MEDICA@MUSC (Medical University of South Carolina)
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P-selectin and Complement’s Role in a Neonatal Model of Germinal Matrix Hemorrhage-Induced Secondary Injury
Get PDFGerminal Matrix Hemorrhage (GMH) is a devastating neurologic pathology in neonates that leads to impaired neurodevelopmental processes and approximately 90% rate of morbidity and mortality within two years in severe cases. Recent studies in our lab have indicated a role for complement in the initiation and propagation of secondary injury after GMH, which includes neuroinflammation and hydrocephalus development. Here we investigate a strategy to target complement inhibition specifically to sites of P-selectin expression, a relevant adhesion molecule at sites of vascular injury/inflammation, as well as investigate the role of P-selectin in leukocyte recruitment and the propagation GMH secondary injury. We prepared two fusion proteins consisting of anti-P-selectin single chain antibodies (scFv) linked to Crry, a complement inhibitor. One of the scFv targeting vehicles (2.12scFv) additionally blocked the cell adhesion site of P-selectin, whereas the other (2.3scFv) bound P-selectin without blocking its function. For our investigations, post-natal mice on day 4 (P4) were subjected to collagenase induced-GMH and treated with 2.3Psel-Crry, 2.12Psel-Crry, or vehicle. Histopathological and behavioral analyses were performed at P14 and P45. After GMH injury, 2.3Psel-Crry treatment resulted in reduced infarct size and neurological deficits with improved survival, whereas 2.12Psel-Crry treatment resulted in worse outcomes compared to vehicle. MRI analyses revealed that 2.3Psel-Crry also reduced post-hemorrhagic hydrocephalus (PHH) development. We also found that 2.12Psel-Crry, but not 2.3Psel-Crry, had an anti-coagulative effect as determined by increased bleeding time and decreased heterotypic platelet interactions. P-selectin expressed on platelets is known to have a pro-coagulative function, and this effect of 2.12Psel-Crry likely explains the worse outcomes when used to treat this hemorrhagic condition. In summary, we show that GMH induces expression of P-selectin, the targeting of which with a complement inhibitor is protective against secondary neuroinflammation and development of PHH. Although unexpected, the worsened outcomes with a targeted construct that also inhibits P-selectin function (ie. 2.12Psel-Crry) can be explained by its effect on interfering with the coagulation cascade. Whereas the 2.3Psel-Crry construct has potential for protecting against the pathogenic sequelae of GMH, the 2.12Psel-Crry construct has promising potential for treatment of conditions that incorporate pathological thrombotic events, such as ischemic stroke
Government Contracts: A Conceptual Framework for Achieving a Sustainable Competitive Advantage for Small Businesses Who Contract Within the Federal Healthcare Sector
No full textA competitive strategy aims to achieve a sustainable competitive advantage (SCA) and enhance a business\u27s performance. However, small firms, particularly small, disadvantaged firms, lack resources, financial capabilities, and managerial skills to sustain themselves, hindering their access to federal markets. Because they are responsible for most of the job creation in the United States, Congress has shown great interest in encouraging the growth and health of small businesses throughout the American economy. Over the years, a variety of policies and programs have been put forth by the US governments to enhance the economic sustainability of Small Disadvantaged Businesses (SDBs). These preferential procurement programs, which include government set-asides and commercial supplier diversity initiatives, are intended to aid these entrepreneurs in overcoming this barrier. Even with these preferential programs, SDBs still struggle to sustain a strong market position. Some studies suggest that federal procurement markets can provide SDBs with an opportunity to leverage their status through preferred procurement programs to achieve a competitive advantage and thrive even when preferred procurement programs are discontinued, dismantled, or reconfigured. This research project examined federal acquisition variables that support a sustainable competitive advantage (SCA) in the federal healthcare sector. The project combines Resource-Based View theory with literature reviews to bridge knowledge gaps of factors enabling successful performance. This research study seeks to develop a conceptual framework of how federal healthcare contracts can support the sustainable competitive advantage (SCA) of small disadvantage businesses (SDBs) operating within the medical industry
Rampage School Shootings in Rural America: A Description of the School and Community Environments Where They Occur
Get PDFSchools are typically seen as safe community institutions that allow children to develop both educationally and socially. But shootings in schools such as the 1999 massacre at Columbine High School, have cast doubt on the assumption that schools are safe places to learn. And although school shootings remain a very rare event, when they do occur, the public demands answers as to how or why such tragedies happen. In an attempt to satisfy this demand for immediate answers, the media often provides an explanation that the public readily accepts, such as a failing in mental health, gun control or a combination of both. However, research has found that these simplistic explanations, are not scientifically grounded. Given the rarity of school shootings, concrete and robust data on the causes or predictors of such violence is elusive. In addition, studies of shootings are limited to retrospective analysis and are typically centered on the characteristics of the shooter themselves. In this research dissertation, I seek to fill gaps in research regarding the environmental factors of schools and the communities where shootings have taken place, specifically in a rural setting
Ubiquitylation of Unphosphorylated c-myc by Novel E3 Ubiquitin Ligase SCFFbxl8
Get PDFOverexpression of c-myc via increased transcription or decreased protein degradation is common to many cancer etiologies. C-myc protein degradation is mediated by ubiquitin-dependent degradation and this ubiquitylation is regulated by several E3 ligases. The primary regulator is Fbxw7 which binds to a phospho-degron within c-myc. Here, we identify a new E3 ligase for c-myc, Fbxl8 (F-box and Leucine Rich Repeat Protein 8), as an adaptor component of the SCF (Skp1-Cullin1-F-box protein) ubiquitin ligase complex, for selective c-myc degradation. SCFFbxl8 binds and ubiquitylates c-myc, independent of phosphorylation revealing that it regulates a pool of c-myc distinct from SCFFbxw7. Reduction of Fbxl8 expression is correlated in 11 distinct tumor tissue types. Loss of Fbxl8 increases c-myc protein levels, protein stability, and cell division while overexpression of Fbxl8 reduces c-myc protein levels. Concurrent loss of Fbxl8 and Fbxw7 trigger a robust increase in c-myc protein levels consistent with targeting distinct pools of c-myc. This work highlights new mechanisms regulating c-myc degradation
Role of Perirhinal to Prefrontal Cortex Reciprocal Connection in Methamphetamine-Induced Memory Deficits
Get PDFChronic use of methamphetamine (meth) disrupts cortical processing across multiple cognitive domains including impulsivity, decision making and memory. Our laboratory has consistently shown that extended access to contingent meth self-administration reliably produces memory deficits in novel object recognition (NOR) tasks designed to test the “what” component of episodic memory in a rodent model. This type of memory is dependent on an intact function of the perirhinal cortex (PRH). However, the ongoing role of the prefrontal cortex (PFC) in this task and the directionality of communication between the PRH and the PFC is not entirely understood. A set of four experiments were designed to characterize the bi-directional connection between the PFC and the PRH during the exploration of novel vs. familiar objects and whether the manipulation of the circuit will restore recognition memory following chronic meth self-administration (SA). Male and female rats were infused with retrograde GFP-tagged adeno-associated virus (AAV) in the PRH (Experiment 1) and the PFC (Experiment 2). Three weeks later rats were tested for NOR with half the animals exploring two familiar objects and half exploring a novel object. Brain tissue was processed for co-labeled cells containing both GFP and c-Fos, an indicator of neuronal activation. Rats spent more time exploring novel vs. familiar objects. During novel object exploration, animals that explored novel objects had more co-labeled cells that project from the PRH to the PFC, but not in cells that project from PFC to the PRH. A dual viral approach was utilized in the second set of experiments to activate the PRH to PFC pathway following meth SA (Experiment 3) or inhibit the PRH to PFC pathway in meth naïve animals (Experiment 4). AAV viral vectors containing CRE-dependent Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) were infused into the PRH while retrograde AAV encoding CRE recombinase was infused into the PFC. A recognition memory deficit was established in meth SA rats and restored through activation of excitatory DREADDS (Experiment 3). In meth naïve animals a NOR memory deficit was also induced by activation of inhibitory DREADDS within the same circuit (Experiment 4). In conclusion, this data set suggests communication from the PRH to the PFC directs novel object recognition
Video Modeling as an Intervention for Young Adults with Autism (ASD) and Intellectual Developmental Disabilities (IDD)
Get PDFUtilizing NLP for Structure Learning to Understand Cancer Screening Uptake Utilizing NLP for Structure Learning to Understand Cancer Screening Uptake
No full textThis talk will demonstrate how NLP combined with a causal analysis approach can be used to predict and understand cancer screening uptake. Screening recommendations for breast, lung and colorectal cancer put together by the U.S. Preventive Services Task Force (USPSTF) are based on reductions in relative risk of mortality by detecting cancers at early stages where more treatment options are available. However, not all those recommended to get screened are being screened, and there are many social and economic barriers to increasing uptake. To maximize the utility of electronic health record (EHR), data in free text problem lists, as well as patient reported family histories of cancer must be extracted. Results from Stanza from (Standford NLP group) can be used with casual analysis approaches to discover underlying variable network structures, and treatment effects. However, named entity recognition (NER) alone is not quite a turnkey solution for concept extraction used in structure learning, and many challenges remain
Braving Our Blind Spots: Using a Virtual Book Discussion Group to Continue Conversations on Implicit Bias in Libraries
No full texthttps://medica-musc.researchcommons.org/faculty-books/1000/thumbnail.jp
ECMO: A Representative Descriptive Analysis Of 2018 Florida Billing Data
Get PDFSince the inception of Extracorporeal Membrane Oxygenation (ECMO) in the early 1970’s, technological advances and increased understanding and implementation of ECMO protocols have produced exponentially better outcomes. With improved outcomes, use of ECMO has dramatically risen in the last several decades. The purpose of this study is to define the modalities of ECMO and their purposes, as well as potential complications and contraindications. Furthermore, research was conducted into determining important factors in patient outcomes such as patient characteristics, readmission rates, and success of the therapy. Patient data was scrutinized to determine if any categorical particularly affected the overall costs and outcomes of ECMO patients. Moreover, odds of readmission were calculated to measure the efficacy of ECMO as a therapy. ECMO is an everchanging modality of therapy and as we continue to experience the benefits of its efficacy, we can better execute care plans, manage concurrent treatments, and offer better encompassing healing improving patient satisfaction and hospital profits. Research demonstrates that prompt assessment and rapid implementation of ECMO therapy are vital to a patient’s positive outcome. It is certain that as the wellness of the American population continues to diminish that we will undoubtedly witness an increasing utilization of ECMO