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Mammalian ER Contact Sites with the Parasitophorous Vacuole of Toxoplasma: Characterization of a Parasite FFAT-Containing Protein in Host ER Recruitment
No full textToxoplasma gondii is an obligate intracellular parasite that infects most species of warm-blooded animals, including humans, to cause the disease toxoplasmosis. This is a zoonotic disease of significant medical and veterinary importance that can be transmitted via several pathways. The CDC estimates that more than 40 million people in the United States may be infected with this single-celled parasite. Healthy individuals are generally asymptomatic; however, pregnant women and individuals with compromised immune systems may experience severe health issues. Toxoplasma gondii actively invades mammalian host cells by establishing a parasitophorous vacuole (PV). This unique replicative and intracellular niche is separated from the host cytoplasm by the PV membrane (PVM). The PVM creates a barrier between the invading T. gondii and the infected cell, protecting the parasite from cellular assaults and resisting fusion with host cellular organelles.
Despite its role as a barrier, the PVM is a dynamic platform that the parasite must overcome to scavenge resources from its host cell. To facilitate nutrient acquisition, the PVM tightly associates with host organelles, such as the endoplasmic reticulum (ER), to form membrane contact sites (MCS). MCS mediates non-vesicular transport between membrane-bound organelles and plays a vital role in lipid homeostasis and cell signaling. Previous fluorescence and electron microscopic observations have shown that the mammalian ER forms MCS with many cellular organelles. The transmembrane ER proteins VAP (VAMP-associated proteins; VAPA and VAPB) and MOSPD2 act as tethers at many ER-based MCS. VAPs interact with various proteins localized to host organelles that have an FFAT motif. It is postulated that T. gondii hijacks the formation of MCS between the ER and the PV to allow for the transfer of resources to the parasite. Thus, the identification and characterization of parasite proteins involved in the formation of MCS would provide novel insights into how this obligate intracellular protozoan survives in an infected cell
An Evaluation of Ignite Reading Virtual Literacy Tutoring in Massachusetts
Get PDFThis mixed-methods evaluation assesses the effectiveness of the Ignite Reading virtual literacy tutoring program implemented in Massachusetts during the 2023-2024 school year. Sponsored by the One8 Foundation, the initiative provided targeted one-to-one tutoring for first-grade students across 13 districts with high concentrations of economically disadvantaged populations. Using a quasi-experimental design, the study compared literacy outcomes of tutored students to both national norms and matched comparison groups using the DIBELS assessment.
Quantitative analyses revealed significant literacy gains for students participating in Ignite Reading, with an effect size of +0.21 SD in the two-group comparison and +1.19 SD in the one-group analysis. Gains were particularly pronounced for Black students (+0.24 SD) and English learners (+0.31 SD), emphasizing the program's potential to reduce achievement gaps. Students with high attendance also demonstrated larger improvements in literacy skills.
Qualitative data from surveys and interviews highlighted strong educator support for the program's individualized, data-driven approach and alignment with evidence-based literacy instruction frameworks. Stakeholders praised the program's scalability, effectiveness in addressing foundational reading deficits, and adaptability within Multi-Tiered Systems of Support (MTSS). Challenges related to scheduling and technology integration were noted but did not diminish overall satisfaction.
The study concludes that Ignite Reading offers a scalable solution to improving early literacy outcomes in diverse educational settings, with significant implications for addressing equity and literacy gaps.One8 Foundatio
HEAVEN’S DOOR
No full textWhat happens to an Ivy League grad bent on discovering the bohemian world of arts and music when he hitchhikes to the Klondike while his father—a wealthy mining lobbyist on his deathbed—waits for him to return home and take over the family business?
Jeffrey Woodward's worldview is turned upside down in the remote Northwestern Canada of the early 1980's as he witnesses the slow but steady demise of a world’s last pristine wilderness and its indigenous inhabitants by the forces of greed and ignorance
ANALYZING THE RELATIONSHIP BETWEEN GROSS DOMESTIC PRODUCT AND HURRICANE RISK TO PREDICT FUTURE HURRICANE DAMAGE IN FLORIDA
Get PDFClimate change is altering the state of all weather events in some form or another. Predicting how these events will behave is a critical part of anticipating the future extent of disasters. Determining future hurricane behavior is particularly challenging due to reduced data quality prior to the 1980s. While this knowledge gap prevents confident hurricane trend forecasting, other aspects that influence hurricane impacts are more well constrained. Here we use an approach to estimate future hurricane damage that assesses what damage might look like under continued increases in exposure of economic activity and infrastructure to hurricanes in Florida. We analyze the relationship between county-level hurricane risk and Gross Domestic Product and use that to estimate annualized average damage.
After defining the relationship between Gross Domestic Product and average damage from a hurricane, the future behavior of hurricanes was projected into best, middle, and worst-case scenarios in order to simulate the uncertainty of hurricane trends. The results showed a very low, positive correlation between average economic damage and hurricane risk, meaning a county with a high Gross Domestic Product does not necessarily indicate that county is at high risk of hurricanes. This also indicates counties with drastically different Gross Domestic Product’s can be at the same level of risk. However, if past trends in economic growth continue, total average economic damage in the 2050s under the worst-case scenario can be expected to more than double. The best-case scenario showed a 40% increase in total average economic damage, but the results of the middle and worst-case scenarios are consistent with current literature
The Politics of Touchability: Beyond Identity and Difference
Get PDFThe dissertation identifies our current political moment as marked by ‘hyper-reflexive’ identity politics both on the left and the right of the political spectrum. Whether it is to ward off and protect constituencies from structural forms of domination (capitalist exploitation, patriarchy, queerphobia, transphobia, racism, imperialism, (settler) colonialism) or, alternatively, to defend these structures of domination, both parties oscillate between the same two strategies: an increasingly detailed (leftist critical or rightist recuperative) analysis of the constitutive powers of hegemonic social structures; and a demand for the untouchability of our most intimate (identity-based) being. Both parties share a specifically culturalist or sociocentric rationality based on exclusion and separation. As an alternative, the dissertation distills the conceptual apparatus common to naturalistic traditions within philosophy (Deleuze, Derrida), queer theory (Bersani, Dean), feminism (Grosz, Haraway), indigenous cosmologies (de Castro, Kohn), and environmental humanities (Connolly, Van Dooren, Tsing). Naturalisms think on the basis of differential commonality: by strategically emphasizing characteristics that make different people, beings, and things similar rather than (untouchably, rigidly) specific, they aim to reignite the courage and confidence to speak across differences without erasing them and consequently foster incipient coalitions for future change. By acknowledging the (productive and destructive) effectivity of both human and non-human forces operative in the world, naturalisms break with the double edict of culturalist thought and present fecund ways to rethink politics beyond notions of universal identity and singular difference
Impacts of Inundation on Fine-Scale Forest Health and Composition within an Air Force Installation
Get PDFScott Air Force Base (SAFB) is experiencing a transition of its bottomland hardwood forest to open canopy wetland and willow habitat in response to increasingly frequent and prolonged inundation. Flooding has resulted in large die-offs of mature hardwood trees that sensitive species (i.e., Myotis bats) are reliant on for habitat. Additionally, impacts from invasive emerald ash borer (Agrilus planipennis) have caused broad scale mortality of green ash (Fraxinus pennsylvanica), a predominant floodplain species on SAFB. Installation managers seek to understand how and why these changes are occurring to mitigate flooding impacts and support sensitive species using future management tools. We hypothesize that the SAFB forest has differing health and composition metrics between zones that experience varying levels of floodwater inundation. We used dendrochronological analyses on green ash trees and vegetative analyses of all trees (>2.5 cm diameter at breast height) to analyze forest health and composition within these two zones of differing inundation. Zone level analyses demonstrated differing tree sizes based on health categories, as well as distinct diversity metrics for mature trees, but not saplings. Analysis at the plot level revealed differences in tree height between zones, but no difference in tree size, density, or abundance. Tree cores revealed similar growth patterns between zones, but overall larger rates of growth in the upland zones. Results indicated differing health and composition between the differentially flooded zones. Trends in the more inundated areas indicated a trajectory toward less preferred bat roosting habitat
LEARNING FROM LICHEN AND OTHER WISE CREATURES
Get PDFWhen we use the natural world as a trashcan, eventually, the waste overflows back into our lives. When we take more than our share, the river dries up. But when we pay attention to the other life forms on the planet, sometimes we discover they have found another way of doing things. A less extractive way. A more collaborative way. And we can be better humans by learning from them. “Learning from Lichen and Other Wise Creatures” is a collection of articles and essays that all touch on the relationship between humans and nature and the people and creatures who have already figured out more mutually beneficial modes of existence
Carbon Dioxide (CO2) Pipelines: Policies to Enable U.S. Carbon Capture Net-Zero Goals
Get PDFDecarbonization of hard-to-abate emitters and full realization of United States (U.S.) net-zero goals can only be fully achieved by establishing a network of carbon dioxide (CO2) pipelines. This network is needed to transport captured CO2 from emitting sources to geologic storage or utilization locations. Existing CO2 pipeline literature is primarily focused on technical and economic issues. There is also a good body of hard policy literature, but soft policy social and behavioral issues have received minimal attention. Nearly all previous literature only provided isolated analysis on narrowly focused policy topics.
This systematic analysis review of literature provides a holistic thematic summary of the most critical hard and soft policy gaps summarized in findings and recommendations needed to achieve U.S. net-zero goals. This approach is especially useful as these combined policies are most effective if analyzed and applied in an orchestrated framework. Key CO2 pipeline issues in this review include public acceptance, safety, land access, market design and development, environment, and governance. Primary soft policy recommendations focus on developing public trust and a coordinated government, industry, and non-governmental organization (NGO) partnership approach to establish social license to operate. Primary hard policy recommendations involve strategic government alignment regarding the relevance of CO2 capture and transport, coordinated multi-state or regional governance, early market development, applying safe construction standards, and managing CO2 as a resource (as opposed to separate regulatory approaches). Central to this analysis is the premise that policymakers should assess CO2 pipeline regulatory needs in a holistic, coordinated manner applying a combination of both hard and soft policy tools
DEVELOPMENTAL SPONTANEOUS NEURAL ACTIVITY TUNES AUDITORY PROCESSING CIRCUITRY
No full textDevelopmental neural activity is critical for establishing proper connections and circuits between neurons in the brain. In developing sensory systems, there are distinct phases of neural activity-dependent circuit modulation: a period of intrinsically generated, ‘spontaneous’ neural activity prior to sensory input and subsequent alterations in circuit properties as a result of environmental input once sensory systems turn online. Pre-sensory activity is thought to be important for refinement and maturation of neurons. However, the precise role of this early patterned activity in stimulating functional maturation of auditory circuits is poorly understood, due to the inability to selectively disrupt this activity, while preserving cochlear function to allow later assessment of sound processing capabilities. In this Thesis, we sought to answer these outstanding questions through targeted disruption of supporting cell function in the developing cochlea, where spontaneous activity is generated. Removal of TMEM16A or Connexin 26 from the cochlea resulted in distinct consequences for generation of spontaneous activity and subsequent detection of acoustic stimuli. Loss of TMEM16A elicited disruption of spontaneous activity and central neurons displayed increased gain, broadened neural tuning, and compaction of auditory processing area as a result. Loss of Connexin 26 only subtly altered spontaneous activity patterns, but these mice were deaf from hearing onset. However, neural activity deprivation during early development triggered similar physiologic changes in central auditory neuron properties. Taken together, these results suggest that early neural activity, both spontaneous and sensory-evoked, is critical for establishing mature auditory processing. Reducing neural activity or disrupting activity patterns results in abnormally elevated gain, likely through homeostatic mechanisms, and changes in the receptive field properties of individual cells. Unexpectedly, our results also reveal that early spontaneous activity defines the spatial territory in midbrain and cortex dedicated to processing tonal stimuli. Congenital deafness or other developmental conditions that disrupt spontaneous and sound-evoked neural activity patterns may induce profound changes in the functional organization and processing of sound within auditory centers. Understanding the distinct changes induced by these altered pre-hearing activity patterns may reveal new ways to enhance the performance of prosthetic hearing devices for individual patients suffering from hearing loss or auditory processing disorders
Uncovering the Potential for Pancreatic Cancer Interception
No full textEvaluation of the immune landscape is improving rapidly with the advent of methods that generate high-parameter spatially resolved data – this allows for an in-depth understanding of the phenotype and spatial relationship of immune cells. This is critical for cancers that exclude immune cells, whereby it is important to understand the immune architecture of the immune cells residing both inside and outside of the tumor boundaries. The work discussed in this dissertation is of particular relevance to certain microscopic precancerous lesions, since the surrounding immune cells may be better primed for intervention with vaccines, for example, rather than when cancer has established.
Pancreatic ductal adenocarcinoma (PDAC) has a 5–year survival rate of 12%. Microscopic precursor lesions, termed pancreatic intraepithelial neoplasia (or PanIN), are initiated at least a decade before overt PDAC develops, thus providing a large window of opportunity for early interception. Here, spatial–omics (proteomic and transcriptomics) was used to evaluate the immune microenvironment of treatment–naïve, patient–matched, pre–malignant lesions and PDAC. Immune cell recruitment is shown to begin during the low–grade PanINs. Interestingly, the recruited immune cells to both PanIN lesions and regions of overt tumor had evidence of organization into distinct tertiary lymphoid structures and provides evidence for a substantial immune population readily available for modulation by immunotherapeutics designed to intercept PDAC progression.
In parallel, a mouse model was characterized to interrogate immunotherapeutics informed by the human analyses. Spatial proteomics were used to confirm which immunological features of PanIN and PDAC progression in the mouse were consistent with features identified in human tissue. Here, we demonstrate similar immune recruitment and organization in pre-malignant PanIN lesions compared to overt PDAC, such as the early immune recruitment to PanINs and immune exclusion in PDAC predominantly comprising of Tregs.
Finally, to rigorously interrogate vaccine platforms in the mouse, it is important to antigen-specificity and functionality of T cells. Described in this dissertation is a novel method using Cytometry-by-Time-of-Flight to identify antigen-specific T cells. This method can be added to an existing panel of antibodies typically used to evaluate immune cell types and functionality in a dissociated sample