Elucidation of the cell signaling pathways mediating innate immunity and host-pathogen interactions

The ability to generate a robust immune response is integral to organismal homeostasis. Cells of the innate immune system are considered the first responders of immunity, and are therefore responsible for sensing both pathogens and endogenous danger signals and initiating a protective inflammatory response. To appropriately sense pathogens and danger signals, cells have developed intricate mechanisms for transducing signals from the extracellular environment into the cell. The integration of these signals is complex, resulting from crosstalk between many signaling pathways, but is critical to generating a coordinated biological response. In additional to the specialized mechanisms of innate immune cells to respond to antigens, these cells (like most) have evolved a complex set of adaptive mechanisms that maintain homeostasis during cell stress. Activation of innate immunity via pathogen invasion or the presence of danger signals can be considered an especially intense form of cell stress, thereby implicating these homeostatic pathways as components of the innate immune response. The work presented in this thesis relates to the molecular mechanisms by which cells of the innate immune system integrate signals from the microenvironment to produce a coordinated biological response. The aim was to elucidate the mechanisms by which innate macrophages transduce extracellular signals to activate important effector pathways, and to describe crosstalk between cell signaling pathways that mediate adaptive responses to cell stress. Finally, we looked to extend our understanding to pathophysiological settings, and investigated the mechanisms by which pathogens that cause cell stress generate an aberrant inflammatory response. In doing so, we described novel components of these signaling pathways, which may be exploited in designing novel therapeutics. In paper I, Gαi2 was identified as a critical signaling molecule in macrophage phenotype determination, functioning to transduce signals from the microenvironment to fine tune macrophage propensity towards an M1 inflammatory or M2 anti-inflammatory phenotype. In paper II, the immune receptor CD38 was shown activate the master transcriptional regulation of the autophagic/lysosome machinery, TFEB. We further identified the large kinase LRRK2 as essential in signal transduction downstream of CD38. In paper III, we described adaptive crosstalk between TFEB, an essential component of the cell stress response, and the typically proliferative WNT signaling pathway. Finally, in paper IV we describe how the SARS-Coronavirus open reading frame-3a causes multimodal necrotic death by activating multiple cell stress and innate immune pathways, resulting in aberrant inflammation. In summary, the work presented in this thesis extends our current understanding of the molecular mechanisms mediating the integration of signals in innate immune cells. We have identified several novel signaling mechanisms, which could lay the foundation for the development of targeted therapeutics

Remittance flows to post-conflict states: perspectives on human security and development

This repository item contains a single issue of the Pardee Center Task Force Reports, a publication series that began publishing in 2009 by the Boston University Frederick S. Pardee Center for the Study of the Longer-Range Future.Migrant remittances – that is, money or other goods sent to relatives in the country of origin– play an increasingly central role in post-conflict reconstruction and national development of conflict-affected states. Private remittances are of central importance for restoring stability and enhancing human security in post-conflict countries. Yet the dynamics of conflict-induced remittance flows and the possibilities of leveraging remittances for post-conflict development have been sparsely researched to date. This Pardee Center Task Force Report is the outcome of an interdisciplinary research project organized by the Boston University Center for Finance, Law & Policy, in collaboration with The Frederick S. Pardee Center for the Study of the Longer-Range Future. The Task Force was convened by Boston University development economist John R. Harris and international banking expert Donald F. Terry, and social anthropologist Daivi Rodima-Taylor, Visiting Researcher at the Boston University African Studies Center, served as lead researcher and editor for the report. The Task Force was asked to research, analyze, and propose policy recommendations regarding the role of remittances in post-conflict environments and their potential to serve as a major source of development funds. The report’s authors collectively suggest a broader approach to remittance institutions that provides flexibility to adapt to specific local practices and to make broader institutional connections in an era of growing population displacement and expanding human and capital flows. Conditions for more productive use of migrants’ remittances are analyzed while drawing upon case studies from post-conflict countries in Africa, Asia and Latin America. The papers in this Task Force Report establish the importance of remittances for sustaining local livelihoods as well as rehabilitating institutional infrastructures and improving financial inclusion in post-conflict environments. Highlighting the increasing complexity of global remittance systems, the report examines the growing informality of conflict-induced remittance flows and explores solutions for more efficient linkages between financial institutions of different scales and degrees of formality. It discusses challenges to regulating international remittance transfers in the context of growing concerns about transparency, and documents the increasing role of diaspora networks and migrant associations in post-conflict co-development initiatives. The Task Force Report authors outline the main challenges to leveraging remittances for post-conflict development and make recommendations for further research and policy applications

Percutaneous tricuspid valvotomy for pacemaker lead-induced tricuspid stenosis

AbstractPermanent pacemaker lead-induced tricuspid regurgitation is extremely uncommon. We report a patient with severe tricuspid stenosis detected 10 years after permanent single chamber pacemaker implantation in surgically corrected congenital heart disease. The loop at the level of the tricuspid valve may have caused endothelial injury and eventually led to stenosis. Percutaneous balloon valvotomy for such stenosis has not been reported from India

End-to-End Joint Antenna Selection Strategy and Distributed Compress and Forward Strategy for Relay Channels

Multi-hop relay channels use multiple relay stages, each with multiple relay nodes, to facilitate communication between a source and destination. Previously, distributed space-time codes were proposed to maximize the achievable diversity-multiplexing tradeoff, however, they fail to achieve all the points of the optimal diversity-multiplexing tradeoff. In the presence of a low-rate feedback link from the destination to each relay stage and the source, this paper proposes an end-to-end antenna selection (EEAS) strategy as an alternative to distributed space-time codes. The EEAS strategy uses a subset of antennas of each relay stage for transmission of the source signal to the destination with amplify and forwarding at each relay stage. The subsets are chosen such that they maximize the end-to-end mutual information at the destination. The EEAS strategy achieves the corner points of the optimal diversity-multiplexing tradeoff (corresponding to maximum diversity gain and maximum multiplexing gain) and achieves better diversity gain at intermediate values of multiplexing gain, versus the best known distributed space-time coding strategies. A distributed compress and forward (CF) strategy is also proposed to achieve all points of the optimal diversity-multiplexing tradeoff for a two-hop relay channel with multiple relay nodes.Comment: Accepted for publication in the special issue on cooperative communication in the Eurasip Journal on Wireless Communication and Networkin

Unmappable ventricular tachycardia after an old myocardial infarction. Long-term results of substrate modification in patients with an implantable cardioverter defibrillator

Purpose The frequent occurrence of ventricular tachycardia can create a serious problem in patients with an implantable cardioverter defibrillator. We assessed the long-term efficacy of catheter-based substrate modification using the voltage mapping technique of infarct-related ventricular tachycardia and recurrent device therapy. Methods The study population consisted of 27 consecutive patients (age 68 +/- 8 years, 25 men, mean left ventricular ejection fraction 31 +/- 9%) with an old myocardial infarction and multiple and/or hemodynamically not tolerated ventricular tachycardia necessitating repeated device therapy. A total of 31 substrate modification procedures were performed using the three-dimensional electroanatomical mapping system. Patients were followed up for a median of 23.5 (interquartile range 6.5-53.2) months before and 37.8 (interquartile range 11.7-71.8) months after ablation. Antiarrhythmic drugs were not changed after the procedure, and were stopped 6 to 9 months after the procedure in patients who did not show ventricular tachycardia recurrence. Results Median ventricular tachycardias were 1.6 (interquartile range 0.7-6.7) per month before and 0.2 (interquartile range 0.00-1.3) per month after ablation (P = 0.006). Nine ventricular fibrillation episodes were registered in seven patients before and two after ablation (P = 0.025). Median antitachycardia pacing decreased from 1.6 (interquartile range 0.01-5.5) per month before to 0.18 (interquartile range 0.00-1.6) per month after ablation (P = 0.069). Median number of shocks decreased from 0.19 (interquartile range 0.04-0.81) per month before to 0.00 (interquartile range 0.00-0.09) per month after ablation (P = 0.001). One patient had a transient ischemic attack during the procedure, and another developed pericarditis. Nine patients died during follow-up, eight patients due to heart failure and one patient during valve surgery. Conclusion Catheter-based substrate modification using voltage mapping results in a long-lasting reduction of cardioverter defibrillator therapy in patients with multiple and/or hemodynamically not tolerated infarct-related ventricular tachyarrhythmia

Starting-up unregistered and firm performance in Turkey

© 2016 The Author(s) Recent years have seen a questioning of the negative representation of informal sector entrepreneurship and an emergent view that it may offer significant benefits. This paper advances this rethinking by evaluating the relationship between business registration and future firm performance. Until now, the assumption has been that starting-up unregistered is linked to weaker firm performance. Using World Bank Enterprise Survey data on 2494 formal enterprises in Turkey, and controlling for other determinants of firm performance as well as the endogeneity of the registration decision, the finding is that formal enterprises that started-up unregistered and spent longer unregistered have significantly higher subsequent annual sales and productivity growth rates compared with those registered from the outset. This is argued to be because in such weak institutional environments, the advantages of registering from the outset are outweighed by the benefits of deferring business registration and the low risks of detection and punishment. The resultant implication is that there is a need to shift away from the conventional eradication approach based on the negative depiction of informal entrepreneurship as poorly performing, and towards a more facilitating approach that improves the benefits of business registration and tackles the systemic formal institutional deficiencies that lead entrepreneurs to decide to delay the registration of their ventures