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Single-cell transcriptomics has emerged as the preferred tool to define cell identity through the analysis of gene expression signatures. However, there are limited studies that have comprehensively compared the performance of different scRNAseq systems in complex tissues. Here, we present a systematic comparison of three well-established high throughput 3’-scRNAseq platforms: Drop-seq, 10x Chromium and BD Rhapsody; using tumours that present high cell diversity. Our experimental design includes both fresh and artificially damaged samples from the same tumours, which also provides a comparable dataset to examine their performance under challenging conditions. The performance metrics used in this study consist of gene sensitivity, mitochondrial content, reproducibility, clustering capabilities, cell type representation and ambient RNA contamination. These analyses showed that BD Rhapsody and 10x Chromium have similar but higher gene sensitivity than Drop-seq, while BD Rhapsody has the highest mitochondrial content. Interestingly, we found cell type detection biases between platforms, including a lower proportion of endothelial and myofibroblast cells in BD Rhapsody and lower gene sensitivity in granulocytes for 10x Chromium. Moreover, the source of the ambient noise was different between plate-based and droplet-based platforms. In conclusion, our reported platform differential performance should be considered for the selection of the scRNAseq method during the study experimental designs.

Cancer-specific small extracellular vesicles (sEVs), known as exosomes, have shown a great promise to serve as novel biomarkers for cancer diagnosis and prognosis in liquid biopsies. However, the high heterogeneity of sEVs posed great technical challenges to acquiring their molecular information. A simple and reproducible method for isolating subpopulations of sEVs can significantly enhance the detection and stratification of these circulating biomarkers and their function. This study used the synergic effects of the immunoaffinity-based approach and inertial microfluidics (ImmunoInertial microfluidics) to isolate specific subpopulations of sEVs. At first, the cancer cell-derived sEVs were captured on microbeads of varying sizes which were functionalized with specific capture antibodies such as epithelial cell adhesion molecule (EpCAM), epidermal growth factor receptor (EGFR), and the programmed death-ligand 1 (PD-L1), facilitating the selective capture of sEVs. The sEVs-bearing microbeads were subsequently introduced to a series of inertial microfluidic channels, called iZExoSub (inertial zigzag microfluidics for exosome subpopulation separation), for size-based bead separation. Results revealed more than 90% efficiency in sEVs subpopulation separation, further proved via flow cytometry analysis data. Our approach is capable of selective isolation and quantitative detection of important biomarkers from sEVs subpopulations with high sensitivity and low cost and has the capacity to process samples of varying volumes, ranging from µL up to mL continuously. This system can outperform FACS machines in terms of sample throughput by orders of magnitudes. In addition, this study emphasized the necessity of using a consistent sEV marker (as capture and detector) across different samples for accurate assessment of subpopulations.

Separation and enrichment of target cells prior to downstream analyses is an essential pre-treatment step in many biomedical and clinical assays. Separation techniques utilizing simple, cost-effective, and user-friendly devices are highly desirable, both in the lab and at the point of need. Passive microfluidic approaches, especially inertial microfluidics, fit this brief perfectly and are highly desired. Using an optimized additive manufacturing technique, we developed a zigzag microchannel for rigid inertial separation and enrichment, hereafter referred to as Z-RISE. We empirically showed that the Z-RISE device outperforms equivalent devices based on curvilinear (sinusoidal), asymmetric curvilinear, zigzag with round corners, or square-wave formats and modelled this behavior to gain a better understanding of the physics underpinning the improved focusing and separation performance. The comparison between rigid and soft zigzag microchannels reveals that channel rigidity significantly affects and enhances the focusing performance of the microchannel. Compared to other serpentine microchannels, zigzag microfluidics demonstrates superior separation and purity efficiency due to the sudden channel cross-section expansion at the corners. Within Z-RISE, particles are aligned in either double-side or single-line focusing positions. The transition of particles from a double-focusing line to a single focusing line introduced a new phenomenon referred to as the plus focusing position. We experimentally demonstrated that Z-RISE could enrich leukocytes and their subtypes from diluted and RBC lysed blood while depleting dead cells, debris, and RBCs. Z-RISE was also shown to yield outstanding particle or cell concentration with a concentration efficiency of more than 99.99%. Our data support the great potential of Z-RISE for applications that involve particle and cell manipulations and pave the way for commercialization perspective in the near future. Refereed/Peer-reviewed

This paper investigates whether firms from developing countries that lag the global technological frontier can learn from technologically successful peers as a means of closing the technological gap with leaders from developed countries. We define technologically successful peers as those that hail from similar home countries, operate in the same industry, and have achieved a certain degree of success in closing the gap with the global technological frontier. We argue that technologically successful peers represent an important reference group for lagging firms and, as such, offer opportunities for lagging firms from developing countries to hasten technological development. We find that lagging firms from developing countries that build upon the knowledge of technologically successful peers achieve higher rates of technological improvement. Moreover, learning from technologically proximal successful peers helps even further with technological improvement. However, there are limits to such learning, with diminishing marginal returns to lagging firms that over rely on successful peers.

Droplet based scRNA-seq systems such as Drop-seq, inDrop and Chromium 10X have been the catalyst for the wide adoption of high-throughput scRNA-seq technologies in the research laboratory. In order to understand the capabilities of these systems to deeply interrogate biology; here we provide a practical guide through all the steps involved in a typical scRNA-seq experiment. Through comparing and contrasting these three main droplet based systems (and their derivatives), we provide an overview of all critical considerations in obtaining high quality and biologically relevant data. We also discuss the limitations of these systems and how they fit into the emerging field of Genomic Cytometry.

Extant research on inward foreign direct investment (FDI) suggests that foreign entrants bring superior technology with them to host countries, thereby providing local firms the opportunity to learn and upgrade their technologies. However, foreign entrants also increase competition in the local market, potentially harming domestic firms. In this study, we extend existing work on inward FDI by investigating the moderating role of technological capabilities on the relationship between inward FDI and local firm innovation. Building upon firm capabilities arguments, we expect that domestic firms with existing technological capabilities are better positioned to stave off foreign competition and better able to learn from foreign entrants. However, we find, somewhat surprisingly, that local technological leaders apply for fewer patents and introduce fewer new products than do local technological laggards subsequent to foreign entry. These results imply that technological capabilities do not buffer domestic firms from the deleterious competition consequences associated with inward FDI.

Corporate social responsibility (CSR) has been shown to provide insurance-like protection that buffers firms from losses when they are sued. But does CSR also buffer firms from being sued? We condu...

It is widely acknowledged that foreign firms are at an institutional disadvantage relative to domestic firms operating in the local market. This “liability of foreignness” typically manifests as inferior performance for foreign firms relative to domestic competitors. Although myriad studies document the liability of foreignness, few demonstrate how individual host country institutions generate specific liabilities. In this study, we explore the regulatory liabilities that foreign firms face using a sample of 189 foreign banks operating in the United States. We find that regulators initiate more enforcement actions, on average, against foreign banks than they do against domestic banks. The effects, however, vary by regulation type and firm characteristics. For example, foreign banks are no more likely to receive risk-related sanctions, but far more likely to receive stakeholder-related sanctions. Foreign banks with higher quality of human capital and more host country experience are less likely to run afoul of all regulations. Foreign banks with more third country experience are less likely to receive risk-related sanctions, but more likely to receive stakeholder-related sanctions. The results highlight the contingent nature of regulatory liabilities, the role of information asymmetry versus regulatory bias in enforcement outcomes, and the liability-reducing effects of resources and capabilities.

Research summary In this study, we introduce a new statistical technique to the field of strategy that accounts for complex interrelated decisions. The technique is meant for situations in which one strategic decision depends critically upon another—e.g., where companies must commit to one decision before making another. We demonstrate the value of the technique in the context of companies choosing countries in which to invest, followed by areas within those countries in which to locate their facilities. We then describe the generic benefits of the statistical technique, offer guidance for how to use it, and provide the programming code so that others can implement it. We explain how the technique is particularly well suited to problems in which companies must decide between multiple options and the sample size is small relative to the number of initial options. Managerial summary Research in strategy and international business has increasingly adopted two-stage models to account for endogeneity. Established approaches, however, deal most effectively with problems characterized by binary first-stage models. We introduce an alternative that allows for multiple choices in the first stage. We use the technique to examine the agglomeration patterns of foreign firms, while accounting for country selection. We find that, conditional on country selection, foreign firms tend to agglomerate in host countries characterized by collectivist cultures, political uncertainty, and economic uncertainty. The results imply that host country characteristics exert a strong influence on the agglomeration preferences of foreign firms. We provide guidance on when to use the empirical estimation technique and furnish details of the estimation procedure so that others can apply the technique to a broader class of selection problems.

Contains fulltext : 240100.pdf (Publisher’s version ) (Open Access) Basal breast cancer is associated with younger age, early relapse, and a high mortality rate. Here, we use unbiased droplet-based single-cell RNA sequencing (RNA-seq) to elucidate the cellular basis of tumor progression during the specification of the basal breast cancer subtype from the luminal progenitor population in the MMTV-PyMT (mouse mammary tumor virus-polyoma middle tumor-antigen) mammary tumor model. We find that basal-like cancer cells resemble the alveolar lineage that is specified upon pregnancy and encompass the acquisition of an aberrant post-lactation developmental program of involution that triggers remodeling of the tumor microenvironment and metastatic dissemination. This involution mimicry is characterized by a highly interactive multicellular network, with involution cancer-associated fibroblasts playing a pivotal role in extracellular matrix remodeling and immunosuppression. Our results may partially explain the increased risk and poor prognosis of breast cancer associated with childbirth.

The purpose of this document is to define minimal standards for a flow cytometry shared resource laboratory (SRL) and provide guidance for best practices in several important areas. This effort is driven by the desire of International Society for the Advancement of Cytometry (ISAC) members in SRLs to define and maintain standards of excellence in flow cytometry, and act as a repository for key elements of this information (e.g. example SOPs/training material, etc.). These best practices are not intended to define specifically how to implement these recommendations, but rather to establish minimal goals for an SRL to address in order to achieve excellence. It is hoped that once these best practices are established and implemented they will serve as a template from which similar practices can be defined for other types of SRLs. Identification of the need for best practices first occurred through discussions at the CYTO 2013 SRL Forum, with the most important areas for which best practices should be defined identified through several surveys and SRL track workshops as part of CYTO 2014. © 2016 International Society for Advancement of Cytometry.

The literature on policy implementation is divided with regards to the impact of street-level bureaucrats on the implementation of public policies. In this paper, we aim to add to and nuance these debates by focusing on ‘institutional work’ – i.e. the creation, maintenance and disruption of institutions – undertaken by central authorities and street-level bureaucrats during public reform processes. On the basis of a case study of the organisational implementation of a retirement pension reform in the Norwegian Labor and Welfare Administration, we argue that institutional work is a useful heuristic device for conceptualising the variety of responses available to street-level bureaucrats during public reforms. We also argue that the responses demonstrate the impact of street-level bureaucrats in these reforms in the context of managerial control and regulation. Finally, we argue that the effectiveness of policy change is dependent on the institutional work of street-level bureaucrats and, in particular, on institutional work that supports the institutions created by politicians and public administrations.

Research summary: Research demonstrates that foreign firms from institutionally distant countries imitate the practices of domestic firms (i.e., adopt an isomorphism strategy). The conjecture has been that pursuing such a strategy can help foreign firms counteract the deleterious performance consequences associated with institutional distance; yet there is scant evidence of such. This study treats isomorphism as an endogenously selected strategy influenced by institutional distance to examine its performance consequences. Using a dataset of 80 foreign banks from 25 countries operating in the United States, we find that foreign firms from institutionally distant home countries benefit initially from selecting an isomorphism strategy. However, the benefits diminish with experience. Managerial summary: Multinational companies experience great difficulty in managing institutional distance, and research suggests that one way to overcome distance-related constraints is to imitate the strategies of local companies. Unfortunately, we do not know enough about the performance-related consequences of engaging in such imitative behavior. This study examines whether imitating local firms improves performance for multinational companies from institutionally distant markets. We find that imitation improves a firm's performance at first; however, with experience those same strategies result in performance decrements. Managers of multinationals should therefore be careful not to get locked into imitative strategies that provide performance benefits upon entry, but that fail to provide benefits over time. Copyright © 2015 John Wiley & Sons, Ltd.

The liability of foreignness is that foreign multinationals pay higher costs of doing business abroad than to domestic firms due to their lack of social embeddedness and lack of institutional knowl...

Here we will present how working environment and wellbeing are affected by the regulatory regimes of the state, with a special emphasis on the role of the labour inspection authorities in Denmark and Norway. As for the activities of the regulatory authorities in both countries, we highlight aspects of their measures that relate to the role of the social parties, the psychosocial and organizational working environment, and employee participation. Both Denmark and Norway score high on the working environment index in Europe. However, both countries still face emerging workplace challenges. Some major trends, such as increasing international competition and new management principles, decreasing support for unions, and neo-liberal inspired wishes for a shift towards soft regulation are likely to change the nature of the working environment and the role of labour inspection. In addition, more directly related shifts are part of the challenges: intensified efforts by the labour inspectorate authorities to curb the labour market black economy may weaken the traditional role of labour inspection, and a changing perception of who is mainly responsible for working environment measures seems to diminish the role of employee participation.

Cancer is a heterogeneous and complex disease. Tumors are formed by cancer cells and a myriad of non-cancerous cell types that together with the extracellular matrix form the tumor microenvironment. These cancer-associated cells and components contribute to shape the progression of cancer and are deeply involved in patient outcome. The immune system is an essential part of the tumor microenvironment, and induction of cancer immunotolerance is a necessary step involved in tumor formation and growth. Immune mechanisms are intimately associated with cancer progression, invasion, and metastasis; as well as to tumor dormancy and modulation of sensitivity to drug therapy. Transcriptome analyses have been extensively used to understand the heterogeneity of tumors, classifying tumors into molecular subtypes and establishing signatures that predict response to therapy and patient outcomes. However, the classification of the tumor cell diversity and specially the identification of rare populations has been limited in these transcriptomic analyses of bulk tumor cell populations. Massively-parallel single-cell RNAseq analysis has emerged as a powerful method to unravel heterogeneity and to study rare cell populations in cancer, through unsupervised sampling and modeling of transcriptional states in single cells. In this context, the study of the role of the immune system in cancer would benefit from single cell approaches, as it will enable the characterization and/or discovery of the cell types and pathways involved in cancer immunotolerance otherwise missed in bulk transcriptomic information. Thus, the analysis of gene expression patterns at single cell resolution holds the potential to provide key information to develop precise and personalized cancer treatment including immunotherapy. This review is focused on the latest single-cell RNAseq methodologies able to agnostically study thousands of tumor cells as well as targeted single-cell RNAseq to study rare populations within tumors. In particular, we will discuss methods to study the immune system in cancer. We will also discuss the current challenges to the study of cancer at the single cell level and the potential solutions to the current approaches.

In some competitions, performance evaluation includes a substantial subjective component. We argue that the inherent uncertainty and ambiguity in subjective evaluation can lead to favorable ex post treatment for reputationally privileged competitors. Post consumption, judges may infer quality that is not directly observed and/or make conservative choices to assuage accountability concerns. We examine these issues in the context of the Olympic Games, comparing country-level performance outcomes across Olympic sports. We find that past performance is predictive of current performance in all sports, but the effect is stronger in subjective outcome sports versus objective outcome sports. That is, past performance is a better predictor of future performance in sports where external judges and referees can influence the outcomes. We find the same pattern in individual boxing matches, with past country-level performance having a stronger effect on subjective boxing outcomes (judges’ decisions) than objective boxing outcomes (knockouts). Data, as supplemental material, are available at http://dx.doi.org/10.1287/mnsc.2014.2144 . This paper was accepted by Jesper Sørensen, organizations.

Research demonstrates that differences in institutions are at the core of the liability of foreignness. Scholars typically conceptualize and measure those differences as an ‘institutional distance’ between countries on cultural, political, and economic dimensions; and studies now show that institutional distance increases risks for firms operating in global markets. Although we have learned a great deal from studies that explicate the strategic and performance risks associated with institutional distance, we understand less than we should about how institutional distance translates into financial risks, and how to express those risks in a financially meaningful way. In this study, we fill that gap by examining how companies (i.e., banks) price institutional distance risks in a sample of 5,649 project finance deals from 2000-2012. Consistent with the underlying theory, we find that banks systematically vary the interest rates that they charge on large-scale project finance loans to account for cultural, political, and economic distance. We describe how managers of (non-financial) multinational corporations might use these findings to help insulate themselves from institutional risks.

Over the past several decades, research in the fields of international business and strategy has devoted increasing attention to outward foreign direct investment (FDI). Despite extensive scrutiny of the firm-specific motivations for, and consequences of, outward FDI; we know relatively little about inward FDI, the impact of inward FDI on host country firms, and especially, how inward FDI affects the innovativeness of those firms. Extant theoretical arguments predict contrasting effects. One line of research highlights the benefits to host country firms. Another line of research highlights the deleterious consequences to host country firms. Utilizing data from 1799 Spanish manufacturing firms from 1990 to 2002, we investigate the relationships between industry-level and firm-level inward FDI and the innovative performance of host country firms. We find that FDI inflows into Spain are negatively associated with the ex post innovation of local firms. We contrast these findings with those using conventional measures of productivity.

Research summary: Research demonstrates that foreign firms from institutionally distant countries imitate the practices of domestic firms (i.e., adopt an isomorphism strategy). The conjecture has been that pursuing such a strategy can help foreign firms counteract the deleterious performance consequences associated with institutional distance; yet there is scant evidence of such. This study treats isomorphism as an endogenously selected strategy influenced by institutional distance to examine its performance consequences. Using a dataset of 80 foreign banks from 25 countries operating in the United States, we find that foreign firms from institutionally distant home countries benefit initially from selecting an isomorphism strategy. However, the benefits diminish with experience. Managerial summary: Multinational companies experience great difficulty in managing institutional distance, and research suggests that one way to overcome distance-related constraints is to imitate the strategies of local companies. Unfortunately, we do not know enough about the performance-related consequences of engaging in such imitative behavior. This study examines whether imitating local firms improves performance for multinational companies from institutionally distant markets. We find that imitation improves a firm's performance at first; however, with experience those same strategies result in performance decrements. Managers of multinationals should therefore be careful not to get locked into imitative strategies that provide performance benefits upon entry, but that fail to provide benefits over time. Copyright (C) 2015 John Wiley & Sons, Ltd.

Building on Barnett’s (2007) theoretical argument that a firm’s ability to profit from social responsibility depends upon its stakeholder influence capacity (SIC), we bring together contrasting literatures on the relationship between corporate social performance (CSP) and corporate financial performance (CFP) to hypothesize that the CSP-CFP relationship is U-shaped. Our results support that hypothesis. We find that firms with low CSP have higher CFP than firms with moderate CSP, but firms with high CSP have the highest CFP. This supports the theoretical argument that SIC underlies the ability to transform social responsibility into profit.

A central and contentious debate in many literatures concerns the relationship between financial and social performance. We advance this debate by measuring the financial–social performance link mutual funds that practice socially responsible investing (SRI). SRI fund managers have an array of social screening strategies from which to choose. Prior studies have not addressed this heterogeneity within SRI funds. Combining modern portfolio and stakeholder theories, we hypothesize that the financial loss borne by an SRI fund due to poor diversification is offset as social screening intensifies because better-managed and more stable firms are selected into its portfolio. We find support for this hypothesis through an empirical test on a panel of 61 SRI funds from 1972 to 2000. The results show that as the number of social screens used by an SRI fund increases, financial returns decline at first, but then rebound as the number of screens reaches a maximum. That is, we find a curvilinear relationship, suggesting that two long-competing viewpoints may be complementary. Furthermore, we find that financial performance varies with the types of social screens used. Community relations screening increased financial performance, but environmental and labor relations screening decreased financial performance. Based on our results, we suggest that literatures addressing the link between financial and social performance move toward in-depth examination of the merits of different social screening strategies, and away from the continuing debate on the financial merits of either being socially responsible or not.

The purpose of this document is to define minimal standards for a flow cytometry shared resource laboratory (SRL) and provide guidance for best practices in several important areas. This effort is driven by the desire of International Society for the Advancement of Cytometry (ISAC) members in SRLs to define and maintain standards of excellence in flow cytometry, and act as a repository for key elements of this information (e.g. example SOPs/training material, etc.). These best practices are not intended to define specifically how to implement these recommendations, but rather to establish minimal goals for an SRL to address in order to achieve excellence. It is hoped that once these best practices are established and implemented they will serve as a template from which similar practices can be defined for other types of SRLs. Identification of the need for best practices first occurred through discussions at the CYTO 2013 SRL Forum, with the most important areas for which best practices should be defined identified through several surveys and SRL track workshops as part of CYTO 2014. © 2016 International Society for Advancement of Cytometry.

Due to financial and demographic reasons, many countries are trying to increase the actual retirement age. Pension reforms are taking place in countries such as France, Greece and the UK. Norway has recently introduced a new pension reform from January 1st 2011 to encourage longer work life careers. These reforms may lead to a variety of options on life/work balance choices at the later stages of working life. Based on earlier studies, the article illustrate the identification of a three overlapping phases of good managerial practices and worker responses affecting the employment of older workers by developing an analytical model ("a three phase perspective on senior policies") of organisational orientations towards older workers. This paper focuses on a possible fourth phase at the end of the working career as well as the transition from work to retirement. The fourth phase consists of both an economic and a social link between employer and employee. Per ragioni di carattere finanziario e demografico, molti paesi si stanno adoperando per innalzare l’attuale eta di pensionamento. Riforme del sistema pensionistico si stanno attuando in Francia, Grecia e nel Regno Unito. La Norvegia ha recentemente introdotto una nuova riforma delle pensioni in vigore a partire dal 1° gennaio 2011 volta a incoraggiare carriere di lavoro piu lunghe. Queste riforme possono condurre a una varieta di opzioni di armonizzazione dei tempi di vita e di lavoro nell’ultima parte di carriera. A partire da studi precedenti, l’articolo illustra tre fasi sovrapposte di buone pratiche manageriali e di risposte da parte dei lavoratori che riguardano l’occupazione degli anziani, attraverso lo sviluppo di un modello analitico ("una prospettiva a tre fasi sulla senior policy") degli orientamenti organizzativi nei confronti dei lavoratori anziani. L’articolo si focalizza su una possibile quarta fase alla fine della carriera di lavoro cosi come sulla transizione dal lavoro al pensionamento. La quarta fase si esprime in un legame sia economico sia sociale tra il datore di lavoro e il lavoratore.

Monocytes express many cell surface markers indicative of their inflammatory and activation status. Whether these markers are affected by diabetes and its complications is not known and was investigated in this study. Blood was obtained from 22 nondiabetic and 43 diabetic subjects with a duration of diabetes >10 years, including 25 without and 18 with clinically significant complications. The number of CD45+CD14+monocytes and the percentage expressing the proinflammatory marker CD16 were determined by flow cytometry. Other markers of monocyte activation and expression of chemokine receptors were also examined. The relationship between monocyte CD16 and clinical data, selected cytokines, and chemokines was also investigated. Diabetes had no effect on total white cell number but increased monocyte number. Diabetes also significantly decreased the number of CD16+monocytes but only in those with diabetic complications. Other markers of monocyte activation status and chemokine receptors were not affected by diabetes or complications status. Diabetes induced plasma proinflammatory cytokines and they were lower in diabetic subjects with complications compared to those without complications. These results suggest that the circulating monocyte phenotype is altered by diabetic complications status. These changes may be causally related to and could potentially be used to predict susceptibility to diabetic complications.