The conversion of trigger events to their digital equivalent is a central component of any timing-based front end, with applications found in mass spectrometry, single channel analyzers, and a huge variety of 3D mapping and ranging systems.At the same time, ever-tightening size, weight, and power budgets for space launches with a skyrocketing (no pun intended) number of launches in the last decade have made application-specific integrated circuit solutions increasingly appealing. However, conventional analog methods of pulse discrimination introduce timing walk or are limited to a narrow range of pulse shapes, while early-stage digitization requires impractically high sample rates for the events in question.

This work presents the analysis, design, and measurement of an integrated constant fraction discriminator with theoretically zero timing walk and a programmable, constant trigger fraction which does not depend on input pulse shape.The specific silicon presented here was designed for the Solar Probe Analyzer for Ions as part of its time-of-flight mass spectrometer to determine the ion composition of space plasmas. This dissertation discusses the front end requirements for a radiation hardened pulse discriminator in the context of SPAN-Ion. We then address the architectural modifications used to achieve a pulse shape-independent constant trigger fraction, as well as the analog and digital hardening techniques required to detect, correct, and/or mitigate radiation-induced effects. Finally, this work presents the first attempt at an integrated pulse-shaping front end for SPAN-Ion, concluding with simulation results from a more recent chip and a discussion of future work both for SPAN-Ion and for further code base development.

The future of personalized regenerative cellular medicine depends on the ability to faithfully differentiate pluripotent cells to tissue stem cells, or reprogram them from other cellular sources. So far, the efforts to generate transplantable multi-potent hematopoietic stem cells (HSC) in vitro have yielded hematopoietic cells with only limited functional potential. Thus, improved understanding of in vivo programs that direct specification of hematopoietic stem versus progenitor cells during embryonic development holds immense clinical implication. However, characterization of the unique properties of these cell populations is currently hindered by the inability to distinguish them prospectively due to the absence of discriminating cell surface markers or genes.

Here, we uncovered lymphatic vessel endothelial receptor-1 (LYVE1) as a unique cell surface marker that identifies definitive hematopoietic stem and progenitor cells and their cellular precursor, the hemogenic endothelium, in the yolk sac. Furthermore, we showed that LYVE1-eGFP-hCre knock-in mouse is a powerful tool to separate the primitive erythropoiesis from definitive, even after the cell admixture upon onset of embryonic circulation. Using this tool, we provide in vivo evidence that the earliest progenitors to seed the fetal liver derive from the yolk sac.

The mechanisms that establish multilineage differentiation potential in hemogenic endothelium are poorly understood. The vascular endothelial growth factor A (VEGF-A) is essential for endothelial development; however, its role in hemogenic endothelium has not been elucidated. Incorporating several unique mouse models of VEGF-A gene targeting, we document that proper VEGF-A dosage is critical for vascular remodeling and generating multipotent HS/PCs in embryonic hemogenic tissues. Our data support the fact that VEGF-A haploinsufficiency is able to establish primitive erythropoiesis and generate transient myelo-erythroid progenitors from the yolk sac. Moreover, we discover a new cellular source of VEGF-A in placental trophoblasts, and show that trophoblast VEGF-A is important for angiogenesis and hematopoiesis in distant hemogenic organs as well.

The chemokine receptor CXCR4, which normally regulates stromal stem cell interactions in the bone marrow, is highly expressed on a variety of malignant hematologic cells, including lymphoma and lymphocytic leukemias. A new treatment concept has arisen wherein CXCR4 may be an effective therapeutic target as an adjunct to treatment of hematologic neoplasms with chemo- and immunotherapy. In the present study, we developed pepducins, cell-penetrating lipopeptide antagonists of CXCR4, to interdict CXCL12-CXCR4 transmembrane signaling to intracellular G-proteins. We demonstrate that pepducins targeting the first (i1) or third (i3) intracellular loops of CXCR4 completely abrogate CXCL12-mediated cell migration of lymphocytic leukemias and lymphomas. Stromal-cell coculture protects lymphoma cells from apoptosis in response to treatment with the CD20-targeted Ab rituximab. However, combination treatment with CXCR4 pepducins and rituximab significantly increases the apoptotic effect of rituximab. Furthermore, treatment of mice bearing disseminated lymphoma xenografts with pepducins alone or in combination with rituximab significantly increased their survival. These data demonstrate that CXCL12-CXCR4 signaling can be effectively inhibited by cell-penetrating pepducins, which represents a potential new treatment strategy for lymphoid malignancies.

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