to the viral invasion beyond the host cell membrane

Alphaviruses cause severe human illnesses including persistent arthritis and fatal encephalitis. As alphavirus entry into target cells is the first step in infection, intensive research efforts have focused on elucidating aspects of this pathway, including attachment, internalization, and fusion. Herein, we review recent developments in the molecular understanding of alphavirus entry both in vitro and in vivo and how these advances might enable the design of therapeutics targeting this critical step in the alphavirus life cycle.

Petricevich and Teece’s (2019) article on the reshaping of globalization raises profound issues on the theory and empirics of international business. The fracture in the world economy between the USA and China is the result of Government policy, but its relationship to rising VUCA (volatility, uncertainty, complexity, and ambiguity) elements in globalization is more complex than simple policy changes. This paper suggests that a reappraisal of theory is required, not least because of the eruption of Covid-19, but that internalization theory is the best source of theoretical restructuring in the face of the new empirical realities facing the global economy.