1983 research outputs found
Sort by
New Methods to Explore Mobile Genetic Elements in Bacteria
No full textMobile genetic elements (MGEs) drive horizontal gene transfer, a fundamental process in bacterial evolution. They play a crucial role in the genetic diversity and adaptability of bacteria, and signifi- cantly impact both microbial ecology and human health. Despite their significance, the full extent of their diversity and the complexity of their interactions have remained largely uncharted. This work introduces two novel methods to explore MGEs. The first one, is a strategy for isolating plasmid- dependent phages, a unique set of phages that exploit plasmid-encoded conjugation proteins as re- ceptors for infecting their host bacteria. With this method, we systematically search for new plasmid- dependent phages targeting IncP and IncF plasmids. Our findings show that plasmid-dependent tec- tiviruses are common and abundant in the environment. Using our diverse collection, we showed that these tectiviruses exhibit profound differences in their host range which is associated with variation in the phage holin protein. Additionally, we isolated phages dependent on the IncF plasmid, includ- ing the first plasmid-dependent tailed phage. Finally, we discuss that some of this phage diversity is routinely missed by metaviromic analyses, underscoring the continued importance of culture-based phage discovery. The second one, consists of a computational strategy to identify CRISPR-targeted MGEs within bacterial genomes. Focusing on Salmonella enterica as a model, I investigate the spacer content and diversity within a large collection of high quality genomes. This analysis challenges pre- vious assumptions, demonstrating that the CRISPR spacers in S. enterica are diverse, and commonly target prophage regions. Overall, this work aims to advance our ability to investigate the currently unexplored diversity of MGEs, with an emphasis on leveraging high throughput methods and large data collections, with tractable and concrete systems that can ultimately be experimentally studied
Combining Human and Automated Scoring Methods in Experimental Assessments of Writing: A Case Study Tutorial
No full textIn a randomized trial that collects text as an outcome, traditional approaches for assessing treatment impact require that each document first be manually coded for constructs of interest by human raters. An impact analysis can then be conducted to compare treatment and control groups, using the hand-coded scores as a measured outcome. This process is both time and labor-intensive, which creates a persistent barrier for large-scale assessments of text. Furthermore, enriching one’s understanding of a found impact on text outcomes via secondary analyses can be difficult without additional scoring efforts. The purpose of this article is to provide a pipeline for using machine-based text analytic and data mining tools to augment traditional text-based impact analysis by analyzing impacts across an array of automatically generated text features. In this way, we can explore what an overall impact signifies in terms of how the text has evolved due to treatment. Through a case study based on a recent field trial in education, we show that machine learning can indeed enrich experimental evaluations of text by providing a more comprehensive and fine-grained picture of the mechanisms that lead to stronger argumentative writing in a first- and second-grade content literacy intervention. Relying exclusively on human scoring, by contrast, is a lost opportunity. Overall, the workflow and analytical strategy we describe can serve as a template for researchers interested in performing their own experimental evaluations of text.Accepted Manuscrip
Inland recreational fisheries contribute nutritional benefits and economic value but are vulnerable to climate change
No full textInland recreational fishing is primarily considered a leisure-driven activity in freshwaters, yet its harvest can contribute to food systems. Here we estimate that the harvest from inland recreational fishing equates to just over one-tenth of all reported inland fisheries catch globally. The estimated total consumptive use value of inland recreational fish destined for human consumption may reach US$9.95 billion annually. We identify Austria, Canada, Germany and Slovakia as countries above the third quantile for nutrition, economic value and climate vulnerability. These results have important implications for populations dependent on inland recreational fishing for food. Our findings can inform climate adaptation planning for inland recreational fisheries, particularly those not currently managed as food fisheries.Author's Origina
Miss Fanny Jean Rides the Escalator: Girls, Folklore, and Modernity
No full textEach tale retains one foot in folklore and one foot in modern introspective essay.
This is the new southern woman, who both embraces and diverges from her roots to make
her own way. These autofiction pieces center around female protagonists tied together
loosely by the theme of struggling for a better life amid tangled Southern roots. Their
backgrounds prove to be as convoluted as the knotty roots of cypress trees that
universally have become associated with the south and as beautiful as the foggy sunsets
every local is familiar with. Hence, the South becomes almost a unifying character itself,
connecting each heroine to her neighbor in the next chapter. A real-life image or
experience sparked the initial inspiration behind each story. However, unlike real life
where subjects and topics are all mingled together, writing in this way allowed for
imaginative play and the addition of creations; it also ensured proper focus on one or two
topics at a time or to take a tangled plot line and focus on only those events that tie into a
particular theme
Multiomic insights into gastroenteropancreatic neuroendocrine tumor biology
No full textGastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare, biologically and clinically heterogeneous malignancies whose incidence has increased significantly over the past few decades in the United States. Therapeutic development for GEP-NETs has lagged due to a paucity of preclinical in vitro and in vivo models, which has also produced an incomplete understanding of the fundamental biology of these tumors. Single-cell genomics permits high-resolution dissection of primary tumor samples with direct patient relevance; combining single-cell and other sequencing modalities therefore promises to yield novel insight into GEP-NET and other solid tumor pathophysiology.
In this dissertation, we first perform single-cell RNA-sequencing of over 24,000 cells from eight freshly resected GEP-NET samples, constructing the first-ever single-cell atlas of these rare malignancies. We demonstrate that tumor and lymphoid cells in the GEP-NET microenvironment only sparsely express immune checkpoint targets, explaining the limited efficacy of immunotherapies directed against these targets in previous clinical trials. In contrast, we show that NET-infiltrating myeloid cells robustly express immunosuppressive genes spanning several distinct pathways. The presence of these myeloid cells in both primary and metastatic NETs, and across three different GEP-NET subtypes, represent a shared opportunity for precision medicine development in this otherwise heterogeneous disease context.
Next, we investigate the cellular biology of tumor and stromal populations from an archival cohort of 37 pancreatic and small intestinal NET samples using a combination of whole exome sequencing, multimodal single-nuclei RNA and ATAC sequencing, and spatial transcriptomics. We define major axes of transcriptional and epigenetic variation across malignant cells from both small intestinal and pancreatic NETs, their relation to underlying genetic states in these tumors, and characterize site-specific differences in the cellular phenotypes of cancer-associated fibroblasts.
Finally, we expand upon inference of relationships between genetic states and cell-type specific transcriptional programs across cancer types. We evaluate cell-type specific enrichment of heritable cancer risk by combining publicly available genome-wide association study data from multiple solid tumor types and single-cell RNA-sequencing datasets from malignant and corresponding normal tissues. Using linkage-disequilibrium score regression, we nominate prostate club epithelium as a potential cellular mediator of prostate adenocarcinoma risk.
Together, our findings elucidate the molecular and cellular biology of well-differentiated GEP-NETs and highlight novel opportunities for translational investigation and therapeutic development in this understudied patient population, with potential extension of these concepts across tumor types.Medical SciencesMedical Science
NK-cell receptor-ligand interactions in chemokine-dependant activity in TNBC and during viral infection
No full textBackground: While the important role of natural killer (NK) cells in eliminating both cancerous and infected cells is well known, many of the specific receptor-ligand interactions that mediate homing, recognition, and killing of target cells via NK cells are still poorly understood. NK cells have been explored more recently and are showing promising success in adoptive cell transfer and immunomodulatory therapies for various cancers and viral infections. However, before being implemented, key aspects of NK-cell biology and challenges in the application of these therapies must be addressed. These include the poor homing of NK cells into the tumor microenvironment of solid tumors and immune evasive strategies that both cancer cells and virally infected cells employ to subvert NK-cell immunity. In this thesis, we explore chemokine and chemokine receptor expression in solid tumors (i.e., triple-negative breast cancer [TNBC]) and peripheral blood NK cells, as well as receptor-ligand interactions in the context of viral immune evasion (i.e., SARS-CoV-2 and mpox virus [MPXV]).
Methods: We analyzed scRNAseq data from 16 TNBC samples, 2 healthy breast tissue controls, and 2 peripheral blood NK (pbNK) cell samples to analyze chemokine and chemokine receptor expression. After identifying CXCL16 as a candidate chemokine expressed on tumor cells, we over-expressed and knocked out CXCL16 in MDA-MB-231 cells, a TNBC cell line, and performed flow cytometric phenotyping and in-vitro motility, proliferation, and NK-cell killing assays. Given that CXCL16 exists in membrane-bound and soluble (cleaved) forms, we also performed in silico analyses of its protein sequence to identify cleavage sites and create membrane-bound and soluble mutants for subsequent in-vitro testing. For virus-focused studies, we carried out bulk mRNAseq analyses in SARS-CoV-2- and MPXV-infected cell lines and scRNAseq analyses on primary respiratory epithelial cells from COVID-19 patients, with a particular focus on NK-cell ligand genes.
Results: Among all chemokines analyzed, we identified CXCL16 as the most abundant, differentially expressed chemokine in TNBC tissues. Correspondingly, there was an enrichment of CXCR6 (the chemokine receptor for CXCL16) among tumor-infiltrating T cells, but no tumor-infiltrating NK cells could be detected in TNBC tissues. Peripheral blood NK cells from healthy donors were analyzed and had undetectable CXCR6 transcript expression. Flow cytometric analyses of MDA-MB-231 cells showed no expression of membrane-bound CXCL16 at baseline but did show expression of CXCR6. Over-expression of CXCL16 in MDA-MB-231 cells via transduction resulted in enhanced motility and reduced proliferation, while no changes could be observed with CRISPR/Cas9 knock-out of CXCL16, consistent with lack of CXCL16 expression at baseline. Remarkably, co-culture of MDA-MB-231 cells with NK cells resulted in increased CXCL16 expression and mixing of NK cells with wild-type and CXCL16-overexpressing MDA-MB-231 cells showed preferential killing of CXCL16-overexpressing cells. CXCL16 sequence analysis predicted an ADAM10/17 cleavage site in the mucin-stalk region which may be responsible for tumor-cell regulation of CXCL16 surface expression and shedding. In our virus-focused studies, scRNAseq analysis of COVID-19 patients showed specific upregulation of NKG2D ligands and sheddases in ciliated respiratory epithelial cells, the target of SARS-CoV-2-infection, and bulk mRNAseq analysis of MPXV-infected A549 cells showed modulation of a variety of NK-cell ligands.
Conclusions: These results suggest a role for CXCL16 in tumorigenesis and susceptibility to NK-cell killing and may be a beneficial target for enhancing NK-cell homing and targeting of solid tumors. Furthermore, we uncovered NK-cell ligands that SARS-CoV-2 and MPXV modulate as a potential means of immune evasion
On the near-optimality of one-shot classical communication over quantum channels
No full textWe study the problem of transmission of classical messages through a quantum channel in several network scenarios in the one-shot setting. We consider both the entanglement assisted and unassisted cases for the point to point quantum channel, quantum multiple-access channel, quantum channel with state and the quantum broadcast channel. We show that it is possible to near-optimally characterize the amount of communication that can be transmitted in these scenarios, using the position-based decoding strategy introduced in a prior work [Anshu, Jain and Warsi, 2017]. In the process, we provide a short and elementary proof of the converse for entanglement-assisted quantum channel coding in terms of the quantum hypothesis testing divergence (obtained earlier in [Matthews and Wehner, 2014]). Our proof has the additional utility that it naturally extends to various network scenarios mentioned above. Furthermore, none of our achievability results require a simultaneous decoding strategy, existence of which is an important open question in quantum Shannon theory.Accepted Manuscrip
The State of Tobacco Use Cessation in the Arab World
No full textIn this dissertation we analyzed the state of tobacco cessation in the Arab World on multiple levels using the socio-ecological model (SEM). We painted a clearer picture on the tobacco cessation status in the Arab World and identified challenges and opportunities in the implementation of demand reduction measures. On the individual and interpersonal levels, we utilized the Global Youth Tobacco Survey to study the smoking cessation behaviors of the youth. We focused on youth for two reasons: (1) the Arab world is relatively young with a third of its population below the age of 15 and (2) national surveillance for adults were lacking; Global Adult Tobacco Surveys were only available for Egypt, 2009 and Qatar 2013. In Study I, we found that most Arab schoolchildren have the desire to quit smoking and have attempted to do so. There was a strong relationship between receiving professional cessation help and positive cessation behavior. We found that receiving cessation help and being taught the dangers of tobacco use in school, were associated with cessation attempts. Conversely, variables such as being a female, a child who smokes five or more cigarettes a day, or being exposed to secondhand smoke at home or school were associated with negative smoking cessation behaviors. We believe that policymakers and researchers could focus on improving the availability and demand for professional cessation services and equip parents with tools to facilitate informed cessation conversation with their youth. On the national policy and organizational levels, we used the latest World Health Organization framework convention on tobacco control (WHO FCTC) reports to assess the national implementation of WHO FCTC Article 14 (key demand reduction measures) in the Arab countries. Additionally, we reviewed the regional and local reports of health professionals from 2012 to 2022, to provide a qualitative summary of the tobacco use cessation services in healthcare settings and tobacco use cessation training in academic institutions. In Study II, we found major inadequacies in the provision of telephone quit lines, the accessibility of nicotine replacement therapy and the inclusion of tobacco dependence treatment curricula in healthcare education. Bahrain, Tunisia, and Sudan received the highest implementation score for WHO FCTC Article 14, among high-income, middle-income, and low-income countries, respectively. A closer look using the regional and local reports found that most healthcare schools do not include tobacco cessation counseling, the 5As or nicotine replacement therapy in their clinical training. These inadequacies were extended to healthcare professionals in their practice where the majority did not provide tobacco use cessation counseling to their patients. Therefore, we urge Arab countries to:
1- Fully implement FCTC Article 14 as a pressing step to reduce the smoking-attributable morbidity and mortality in Arab population.
1- Continuously monitor smoking prevalence and smoking cessation services.
2- Design youth-centered and culturally adapted tobacco cessation programs.
3- Develop and adapt a national strategy for tobacco cessation.
4- Integrate tobacco dependence treatment training in health professional education as part of the national standards of healthcare school accreditation.
5- Utilize existing infrastructure of primary health centers to provide cost-effective, broad-reaching tobacco cessation activities
'Forsaking All Others': Impact of Wives' Social Classes on U.S. Military Officers' Political Loyalties in 1860-1861
No full textThis thesis examines how the social classes of military wives influenced U.S. officers’ loyalty decisions prior to the beginning of the Civil War in 1861. The scholarship concludes that these loyalty decisions were made independently by the husband, and primarily based on how an officer’s home state voted on the secession question. It considers a wife’s social class to be no more important than other random, secondary factors that might have entered into a man’s decision-making process. This thesis attempts to show how a woman’s social class was an avenue for her to develop a particular type of marital partnership that rested on a foundation of sacramental loyalty. U.S. military officers generally allowed themselves to be bound by this loyalty, regardless of their oaths to faithfully serve their country
“The Fatal Blemish”: Purity, Consistency and Chemical Engineers at the Origin of a New Visual Order, 1890–1930
No full textThis article follows the early history of the Eastman Kodak Company, examining how the photographic company came to be led by experts in chemistry, who created manufacturing processes that were crucial to the mass manufacture of motion pictures. It argues that celluloid film, the substance necessary for motion pictures, was central to the evolution of Kodak into an industrial chemical company. Kodak’s work to manage the specific technological problems and risks created by this material was itself constitutive of the new industrial shape the firm took. In embracing an intraplant goal of purity of raw materials and finished goods, Kodak made it possible for cinema to become a mass medium, with moving images able to look the same way across time and space, over countless copies. Kodak’s transformation, however, was uneven, as the firm’s photosensitive emulsion continued to be made according to far more empirical, secretive, and artisanal procedures, developed by a photographer without a high school degree. These artisanal processes coexisted alongside a highly standardized plant regime, and both were required to make celluloid film. This history demonstrates one way in which broad cultural transformations of the early twentieth century were closely tied to material and practical transformations within industrial firms.History and LiteratureAccepted Manuscrip