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The representation of aerosol processes and the skill in simulating the Asian summer monsoon vary widely across climate models. Yet, for the second half of the twentieth century, the models from the Coupled Model Intercomparison Project Phase 5 (CMIP5) show a robust decrease of average precipitation in the South and Southeast Asian (SSEA) continental region due to the increase of anthropogenic aerosols. When taking into account anthropogenic aerosols as well as greenhouse gases (GHGs), the 15 CMIP5 models considered in this study yield an average June–September precipitation least squares linear trend of −0.20 ± 0.20mm d−1 (50 years)−1, or −2.9%, for all land points in the SSEA region (taken from 75 to 120◦E and 5 to 30◦N) in the years from 1950 to 1999 (multimodel average ± one standard deviation) in spite of an increase in the water vapor path of +0.99 ± 0.65 kg m−2 (50 years)−1 (+2.5%). This negative precipitation trend differs markedly from the positive precipitation trend of +0.29 ± 0.14mm d−1 (50 years)−1, or +4.1%, which is computed for GHG forcing only. Taking into account aerosols both decreases the water vapor path and slows down the monsoon circulation as suggested by several previous studies. At smaller scales, however, internal variability makes attributing observed precipitation changes to anthropogenic aerosols more difficult. Over Northern Central India (NCI), the spread between precipitation trends from individual model realizations is generally comparable in magnitude to simulated changes due to aerosols, and the model results suggest that the observed drying in NCI might in part be explained by internal variability.

Diese Arbeit befasst sich mit der Lichttransmission im retinalen Gewebe. Aufgrund der inversen Konfiguration der Wirbeltiernetzhaut muss das ins Auge eintretende Licht zahlreiche Zellschichten durchdringen, bevor es von den Photorezeptoren detektiert wird. Die Autorin geht davon aus, dass die morphologische Heterogenität dieser Zellschichten mit einer optischen Heterogenität einhergeht, welche den Lichttransport zu den Photorezeptoren beeinflusst. In den Versuchsbeschreibungen wird erläutert, wie das native Netzhautgewebe von Meerschweinen verschiedenen osmotischen Stimuli ausgesetzt wurde, um morphologische Veränderungen zu provozieren. Durch die parallele Beobachtung der Durchmesser ausgewählter Zellen der äußeren und inneren Netzhaut, sowie der quantitativen Lichtdurchlässigkeit des Gewebes, konnte die Autorin die morphologischen Veränderungen zur retinalen Lichtdurchlässigkeit in Beziehung setzen. Die Ergebnisse zeigen, dass Zellschwellungen zu einer Erhöhung der quantitativen Lichtdurchlässigkeit und Zellschrumpfungen zu einer Verringerung dieser führen. Es werden folgende Schlüsse gezogen: Die osmotischen Stimuli bewirken Volumenregulationsprozesse, infolge derer sich lokale Brechungsindizes und Extinktionskoeffizienten ändern und die retinale Lichtdurchlässigkeit beeinflussen. Zudem konnte die Autorin durch Versuche mit nativen Primatennetzhäuten nachweisen, dass die Abbildungsqualität im Zentrum der Fovea centralis am besten ist, weil die inneren Netzhautschichten dort nicht vorhanden sind und das Licht direkt auf die Photorezeptoren trifft. Diese Arbeit zeigt, dass die Wirbeltiernetzhaut ein optisch aktives Medium ist, dessen Morphologie die Lichttransmission durch das Gewebe beeinflusst.

<p>Mutations in the gene SHANK2, which encodes a synaptic scaffolding protein, have been shown to cause a spectrum of neuropsychiatric disorders including: intellectual disability, autism spectrum disorders (ASDs), bipolar disorder (BD), and schizophrenia. However, many aspects of SHANK2 including the array of isoforms expressed, the expression pattern of the protein, biochemical and regulatory mechanisms, and in vivo protein function remain elusive. This body of work aims to uncover the function of the SHANK2 gene and its role in neuropsychiatric disorders using in vitro and in vivo experimental systems.</p> <p>Using a molecular genetics approach, I revealed the transcript architecture of the mouse Shank2 gene including characterization of promoters, isoforms and protein domains. I then outlined the temporal and spatial pattern of the Shank2 isoform expression throughout development. To further explore the protein’s function, we sought to identify novel SHANK2 interacting proteins using a yeast-2-hybrid screen and characterized the interacting proteins. Lastly, in order to understand how Shank2 deficiencies alter brain function we generated and characterized both Shank2 conventional (∆e24) and conditional mutant mice (e24floxed) by deleting or floxing exon 24 that encodes the Homer binding site and has nonsense mutations in human patients with neuropsychiatric disorders.</p> <p>Collectively, these studies 1) provide insight into the transcriptional regulation of Shank2 during brain development; 2) support the value of using Shank2 to further dissect the pathophysiology and circuitry mechanism underlying manic and autism like behaviors; 3) offers a novel mechanistic link between ubiquitination-mediated protein modification and SHANK2 function that may elucidate the molecular basis underlying SHANK2-related neuropsychiatric disorders. Ultimately, these findings may lead to the development of new therapeutic interventions for SHANK2-related neuropsychiatric disorders.</p> / Dissertation

Plasmonic nanoparticles, specifically gold and silver nanoparticles, exhibit unique optical, physical, and chemical properties that are exploited in many biomedical applications. Due to their nanometer size, facile surface functionalization and enhanced optical performance, gold and silver nanoparticles can be used to investigate cellular biology. The work herein highlights a new methodology that has exploited these remarkable properties in order to probe various aspect of cancer cell biology, such as cell cycle progression, drug delivery, and cell death. Cell death mechanisms due to localized gold and silver nanoparticle exposure were also elucidated in this work. Chapter 1 introduces the reader to the synthesis and functionalization of gold and silver nanoparticles as well as reviews their implementation in biodiagnostic and therapeutic applications to provide a foundation for Chapters 3 and 4, where their use in spectroscopic and cytotoxic studies are presented. Chapter 2 provides the reader with detailed explanations of experimental protocols for nanoparticle synthesis and functionalization, in vitro cellular biology experiments, and live-cell Raman spectroscopy experiments that were utilized throughout Chapters 3 and 4. Chapter 3 presents the use of nuclear-targeted gold nanoparticles in conjunction with a Raman microscope modified to contain a live-cell imaging chamber to probe cancer cell cycle progression (Chapter 3.1), examine drug efficacy (Chapter 3.2), monitor drug delivery (Chapter 3.3), and detect apoptotic molecular events in real-time (Chapter 3.4). In Chapter 4, the intracellular effects of gold and silver nanoparticles are explored through live-cell Rayleigh imaging, cell cycle analysis and DNA damage (Chapter 4.1), as well as through the elucidation of cytotoxic cell death mechanisms after nanoparticle exposure (Chapter 4.2) and live cell imaging of silver nanoparticle treated cancer cell communities (Chapter 4.3).

Providing performance and isolation guarantees for applications running in virtualized datacenter environments requires continuous management of the underlying physical resources. For communication- and I/O-intensive applications running on such platforms, the management methods must adequately deal with the shared use of the high-performance fabrics these applications require. In particular, new classes of latency-sensitive and data-intensive workloads running in virtualized environments rely on emerging fabrics like 40+Gbps Ethernet and InfiniBand/RoCE with support for RDMA, VMM-bypass and hardware-level virtualization (SR-IOV). However, the benefits provided by these technology advances are offset by several management constraints: (i) the inability of the hypervisor to monitor the VMs’ usage of these fabrics can affect the platform’s ability to provide isolation and performance guarantees, (ii) the hypervisor cannot provide fine-grained I/O provisioning or perform management decisions for VMs, thus reducing the degree of consolidation that can be supported on the platforms, and (iii) without such support it is harder to integrate these fabrics into emerging cloud computing platforms and datacenter fabric management solutions. This is made particularly challenging for workloads spanning multiple VMs, utilizing physical resources distributed across multiple server nodes and the interconnection fabric. This thesis addresses the problem of realizing a flexible, dynamic resource management system for virtualized platforms with high performance fabrics. We make the following key contributions: (i) A lightweight monitoring tool, IBMon, integrated with the hypervisor to monitor VMs’ use of RDMA-enabled virtualized interconnects, using memory introspection techniques. (ii) The design and construction of a resource management system that leverages IBMon to provide latency-sensitive applications performance guarantees. This system is built on microeconomic principles of supply and demand and can be deployed on a per-node (Resource Exchange) or a multi-node (Distributed Resource Exchange) basis. Fine-grained resource allocations can be enforced through several mechanisms, including CPU capping or fabric-level congestion control. (iii) Sphinx, a fabric management solution that leverages Resource Exchange to orchestrate network and provide latency proportionality for consolidated workloads, based on user/application-specified policies. (iv) Implementation and experimental evaluation using InfiniBand clusters virtualized with the Xen or KVM hypervisor, managed via the OpenFloodlight SDN controller, and using representative data-intensive and latency-sensitive benchmarks.

We present the development of the adjoint of a physically based cirrus formation parameterization that computes the sensitivity of formed crystal number concentration to numerous model variables (e.g., updraft velocity, soluble aerosol geometric mean diameter and number concentration, insoluble aerosol geometric mean diameter and number concentration, and ice deposition coefficient). The adjoint is demonstrated in the CESM Community Atmosphere Model Version 5.1, where sensitivity information is computed and used to quantify which variables are most responsible for modeled variability in formed crystal number concentration. The sensitivity of formed crystal number concentration to updraft velocity is positive and largest over the tropics where regions of deep convection are collocated with large sulfate number concentrations. Sensitivity to sulfate number concentration is largest over the tropics where updraft cooling is sufficient and sulfate number concentration is low, pointing to a sulfate limited regime. Outside of the tropics, crystal production is dominated by heterogeneous freezing; unexpectedly, sensitivities to insoluble aerosol number concentration for accumulation and coarse mode dust, black carbon, and organic carbon are negative in sign here. This is a result of infrequent, anomalously high updraft velocity events causing shifts in the dominant modes of freezing which act to bias sensitivity information when annually averaged. Updraft velocity is responsible for ~95% of the variability in formed crystal number concentration in the high latitudes of the Northern Hemisphere. In the tropics, sulfate number concentration controls variability in formed crystal number concentration since crystal production here is sulfate limited. Insoluble aerosol species play a secondary role in influencing the variability of crystal concentrations; coarse mode dust is the largest contributor to crystal number variability at nearly 60%, although the spatial extent of this influence is small and concentrated over highly localized dust events. When globally averaged, nearly 90% of the variability in crystal number concentration can be described by only updraft velocity, sulfate number, temperature, and coarse mode dust number concentration. Although these results depend on parameter assumptions, the robustness of the underlying physics of the cirrus formation parameterization used throughout this work suggests that this approach can be a powerful method for efficiently identifying the origin of microphysical dependencies within large scale atmospheric simulations.

Genome editing mediated by engineered nucleases, including Transcription Activator-Like Effector Nucleases (TALENs) and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) / CRISPR-associated (Cas) systems, holds great potential in a broad range of applications, including biomedical studies and disease treatment. In addition to creating cell lines and disease models, this technology allows generation of well-defined, genetically modified cells and organisms with novel characteristics that can be used to cure diseases, study gene functions, and facilitate drug development. However, achieving both high efficiency and high specificity remains a major challenge in nuclease-based genome editing. The objectives of this thesis were to optimize the design of TALENs to achieve high on-target cleavage activity, and analyze the off-target effect of CRISPR/Cas to help achieve high specificity. Based on experimental evaluation of >200 TALENs, we compared three different TALEN architectures, proposed new TALEN design rules, and developed a Scoring Algorithm for Predicting TALEN Activity (SAPTA) to identify optimal target sites with high activity. We also performed a systematic study to demonstrate the off-target cleavage by CRISPR/Cas9 when DNA sequences contain insertions or deletions compared to the RNA guide strand. Our results strongly indicate the need to perform comprehensive off-target analysis, and suggest specific guidelines for reducing potential off-target cleavage of CRISPR/Cas9 systems. The studies performed in this thesis work provide important insight and powerful tools for the optimization of engineered nucleases in genome editing, thus making a significant contribution to biomedical engineering and medical applications.

The theme of this work is the observation and understanding of the effects of pore functionalization on adsorption properties of stable Metal-Organic Frameworks (MOFs). Over the first two sections of this work, sets of materials with representative pore sizes and functional groups are studied for adsorption properties. Observed trends are used to identify the best pore properties achievable via functionalization for adsorption systems. The third section of this work provides perspective on MOF materials and proposes target pore features for an efficient adsorbent for carbon dioxide capture from flue gas. First, the highly stable UiO-66 series of materials was selected for a pure-component adsorption study. The selectivity and capacity for CO2 can be best enhanced with the smallest, most polar functional group, such as an amino group, but significantly enhance water adsorption. Large, non-polar groups do not yield a completely hydrophobic material, but may be useful for humid gas separations as pore filling with water is inhibited. Next, a breakthrough study was conducted using CO2:CH4 and CO2:N2 mixtures on a set of stable MOFs. UiO-66-NH2 and UiO-66-DM, where DM=dimethyl, outperform predictions based on published isotherms and have dynamic CO2:CH4 selectivity comparable to zeolite NaY. UiO-66-DM may be a good candidate for further study due to the combination of partial hydrophobicity and good selectivity. Finally, by combining a review of literature with observations made in this work, a perspective on MOFs as efficient humid gas separation materials is provided. The presence of water vapor prevents use of current high performance adsorbents, but several MOF pore features show promise for these separations. The designable nature of MOFs allows for targeted design of size-matched pores and single-molecule traps which can selectively or cooperatively adsorb CO2 in the presence of water. Also, many MOF materials would be well suited for advanced pressure swing adsorption cycles and engineered sorbents, which enables greater material utilization and system efficiency.

The type of media shared through social media channels has shifted from text content to include an increasingly large number of images. Visual traces resulting from people's online social behavior have the potential to reveal insights about our habits, activities and preferences. The role of social network-related factors have been well studied in previous research. Yet, few studies have sought to understand how user behavior in social networks is dependent on the image itself. The goal of my dissertation is to understand how people engage with image content, and I seek to uncover the role of presentation and image content on people's preferences. To achieve this goal, I study the image sharing communities, Flickr, Instagram and Pinterest, using quantitative and qualitative methods. First, I show how colors -- a fundamental property of an image -- could impact the virality of an image on Pinterest. I consider three dimensions of color: hue, saturation and brightness and evaluate their role in the diffusion of the image on Pinterest, while controlling for social network reach and activity. Next, I shift the focus from abstract colors to a higher-level presentation of images. I study the role of filters on the Flickr mobile application as proxies to visual computation. To understand how people use filters, I conduct an interview study with 15 Flickr mobile users about their filter use. I analyze Flickr mobile images to discover the role of filters in engaging users. Presentation is not the only factor that makes an image interesting. To gain deeper insights in what makes an image more engaging in social image sharing sites, I study the images of people on the Instagram network. I compare images of people with those that do not have faces and find that images with human faces are more engaging. I also look at the role of age and gender of people in the image in engaging users. Finally, I examine different content categories, with and without filters, and study the impact of content category on engagement. I use large-scale data from Flickr and interviews with Flickr mobile users to draw insights into filter use and content engagement. This dissertation takes a first step toward understanding content and presentation of images and how they impact one aspect of user behavior online. It provides several theoretical and design implications for effective design, creation and imposition of rules on image sharing communities. This dissertation opens up a new direction for future research in multimedia-mediated communication.