Modeling the human bone marrow niche in mice: From host bone marrow engraftment to bioengineering approaches

Xenotransplantation of patient-derived samples in mouse models has been instrumental in depicting the role of hematopoietic stem and progenitor cells in the establishment as well as progression of hematological malignancies. The foundations for this field of research have been based on the development of immunodeficient mouse models, which provide normal and malignant human hematopoietic cells with a supportive microenvironment. Immunosuppressed and genetically modified mice expressing human growth factors were key milestones in patient-derived xenograft (PDX) models, highlighting the importance of developing humanized microenvironments. The latest major improvement has been the use of human bone marrow (BM) niche-forming cells to generate human-mouse chimeric BM tissues in PDXs, which can shed light on the interactions between human stroma and hematopoietic cells. Here, we summarize the methods used for human hematopoietic cell xenotransplantation and their milestones and review the latest approaches in generating humanized BM tissues in mice to study human normal and malignant hematopoiesis

Transforming ophthalmic education into virtual learning during COVID-19 pandemic : a global perspective

Objective: The coronavirus disease 2019 (COVID-19) pandemic has imposed measures of social distancing and barriers in delivery of "in person" education. Institutions, involved in training the next generation of ophthalmologists, are using alternative teaching methods to maintain the standard of education. Methods: We conducted a worldwide survey among physicians, who are actively involved in Ophthalmology-related education, between 3 and 14 April 2020. The expert survey, developed on the basis of literature search and focus group discussions, comprised 23 questions addressing the use of e-learning in Ophthalmology during the COVID-19 pandemic. Results: A total of 321 participants from both academic and non-academic institutions worldwide, with variable practice experience and expertise, completed the survey. Before the pandemic, the majority of participants used traditional training modalities, including lectures, grand rounds and journal clubs, and 48% did not use any e-learning. There was a statistically significant increase in the use of all e-learning alternatives during the pandemic (p < 0.001), associated mainly with the availability of e-learning facilities (p < 0.001) and the academic character of institutions (p < 0.001). Zoom\uae was recognized as the mostly used platform for virtual teaching. Although theoretical teaching may take place, the surgical training of residents/fellows was dramatically reduced. The latter was significantly associated with participants' perspectives about teaching practices (p < 0.001). Conclusion: COVID-19 pandemic imposed great challenges in the educational field of Ophthalmology. The experience related to virtual training in Ophthalmology, gained during the pandemic, may change the traditional teaching practices in the world and provide new educational opportunities

The graduation performance of technology business incubators in China's three tier cities: the role of incubator funding, technical support, and entrepreneurial mentoring

This study examines the effects of technology business incubator (TBI)’s funding, technical support and entrepreneurial mentoring on the graduation performance of new technology-based firms in China’s three tier cities. Using new dataset on all TBIs and incubated new technology-based firms from government surveys conducted over five consecutive years from 2009 to 2013 combined with archival and hand-collected data, we find the effects of incubator services on the early growth of new technology-based firms vary according to the local context. Technical support facilities and entrepreneurial mentoring from TBIs are found to have significantly and positively influenced the early development of the firms in the four most affluent tier 1 cities, whilst these effects become less pronounced for the tier 2 and tier 3 cities. These two services are also found to influence graduation performance in the government and university types of TBI respectively. Results support the notion that the effectiveness of an incubators services is shaped by the level of a city’s socio-economic development and that the city location of a TBI does impact the graduation performance of its incubatees

A spill over effect of entrepreneurial orientation on technological innovativeness:an outlook of universities and research based spin offs

partially_open5siBy shifting towards Romer’s (Am Econ Rev 94:1002–1037, 1986) economy and so the spread of knowledge economy, universities started to adopt a collaborative approach with their entrepreneurial ecosystem. They turn out to be risk taker, autonomous, proactive, competitive, and innovative. In a nutshell, they are entrepreneurial oriented with the aim to generate new innovative ventures, known as research-based spin offs. Doubly, this has induced an improvement of technology transfer and the degree of entrepreneurship in the current knowledge economy. However there still is a paucity of studies on the spill over effect of entrepreneurial orientated universities and research-based spin off on technology transfer need to be more explored. Therefore, the article investigates the link between entrepreneurial orientation and such spill overs by offering an outlook of two universities and two research-based spin offs in the United Kingdom. The scope is to provide a deep view of technological innovativeness in a research context, entrepreneurial oriented. Our research suggests that entrepreneurial attitude has become an imperative to succeed in the context where British institutions currently operate. Entrepreneurship brings the necessary technological innovation to the university and its students, which results in better positioning of the university at national and international levels, with the subsequent impact on their ability to attract not only new students and academics but also funding to conduct their research.openScuotto, Veronica; Del Giudice, Manlio; Garcia-Perez, Alexeis; Orlando, Beatrice; Ciampi, FrancescoScuotto, Veronica; Del Giudice, Manlio; Garcia-Perez, Alexeis; Orlando, Beatrice; Ciampi, Francesc

Inhibition of IFN-γ-dependent antiviral airway epithelial defense by cigarette smoke

<p>Abstract</p> <p>Background</p> <p>Although individuals exposed to cigarette smoke are more susceptible to respiratory infection, the effects of cigarette smoke on lung defense are incompletely understood. Because airway epithelial cell responses to type II interferon (IFN) are critical in regulation of defense against many respiratory viral infections, we hypothesized that cigarette smoke has inhibitory effects on IFN-γ-dependent antiviral mechanisms in epithelial cells in the airway.</p> <p>Methods</p> <p>Primary human tracheobronchial epithelial cells were first treated with cigarette smoke extract (CSE) followed by exposure to both CSE and IFN-γ. Epithelial cell cytotoxicity and IFN-γ-induced signaling, gene expression, and antiviral effects against respiratory syncytial virus (RSV) were tested without and with CSE exposure.</p> <p>Results</p> <p>CSE inhibited IFN-γ-dependent gene expression in airway epithelial cells, and these effects were not due to cell loss or cytotoxicity. CSE markedly inhibited IFN-γ-induced Stat1 phosphorylation, indicating that CSE altered type II interferon signal transduction and providing a mechanism for CSE effects. A period of CSE exposure combined with an interval of epithelial cell exposure to both CSE and IFN-γ was required to inhibit IFN-γ-induced cell signaling. CSE also decreased the inhibitory effect of IFN-γ on RSV mRNA and protein expression, confirming effects on viral infection. CSE effects on IFN-γ-induced Stat1 activation, antiviral protein expression, and inhibition of RSV infection were decreased by glutathione augmentation of epithelial cells using N-acetylcysteine or glutathione monoethyl ester, providing one strategy to alter cigarette smoke effects.</p> <p>Conclusions</p> <p>The results indicate that CSE inhibits the antiviral effects of IFN-γ, thereby presenting one explanation for increased susceptibility to respiratory viral infection in individuals exposed to cigarette smoke.</p

Comparative Expression Profiling of the Chlamydia trachomatis pmp Gene Family for Clinical and Reference Strains

Chlamydia trachomatis, an obligate intracellular pathogen, is a leading worldwide cause of ocular and urogenital diseases. Advances have been made in our understanding of the nine-member polymorphic membrane protein (Pmp) gene (pmp) family of C. trachomatis. However, there is only limited information on their biologic role, especially for biological variants (biovar) and clinical strains.We evaluated expression for pmps throughout development for reference strains E/Bour and L2/434, representing different biovars, and for clinical E and L2 strains. Immunoreactivity of patient sera to recombinant (r)Pmps was also determined. All pmps were expressed at two hours. pmpA had the lowest expression but was up-regulated at 12 h for all strains, indicating involvement in reticulate body development. For pmpD, expression peaked at 36 h. Additionally, 57.7% of sera from infected and 0% from uninfected adolescents were reactive to rPmpD (p = 0.001), suggesting a role in immunogenicity. pmpF had the highest expression levels for all clinical strains and L2/434 with differential expression of the pmpFE operon for the same strains. Sera were nonreactive to rPmpF despite immunoreactivity to rMOMP and rPmpD, suggesting that PmpF is not associated with humoral immune responses. pmpFE sequences for clinical strains were identical to those of the respective reference strains. We identified the putative pmpFE promoter, which was, surprisingly, 100% conserved for all strains. Analyses of ribosomal binding sites, RNase E, and hairpin structures suggested complex regulatory mechanism(s) for this >6 Kb operon.The dissimilar expression of the same pmp for different C. trachomatis strains may explain different strain-specific needs and phenotypic distinctions. This is further supported by the differential immunoreactivity to rPmpD and rPmpF of sera from patients infected with different strains. Furthermore, clinical E strains did not correlate with the E reference strain at the gene expression level, reinforcing the need for expansive studies of clinical strains

Gene therapy for monogenic liver diseases: clinical successes, current challenges and future prospects

Over the last decade, pioneering liver-directed gene therapy trials for haemophilia B have achieved sustained clinical improvement after a single systemic injection of adeno-associated virus (AAV) derived vectors encoding the human factor IX cDNA. These trials demonstrate the potential of AAV technology to provide long-lasting clinical benefit in the treatment of monogenic liver disorders. Indeed, with more than ten ongoing or planned clinical trials for haemophilia A and B and dozens of trials planned for other inherited genetic/metabolic liver diseases, clinical translation is expanding rapidly. Gene therapy is likely to become an option for routine care of a subset of severe inherited genetic/metabolic liver diseases in the relatively near term. In this review, we aim to summarise the milestones in the development of gene therapy, present the different vector tools and their clinical applications for liver-directed gene therapy. AAV-derived vectors are emerging as the leading candidates for clinical translation of gene delivery to the liver. Therefore, we focus on clinical applications of AAV vectors in providing the most recent update on clinical outcomes of completed and ongoing gene therapy trials and comment on the current challenges that the field is facing for large-scale clinical translation. There is clearly an urgent need for more efficient therapies in many severe monogenic liver disorders, which will require careful risk-benefit analysis for each indication, especially in paediatrics