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The role of ERK signaling in the cell cycle
Get PDFThe extracellular-signal-regulated kinase (ERK)/mitogen-activated protein (MAP) kinase signaling pathway plays essential roles in cell cycle and proliferation. The well-accepted model is that ERK signaling drives cell cycle progression through stimulating Cyclin D expression. Here we found that overexpressing Cyclin D does not suffice to bypass the need for ERK signaling in cell cycle progression, specifically through the G1/S transition. Flow cytometry ad immunofluorescence showed that ERK-inhibited cells were arrested in G1 regardless of Cyclin D expression, and these cells had elevated p21 and p57 levels and did not completely hyperphosphorylate Rb. Rb knockout cells overexpressing Cyclin D were able to proliferate slowly under ERK inhibition. Thus, ERK signaling is responsible for maintaining Rb hyperphosphorylation for cell cycle progression
“We Will Not Continue to Be a Sacrifice Zone”: Community-Driven Investigations of Air Quality in Curtis Bay, South Baltimore
No full textCurtis Bay (CB) is a fenceline community in South Baltimore, Maryland, where residents have long expressed concerns about industrial pollution and its health impacts. One such facility is an open-air coal terminal that has operated for over a century. Community members have reported coal dust accumulation on homes and laundry, foul odors, and high rates of respiratory issues such as asthma. In December 2021, an explosion at the terminal heightened these concerns. To address the lack of consistent and widespread air monitoring in Curtis Bay, we deployed an air sensor network (June 2022–June 2023) across 10 locations to measure particulate matter (PM), black carbon (BC), and gases such as carbon monoxide (CO) and nitrogen dioxide (NO2). We found that PM and black carbon concentrations varied significantly across sites and were often higher than at regional monitoring locations in Beltsville and Glen Burnie, Maryland. Additionally, data pooled from all locations in the network exceeded multiple WHO Air Quality Guidelines. We also applied non-negative matrix factorization (NMF) to identify pollution sources, revealing four factors, including one dominated by larger PM and black carbon. We observed that exceedances of mathematical thresholds for that factor lasted longer at sites closest to the terminal. We also utilized NMF to highlight industrial events in the Curtis Bay area that were identified by our collaborative team. Finally, using a fixed-effects modeling approach, we found that PM and BC concentrations were highest when visible bulldozer activity coincided with sensor locations being downwind of the terminal. Most NMF factors, with the exception of one dominated by NO, were also elevated during the co-occurrence of bulldozer activity and downwind conditions. Elevations in smaller PM may indicate that mechanically generated dust does not consist solely of coarse particles such as PM10 and total suspended particles (~PM40) in the Curtis Bay area. This research fills a critical gap in air quality monitoring in an environmental justice community and has directly contributed to an ongoing community-government-academic collaboration
“In Cobwebs, In Storms, In Chains”: The Gothic In Spanish American Short Fiction
Get PDFThis dissertation demonstrates the Gothic’s long historical presence, focusing on short-form literature during the twentieth century. While doing so, it also seeks to explore the shortcomings of genre and Gothic studies while providing a different perspective on them; a new model inspired by the work of Gilles Deleuze and Félix Guattari.
Within contemporary Gothic studies, the Gothic is a genre (a set of historically bound tropes and conventions juxtaposing the horrifying and the appealing) and a mode (the deterritorialized negative affects inspired by such tropes and conventions) but also a hermeneutic tool that focuses on how both genre and mode can abject Otherness and deal with the “unwillingness of the past to go away” (Sage & Lloyd Smith 4). This dissertation seeks to unify these three faces of the Gothic into a single entity (the Gothic Abstract Machine, the ‘diagram’ of the Gothic) and use this tool to analyze its elements within short fiction, the medium where its prominence is most discernible and pervasive across Spanish America.
My theoretical framework allows me to understand the passion and fear that the characteristically technological Argentinean modernity project inspired in twentieth-century writers (Leopoldo Lugones’ Las fuerzas extrañas and Horacio Quiroga’s Cuentos de Amor de locura y de muerte), the portrayal of Andean indigeneity as a seductive and dangerous threat to the modernizing project (La venganza del condor), the construction of national identity in permanent negotiation with Death after the Mexican revolution (Pedro Páramo and Aura), and the affect-driven voices of domestic abuse victims and animals in Tiempo destrozado. As such, this dissertation finds that the specters of miscegenation, ever-progressing technology, uncontrollable nature, colonialism, identity, domestic violence, and death herself are constitutive components of the Spanish American short-form canon.
Thus, this dissertation concludes that one cannot speak of a single Spanish American Gothic but of a multiplicity of Gothic Assemblages that run through these countries such as a Mexican Gothic, an Indigenista version of the mode, the modernista’s interpretation of it, and a Female Gothic. All these assemblages point towards the same Abstract Machine that ties them together
IGF-1R Inhibition Induces EGFR Upregulation In Uveal Melanoma, Suggesting A Novel Dual Inhibition Therapeutic Strategy
Get PDFUveal melanoma is a type of cancer that arises from melanocytes in the eye, with approximately 7,000 new cases reported annually worldwide. It is an aggressive disease, and nearly half of patients develop metastases even after treatment of the primary tumor. Expression of insulin-like growth factor receptor (IGF-1R) is associated with increased uveal melanoma cell proliferation and shorter survival. Unfortunately, targeting IGF-1R alone has demonstrated limited clinical efficacy in uveal melanoma patients, suggesting that combination treatment is needed. This study aims to investigate the effect of IGF-1R inhibition on epidermal growth factor receptor EGFR expression levels in uveal melanoma cells, and to evaluate whether dual inhibition of EGFR and IGF-1R enhances antitumor efficacy. We found that treatment with linsitinib, an IGF-1R inhibitor, significantly increased protein levels of EGFR. In addition, IGF-1R inhibition increases activation of EGFR signaling in uveal melanoma cells – a pathway which plays important roles in tumor development and progression. This compensatory upregulation of EGFR after IGF-1R inhibition may account for the inefficient anticancer effects of monotherapy in uveal melanoma patients. Indeed, we found that combination treatment with EGFR and IGFR-1R inhibitors synergistically increased anticancer effects on uveal melanoma cells. These results highlight the potential of co-targeting of IGF-1R and EGFR, and represent a new therapeutic approach for uveal melanoma
Analysis of Borrelia burgdorferi derived extracellular vesicles from bacterial cultures and plasma
No full textLyme Disease is the most common tickborne disease in the United States with over 63,000 cases reported in 2022. However, the actual number of cases of Borrelia burgdorferi (Bb) is estimated to be ten-fold higher. Post-Treatment Lyme Disease Syndrome (PTLDS) is a condition where a patient experiences chronic symptoms despite being treated with antibiotics. There is controversy around whether PTLDS is caused by a persistent bacterial infection or post-infection auto-immune reactivity. Some evidence suggests the failure of symptoms to resolve with more aggressive antibiotic therapy could be due to antibiotic tolerance of persistent bacteria. This persistence phenotype is induced and maintained by the bacterial stringent response pathway. We hypothesize that mRNA transcripts encoding stringent response proteins can be isolated from bacteria-derived microvesicles from the serum of mice infected with Bb. Bb extracellular vesicle (BbEV) isolation from bacterial cultures and mouse plasma was conducted using size- exclusion chromatography or ultracentrifugation. It was followed by a density gradient to separate the BbEV from mouse-derived EVs. The BbEVs were tested by performing a RNA extraction, RT-PCR, and analyzing fractions on the Zetaview particle analyzer. We have been able to confirm the ability to extract extracellular vesicles from bacterial cultures and are continuing to optimize the assays to detect BbEVs in Bb-infected mouse plasma. In conclusion, while the controversy of the mechanism of PTLDS is still debated, this study is laying the groundwork for utilizing BbEVs in plasma for detection of genes representative of bacterial infection and potentially of pathways promoting persistence that could lead to PTLDS
A ROBOTIC SYSTEM FOR STUDYING HAPTIC SHAPE PERCEPTION
No full textEvery object in the natural world has a three-dimensional shape, which we perceive through our senses of vision and touch. Despite major advances in our understanding of visual shape representation over the past several decades, our understanding of haptic shape encoding—especially at higher cortical areas—has severely lagged behind. This knowledge gap is largely due to a simple experimental challenge: it is hard to present large numbers of tightly-parameterized stimuli during grasping experiments. To overcome this technical barrier, we have developed a robotics-based system for high-throughput stimulus presentation for grasping studies in non-human primates (NHPs). In this work, we describe the design and implementation of the system, as well as demonstrate its use in a novel haptic shape comparison task. Our results show high-performance in discriminating shape, with errors being correlated to a neural network shape similarity score. Further, we present a software package for programmatic generation of large haptic and visual stimulus libraries. This work establishes a new experimental paradigm for studying haptic perception with considerably higher sampling density than has previously been possible. Through our system and accompanying software, we aim to facilitate further research into haptic shape perception, uncovering the brain’s ability to feel the world around it
When Prototypes Betray You: Systematically Detecting Prototype Pollution Vulnerabilities and Their Gadgets from One Million Real-World Websites
Get PDFPrototype pollution is a relatively new yet critical JavaScript vulnerability that allows attackers to inject properties into prototypical objects, such as Object.prototype. This manipulation can lead to severe consequences, including Cross-site Scripting (XSS) and cookie manipulation. These consequences are often facilitated through code snippets known as gadgets, which alter the control or data flow of the victim program. Therefore, a systematic methodology for studying prototype pollution involves both prototype pollution vulnerabilities themselves and their related gadgets. Prior works in server-side applications face challenges in scalability and accuracy when applied to client-side JavaScript. Moreover, existing methods often struggle to identify complex gadgets that require the injection of intricate property values.
In this dissertation, we propose a systematic methodology for thoroughly studying the scale, impacts and severity of client-side prototype pollution. The first component of this methodology, named ProbeTheProto, is the first large-scale measurement framework for detecting client-side prototype pollution among one million real-world websites. ProbeTheProto utilizes dynamic taint analysis to track so-called joint taint flows that connect property lookups and value assignments, together with an input/exploit generation to guide these flows into sensitive locations related to further consequences. This study reveals 2,917 zero-day, exploitable prototype pollution vulnerabilities across 2,738 real-world websites, including ten among the top 1,000. We further verify that 48 vulnerabilities lead to XSS, 736 to cookie manipulations, and 830 to URL manipulations.
The second component of the proposed methodology, called GALA, is a dynamic analysis framework designed to systematically detect client-side prototype pollution gadgets across one million real-world websites. GALA operates by leveraging existing defined values from non-vulnerable websites and applying them to vulnerable ones where such values are undefined, thus guiding the injected properties to flow into sensitive locations within gadgets.
Our implementation of GALA has led to the discovery of 133 zero-day gadgets not identified by prior works. Among them, one vulnerability was from Meta’s software and another from the Vue framework, both of which have acknowledged and addressed these issues. We have responsibly disclosed all identified vulnerabilities to the respective developers, contributing to enhanced security across numerous platforms
GLUTAMINE METABOLISM ANTAGONIST MAY OVERCOME TREATMENT RESISTANCE BY INDUCTION OF DNA DAMAGE SIGNALING AND DSBS
Get PDFGlutamine is a critical metabolic substrate that supports cell proliferation and genomic stability via nucleotide biosynthesis. In this study, we investigated whether targeting glutamine metabolism could enhance therapeutic efficacy and overcome resistance in ovarian cancer. We selected DON, a broad-spectrum glutamine inhibitor, and its tumor-activated prodrug, JHU083, for mechanistic studies. Global phosphoproteomic analysis revealed that glutamine inhibition activated key DNA damage repair pathways, including ATM signaling, cell cycle checkpoints, and chromosomal replication control. Notably, glutamine antagonism impaired homologous recombination (HR) repair and induced DNA double-strand breaks (DSBs). These results suggest that targeting glutamine metabolism may represent a promising strategy for treating chemoresistant cancers that rely on HR proficiency, and support the future development of metabolism-based precision therapies
IMPROVING THE USE OF ADVANCE DIRECTIVES THROUGH EHR-BASED SUPPORT: AN EVIDENCE REVIEW, CASE STUDY, AND RECOMMENDATIONS
Get PDFProblem Statement:
An advance directive (AD) is a “legal document that provides instructions for medical care and only [goes] into effect if you cannot communicate your own wishes. The two most common advance directives for health care are the living will and the durable power of attorney for health care” (National Institute on Aging [NIA], 2022). Despite their importance, many patients do not have ADs incorporated into their electronic health records (EHRs). This study aims to explore the effective integration of ADs within EHR systems, assess potential disparities in the availability of ADs within EHRs, and provide recommendations to enhance the use of EHRs for advance care planning (ACP) .
Methods/Study Population:
This dissertation utilized secondary data from an ongoing study within the Johns Hopkins Health System (JHHS). Specifically, data were were obtained from the NIH funded “SHARING Choices” study. The study population comprised approximately 20,000 patients 65 years and older who visited JHHS primary care clinics between 2018 to 2020.
Results:
The findings provide valuable insights into the use of EHRs for ADs. Notably, older adults and those with more co-morbidities were more likely to have an AD in the EHR. The logistic regression analysis suggested that these two factors were associated with the greatest increased likelihood of whether a patient had an AD in their EHR. Additionally, racial disparities were evident: White patients were more likely than Black patients to have an AD in their EHR, and Asian patients were less likely than both White and Black patients to have an AD in their EHR. Sex was the least significant variable for whether an AD was in the EHR. Furthermore, patients who were single had a higher likelihood of having an AD in the EHR compared to those with a partner.
Conclusions and Recommendations:
This study identifies disparities that warrant further examination and highlighted potential research opportunities in various demographic and social areas.
The dissertation also proposes improvements to the ACP workflow and design, as well as identifying specific EHR systems, regulations, and change management strategies that could enhance health informatics support for ACP
GLUTAMINE BLOCKADE STALLS TUMOR GROWTH AND REPROGRAMS TUMOR INFILTRATING MYELOID CELLS IN MOUSE MODELS OF SOFT TISSUE SARCOMAS
No full textThe endogenous immune system possesses the ability to eliminate tumors; however, this potential is often hindered by immunosuppressive mechanisms that tumors exploit. While immunotherapeutic strategies, such as immune checkpoint blockade, have successfully lifted some of these barriers, many patients fail to respond. Myeloid cells have been strongly implicated in this resistance across multiple cancer types, including sarcomas. These cells exhibit remarkable plasticity, enabling them to adapt to therapeutic interventions and sustain an immunosuppressive tumor microenvironment. Attempts to deplete myeloid cells or disrupt their function have largely been unsuccessful due to their resilience and ability to compensate for therapeutic pressures. We hypothesized targeting the metabolic dependencies of myeloid cells might steer them into an anti-tumor cell type. Glutamine antagonism, particularly through the novel prodrug JHU083, has emerged as a promising approach. By inhibiting glutamine metabolism, this strategy not only restricts tumor growth but also reprograms myeloid cells from an immunosuppressive to a tumoricidal phenotype, ultimately enhancing anti-tumor immune responses. In this study, we performed a comprehensive immune profiling of Undifferentiated Pleomorphic Sarcomas (UPS), a subtype of sarcoma that remains in dire need of effective therapeutic interventions. Our findings revealed a predominant immunosuppressive myeloid cell infiltrate, likely contributing to the poor efficacy of current immunotherapies. To overcome this resistance, we investigated the effects of glutamine blockade in a genetically engineered mouse model of immunotherapy-resistant soft tissue sarcomas. Treatment with JHU083 not only suppressed tumor growth but also led to significant changes in myeloid cell abundance, transcriptomic profiles, and metabolic states. Notably, our observations support that JHU083 reprogrammed these cells to support anti-tumor immunity rather than tumor progression, reinforcing the potential of metabolic interventions in overcoming myeloid-driven resistance. Overall, our findings support the clinical evaluation of glutamine antagonism, particularly in sarcomas and other malignancies characterized by myeloid cell enrichment. By reshaping the immune microenvironment, this approach holds promise for improving immunotherapy efficacy in historically resistant cancer