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The Development of Indexicality: Perceptual evidence from 4- to 18-year-olds
Get PDFDespite the importance of the pre-adult developmental period to sociolinguistic theory (Labov 1972, Eckert 2000), children and teens remain understudied when it comes to understanding how indexicality develops. The present study seeks to bring the existing scholarship on child and teen evaluation of language varieties into a clearer dialogue with contemporary theories of indexicality focusing on the social meaning of individual variables. We conducted a matched guise task with listeners from age groups across the lifespan. From a larger dataset, we focus here on comparing the status ratings of adult listeners with those of children and teens, for six American English sociolinguistic variables. Listeners heard short audio stimuli containing unmarked or marked variants and were asked “Do you think this person would be a good teacher?”. Our results show that listeners as young as 4 years old can differentiate variants for status, and that teenagers aged 13-18 tend to pattern with adults in rating unmarked variants more positively for status. In addition, we identify a range of developmental patterns across variables: some, like creaky voice and /r/-insertion, show a unidirectional pattern, suggesting a linear development of status differentiation. For other variables, only listeners in middle childhood differ significantly from adults – for example, 10-12 year olds do not differentiate (ING) variants for status – highlighting the need for further research exploring the social meanings of variants in this developmental period in particular. Finally, 4-6 year olds differed from adults most often, but in varied ways, highlighting this period as one of transitions in which children begin to shift from a caregiver model to a peer-oriented one. In all, the results serve to bolster our call for increased attention to the indexical systems of children and teens, whose rich social-semiotic landscapes deserve further study
Deciphering The Heterogeneity Of Hiv Reservoir Immunology: A Single-Cell Perspective
Get PDFSince its initial documentation in 1981, the acquired immunodeficiency syndrome (AIDS) epidemic has impacted more than 70 million people. As the causative agent of AIDS, human immunodeficiency virus (HIV) is a retrovirus that integrates a copy of its viral genome (termed provirus) into the genome of target cells known as CD4+ T cells. With antiretroviral therapy (ART), persons living with HIV (PLWH) can suppress viral replication and prevent progression to AIDS. However, ART is usually a lifelong requirement as interruption can lead to viral rebound via transcription at the integrated viral genome. During early HIV infection, some infected cells can enter a quiescent state that results in a state of infection known as latency. Persistent infection and reversible latency are characteristics of the HIV reservoir. As a result, there is no universally accessible cure for HIV. A functional cure of HIV – which is to suppress viral replication without ART – is a primary goal of HIV cure research. Such a strategy requires an in-depth understanding of the HIV reservoir but many CD4+ T cells, each with different function and phenotype, contribute to the collective HIV reservoir that is located throughout different tissue environments. To address this challenge, this study deciphers the reservoir through the lens of tissue versus blood compartmentalization at a subset resolution to address the impact of residency and circulation as well as with a novel single-cell approach to enable a comprehensive analysis of the HIV reservoir during ART. While the characteristics of integration were generally the same across compartments, there was a lack of overlap between tissues and blood to suggest the existence of sub-reservoirs where there may be unique reservoirs based on residency status. Furthermore, the single-cell profiling revealed extensive heterogeneity between and within individuals with some infected cells displaying a poised signature for reactivation. These results provided a clearer picture of the HIV reservoir to come closer to the goal of a functional cure that can effectively target latency across the location and phenotypic diversity of the HIV reservoir
Control Of Thermogenesis By Nuclear Receptor Corepressors And Rev-Erbs In Brown Adipose Tissue
Get PDFBrown adipose tissue (BAT) is a key thermogenic organ, whose expression of Uncoupling Protein 1 (UCP1) and ability to maintain body temperature in response to acute cold exposure requires histone deacetylase 3 (HDAC3). HDAC3 exists in tight association with nuclear receptor corepressors NCoR1 and NCoR2 (also known as Silencing Mediator of Retinoid and Thyroid Receptors, or SMRT), but the functions of NCoR1/2 in BAT have not been established. This corepressor complex of HDAC3 and NCoR1/2 can interact with a variety of nuclear receptors, including REV-ERBa/b which are related nuclear receptors (NRs) that couple the molecular clock with metabolism. Here we report that, as expected, genetic loss of NCoR1/2 in BAT (NCoR1/2 BAT-dKO) leads to loss of HDAC3 activity. In addition, HDAC3 is no longer bound at its physiological genomic sites in the absence of NCoR1/2, leading to a shared deregulation of BAT lipid metabolism between the NCoR1/2 BAT-dKO and HDAC3 BAT KO mice. Despite these commonalities, however, loss of NCoR1/2 in BAT does not phenocopy the cold sensitivity observed in the HDAC3 BAT-KO, nor does loss of either corepressor alone. Instead, BAT lacking NCoR1/2 is inflamed, particularly with respect to the IL-17 axis that increases thermogenic capacity by enhancing innervation. Integration of BAT RNA-seq and ChIP-seq data revealed that NCoR1/2 directly regulate Mmp9, which integrates extracellular matrix remodeling and inflammation. We also find that REV-ERBa/b do not tissue-autonomously control acute and circadian BAT thermogenesis. However, BAT REV-ERBa/b do regulate lipogenesis via Srebp1c in conditions of chronic cold. These findings reveal pleiotropic functions of the NCoR/HDAC3 corepressor complex in BAT, and one of their associated nuclear receptor partners, REV-ERBa/b. In sum, HDAC3-independent suppression of BAT inflammation counterbalances NCoR1/2 stimulation of HDAC3 activity in the control of thermogenesis, while REV-ERBa/b only control thermogenesis in BAT via fuel availability
Optical Imaging Of Tissue Physiology With Exogenous Contrast Agents
Get PDFThis thesis describes experiments and analyses which push the frontier per what one can learn from optically emitting exogenous contrast agents in living tissue. The first set of experiments concurrently measured cerebral blood flow and bothintravascular- and extravascular-tissue oxygen concentration in a rat brain during functional activation; the new instrumentation needed to collect this information used contrast agent phosphorescence lifetime to determine oxygen concentration and speckle contrast imaging to probe blood flow. The concurrent measurement of multiple physiological parameters with high temporal resolution (∼7 Hz) provided a unique opportunity to observe the interconnected dynamics of oxygen exchange, blood flow, and cerebral oxygen metabolism. The experiments showed that initial metabolic changes trigger a blood flow response; comprehensive theoretical modeling of the data exposed potential weaknesses of the well-known and often-used two-compartment oxygen diffusion model, and the experiments as a whole introduced a new tool for characterization of oxygen metabolism and neurovascular coupling in the brain.
The second set of experiments developed instrumentation and a simple theoretical methodology for imaging fluorescent targets in turbid media such as tissue. This approach used the ideas of spatial frequency domain fluorescence diffuse optical tomography (SFD-FDOT). The new reconstruction algorithm modified the more complex SFD-FDOT reconstruction method to rapidly acquire the depth of fluorescent target(s) and then estimate the transverse margins of the fluorescent target(s). Tissue phantom experiments demonstrated the instrumentation and algorithm, and assessed limitations. The new methodology could be useful for image guidance during tumor resection surgery, and could also provide rapid and useful constraining information for more comprehensive fluorescent tomography
Layers Of Maturation In Cortical Hierarchies
Get PDFHierarchies form critical scaffolds for top-down processing but are often multiplex. In the brain, multiple layers of complex hierarchies intersect, dissociate, and re-converge over the lifespan. Although aspects of local hierarchical organizations are well-mapped for sensory systems, the fashion by which hierarchical organization extends globally is unknown. Human neuroimaging provides a means by which to observe both the developmental emergence and functions of global neurohierarchical organization. Here, we leveraged these advances to distill multiple layers of hierarchical formation across diverse brain-tissue quantifications. We demonstrate that these layers form common and dissociable biomarkers of the developmental emergence of complex cognition. Our results indicate that multiplex neurocognitive development both processes across a normative hierarchical pattern and contributes to engraining the pattern into cortical function. Further, our results suggest that neurocognitive development is largely contemporaneous with neurocognitive aging in an integrated, flexible lifespan sequence
Development And Application Of Patient-Derived Glioblastoma Organoids For Studying Tumor Heterogeneity And The Immune-Related Microenvironment
No full textNeurological diseases, including brain cancers, involve complex interactions between different cell types in typified cytoarchitectures and microenvironmental niches; however, many laboratory models inadequately capture this heterogeneity and thus limit the investigation of important underlying biological processes. Building on our work with brain organoid models of early neural development, we established patient-derived glioblastoma (GBM) organoids (GBOs) as models of inter- and intra-tumoral heterogeneity. We performed extensive histological, genetic, and transcriptomic analyses to demonstrate that these GBOs maintain the diverse cellular composition, somatic mutational landscape, and transcriptomic states of their corresponding parental tumors. Importantly, non-neoplastic tumor resident cells, such as macrophages, microglia, vascular cells, and oligodendrocytes are preserved in GBOs, allowing for investigation of the tumor microenvironment with this cellular context intact. GBOs are amenable to a wide range of experimental manipulations, such as orthotopic xenograft for studies of tumor cell infiltration and drug screening for personalized medicine or chemical genetics. These studies validate the fidelity of GBOs to their parental tumors and highlight the unique advantages and opportunities available with this laboratory model of GBM
Chimeric antigen receptor modified (CAR) T cell therapy has achieved remarkable outcomes in certain treatment resistant malignancies, however, trials in GBM have yet to yield broad success. Correlative studies have pointed towards an adaptive tumor response in opposition to the cellular immunotherapy as important in mediating overall treatment inefficacy, though the specific cellular and molecular components of this response remain unknown. We sought to dissect the dynamic evolution of the tumor and CAR T cell interactions in a co-culture model with GBOs using single cell multi-modal analysis platform. We identified components of a closely interconnected network of cell-cell interactions that led to concomitant shifts in cellular states upon T cell activation. Unexpectedly, we also observed that the immunosuppressive tumor response coincided with the downregulation of glioma stem cell signatures in both antigen-positive and antigen-negative neoplastic cells. Soluble factors in the conditioned media from the co-cultures could recapitulate this phenotype, and we found that IFNɣ was required in this context, but it alone was not sufficient. These results indicate that the GBM stem cell like state could be influenced by immune activity and suggest a broader role for immunotherapies in the treatment of this disease
Saharan Fallout: French Explosions In Algeria And The Politics Of Nuclear Risk During African Decolonization (1960–66)
No full textBetween 1960 and 1966, French forces began to prove their nuclear weapon capabilities by conducting seventeen nuclear explosions in the Algerian Sahara. This dissertation pursues an international history of French nuclear ambitions and the resistance and the criticism that they faced at regional, international, and global scales. It does so by tracking radioactive debris from the French explosions—Saharan fallout—and the scientists, activists, diplomats, and other officials who tracked it during the 1960s. This methodology relies on declassified archives—from France, the United States, United Kingdom, Canada, and international organizations—produced for these purposes of nuclear surveillance. Concerns extended beyond the health effects of radiation exposure. The presence of Saharan fallout constellated transnational networks of scientists and technicians across African territories bordering the Algerian desert. It also bred criticism that French explosions violated African sovereignty and heightened geopolitical inequalities during an unprecedented era of decolonization. The French blasts coincided with the Algerian War (1954–62), continued after Algerian Independence, and intersected with decolonization struggles in neighboring African territories. At the same time, Saharan fallout illuminated processes of Cold War realignment shaped by concerns about radiation exposure and nuclear risk during a widening arms race. By examining convergences between political contestation and fallout trajectories, this dissertation shows that the international controversy created by the French explosions in Algeria exceeded debates about nuclear proliferation and nuclear deterrence. These first French blasts, and the threat of radioactive contamination that they imposed on many African territories, spurred participation in nuclear weapons governance by the continent’s new national leaders and their newly independent allies. This dissertation concludes by evaluating the importance of the Saharan nuclear sites, and ongoing discussions about environmental remediation and victim compensation, in Franco-Algerian relations today
Network-Wide Monitoring And Debugging
Get PDFModern networks can encompass over 100,000 servers. Managing such an extensive network with a diverse set of network policies has become more complicated with the introduction of programmable hardwares and distributed network functions. Furthermore, service level agreements (SLAs) require operators to maintain high performance and availability with low latencies. Therefore, it is crucial for operators to resolve any issues in networks quickly. The problems can occur at any layer of stack: network (load imbalance), data-plane (incorrect packet processing), control-plane (bugs in configuration) and the coordination among them. Unfortunately, existing debugging tools are not sufficient to monitor, analyze, or debug modern networks; either they lack visibility in the network, require manual analysis, or cannot check for some properties. These limitations arise from the outdated view of the networks, i.e., that we can look at a single component in isolation. In this thesis, we describe a new approach that looks at measuring, understanding, and debugging the network across devices and time. We also target modern stateful packet processing devices: programmable data-planes and distributed network functions as these becoming increasingly common part of the network. Our key insight is to leverage both in-network packet processing (to collect precise measurements) and out-of-network processing (to coordinate measurements and scale analytics). The resulting systems we design based on this approach can support testing and monitoring at the data center scale, and can handle stateful data in the network. We automate the collection and analysis of measurement data to save operator time and take a step towards self driving networks
Responding To Media Coverage Of Gender-Based Violence In Argentina And The United States: A Mixed Methods Study Of The Intersecting Roles Of Gender, Class, And Racialized Ethnicity Among General And Activist Publics
No full textYears after the emergence of anti-violence feminist movements in the Americas—the Ni Una Menos in Argentina and the #MeToo in the United States—how do feminist expert publics and ordinary citizens evaluate and respond to the media coverage of gender-based violence (GBV) in their countries? Have feminist activists been successful in promoting a gender equality framework among their citizenries? Do audiences care and react to news about sexual harassment—as a case of GBV—equally, regardless of the class and ethnoracial background of the women harmed by it? To respond to this, I draw from three mixed methods, comparative case studies: Study 1 is an interview-based study with 52 feminist expert publics in Argentina (N=29) and in the U.S. (N=23); Study 2 are comparative survey experiments in Argentina (N=1,003) and the U.S. (N=1,004); Study 3 is an interview-based study with 55 survey respondents in Argentina (N=30) and the U.S. (N=25). In Study 1, I analyze how cross-country feminist expert publics evaluate media representations of GBV and develop their own feminist media interventions and practices to help shape how the media and society writ large talk and think of GBV. In Study 2, I explore how diverse audiences in terms of age, gender, racialization, ideology, socioeconomic status, and region in both countries respond to news about sexual harassment depending on the intersectional identity of the woman harassed. In Study 3, I interview a subset of these survey respondents in both countries to explore causal mechanisms, their evaluations of issues related to media, class and race/ethnicity, and their convergences and divergences with feminist expert publics. Based on the analysis of these mixed methods, comparative findings, I conclude by offering a framework of what are some of the factors that help explain how media and communication representations and practices can help promote, or hinder, gender equality frameworks of GBV among the citizenries
Injectable Hydrogels To Deliver Extracellular Vesicles For Treatment After Myocardial Infarction
Get PDFThere is a tremendous clinical need to develop new therapies to limit the progression to heart failure after myocardial infarction (MI). Recent studies have suggested that extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) can mediate cardioprotection and preserve function post-MI due to their key roles in paracrine signaling with angiogenic, proliferative, anti-inflammatory, and anti-apoptotic effects via transfer of proteins and miRNAs. Despite this interest, there are still challenges related to EV scale-up, sustained delivery, and analysis in clinically-relevant animal models that need to be addressed prior to their translation.With these considerations in mind, the overall goals of this dissertation were to (i) develop injectable hydrogels, which allow localization and sustained release, for minimally invasive delivery of EVs to the heart, (ii) scale-up production of MSC-EVs to generate doses required for preclinical large animal studies, and (iii) investigate the timing of EV presentation on cardiac repair. First, three MSC culture systems (tissue culture plastic, microcarriers in a spinner flask, and perfusion bioreactor) were explored towards scaling up EV production to generate large doses. MSC-EVs were characterized for size, distribution, yield, morphology, content and in vitro potential, which motivated microcarriers to create large doses for pre-clinical studies. The therapeutic potential of MSC-EVs delivered from injectable hydrogels was then investigated in a porcine MI model, which indicated improvements in infarct area with EV delivery. Secondly, extended delivery of EVs through an interpenetrating network (IPN) hydrogel was studied with metabolic labeling to understand the timing, release, and biodistribution of MSC-EVs. The therapeutic potential of extended MSC-EV delivery was studied in a rat model of MI, with the IPN delivery of EVs improving outcomes of vascularization over controls. Finally, a radiopaque hydrogel system was developed to evaluate hydrogel localization after injection via a SPECT/CT imaging system towards clinical translation. Overall, this thesis highlights the importance of cell culture conditions for scale-up of MSC-EVs for cardiac repair and the use of injectable hydrogels as a therapeutic delivery vehicle towards translation of these therapeutics for clinical use