UMBC Biological Sciences Department

Permanent URI for this collectionhttp://hdl.handle.net/11603/54

With more than 30 tenured and tenure-track faculty members and lecturers, UMBC’s Department of Biological Sciences is one of the university’s largest academic departments encompassing a wide breadth of research and teaching. Research faculty in the Biological Sciences focus on:

Cell Biology
Computational Biology
Developmental Biology & Immunology
Evolutionary Biology
Molecular Biology & Genetics
Neuroscience
Plant Biology

The department offers a full complement of baccalaureate and graduate programs leading to B.A., B.S., M.S., and Ph.D. degrees, which are recognized for their emphasis on research, scientific approach, faculty contact, and extensive laboratory offerings. These programs serve to train a broad spectrum of future biologists and researchers, and to prepare students for graduate and professional schools.

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Mapping the Edges of Mass Spectral Prediction: Evaluation of Machine Learning EIMS Prediction for Xeno Amino Acids
(2025-01-14) Brown, Sean M.; Allgair, Evan; Kryštůfek, Robin
Mass spectrometry is one of the most effective analytical methods for unknown compound identification. By comparing observed m/z spectra with a database of experimentally determined spectra, this process identifies compound(s) in any given sample. Unknown sample identification is thus limited to whatever has been experimentally determined. To address the reliance on experimentally determined signatures, multiple state-of-the-art MS spectra prediction algorithms have been developed within the past half decade. Here we evaluate the accuracy of the NEIMS spectral prediction algorithm. We focus our analyses on monosubstituted α-amino acids given their significance as important targets for astrobiology, synthetic biology, and diverse biomedical applications. Our general intent is to inform those using generated spectra for detection of unknown biomolecules. We find predicted spectra are inaccurate for amino acids beyond the algorithms training data. Interestingly, these inaccuracies are not explained by physicochemical differences or the derivatization state of the amino acids measured. We thus highlight the need to improve both current machine learning based approaches and further optimization of ab initio spectral prediction algorithms so as to expand databases for structures beyond what is currently experimentally possible, even including theoretical molecules.
ZNF217 promotes ovarian cancer progression through cancer cell intrinsic and extrinsic mechanisms
(2024-01-01) Wardrup, Kathryn; Padmanabhan, Achuth; Biological Sciences; Biological Sciences
High-grade serous ovarian cancer (HGSOC) remains the most lethal gynecological malignancy in the United States. Due to the absence of a reliable early diagnostic biomarker and the vague presentation of early clinical symptoms, most women will receive a diagnosis in a metastatic stage of disease progression. At this point, the efficacy of extant therapeutic strategies drops significantly, resulting in disappointing 5-year survival outcomes of less than 30%. This unfortunate clinical reality highlights the urgent need to identify new drug targets and more effective therapeutic strategies to treat metastatic ovarian cancer. Achieving this goal has proved challenging, largely due to the knowledge gap in our understanding of factors that drive metastasis and drug resistance in ovarian cancer. For these reasons, my thesis project has focused on identifying factors that contribute to ovarian carcinogenesis with the goal of identifying new molecular targets for the development of more efficacious therapeutic strategies. One such emergent molecular target is the transcription factor, Zinc Finger Protein 217 (ZNF217). The genomic locus harboring ZNF217 (20q13.2) is frequently amplified in many human cancers, including ovarian cancer. Consistently, ZNF217 mRNA is elevated in ovarian tumors. Importantly, elevated ZNF217 mRNA levels were found to correlate with poor clinical outcome in ovarian cancer patients. Despite this compelling link, very little is known about the role of ZNF217 in ovarian cancer pathogenesis. To address this critical knowledge gap, my thesis project focused on understanding the role of ZNF217 in ovarian carcinogenesis. Using clinically relevant in vitro as well as in vivo models, I establish that ZNF217 functions as a potent oncogene that promotes cell proliferation, epithelial-to-mesenchymal transition (EMT), metastasis, and chemoresistance in ovarian cancer cells. I show that ZNF217’s ability to drive these oncogenic phenotypes is dependent upon its ability to bind DNA and alter the expression of its downstream target genes. Interestingly, I discovered that ZNF217 co-operates with estrogen to promote metastatic phenotypes in ovarian cancer cells. These data underscore the critical role elevated ZNF217 may play in estrogen receptor-positive ovarian cancers. In addition to this, I show that ZNF217 overexpression impacts the expression of various cytokines and chemokines that are known to facilitate an immune-suppressive tumor microenvironment. These data suggest that ZNF217 overexpression could potentially impact the ovarian tumor microenvironment and the response of ovarian cancer cells to immunotherapy. Finally, my work demonstrates that ZNF217 stability is influenced by glucose availability in the microenvironment. Glucose deprivation caused ZNF217 depletion in cells and this effect was phenocopied by small molecules that activate the AMP-activated protein kinase (AMPK), an enzyme that regulates cellular energy levels. These data suggest that the effect of glucose on ZNF217 is likely mediated via the AMPK pathway. Taken together, my work shows that ZNF217 impacts ovarian cancer progression through both cancer cell intrinsic as well as extrinsic mechanisms. By establishing ZNF217 as a critical factor driving ovarian cancer progression and metastasis and identifying potential pathways that regulate ZNF217 levels in ovarian cancer cells, this thesis has laid groundwork to investigate ZNF217’s utility as a therapeutic target in metastatic ovarian tumors.
Dissecting the relationship between inflammation and the development of preneoplastic lesions in a mouse model of Interleukin-1?-mediated prostatic inflammation
(2024-01-01) Voskanian, Alin; Bieberich, Charles C; Biological Sciences; Biological Sciences
Prostate cancer is the second most common cancer in the USA and the fourth most common worldwide. Understanding the molecular mechanisms underlying the onset of this disease could lead to the development of earlier detection methods and effective treatments. Two histologically defined lesions that are precursors to human prostate cancer have been identified. Prostatic Intraepithelial Neoplasia (PIN) manifests as an abnormal accumulation of epithelial cells, often with nuclear atypia and enlarged nucleoli, within preexisting benign prostatic acini or ducts. Proliferative Inflammatory Atrophy (PIA) is described as an inflamed prostate gland with atrophic cells and a high percentage of mitotic epithelial cells. Chronic prostatic inflammation is known to increase prostate cancer risk. To better understand the role of chronic inflammation in the natural history of prostate cancer, with a focus on the emergence of early lesions, I employed a mouse model to undertake detailed molecular and histopathological analyses of the changes that occur in prostate epithelial cells upon prolonged exposure to inflammatory insult. In chapter one I discuss the merits of existing mouse prostatic disease models and highlight the advantages of the Induced Mouse Prostate Inflammation-IL1-driven (IMPI 1) model to study inflammation. In this model, consistent long-term prostatic inflammation occurs upon administration of doxycycline. In chapter two, I report the results of experiments designed to determine the histopathological and transcriptomic consequences of prolonged chronic inflammation in IMPI-1 mice and highlight the discovery of a gene expression signature that mimics key molecular features of human PIA. To gain understanding of the cells involved in the development of PIA and PIN lesions, in Chapter three, I report the results of bioinformatic analyses to compare gene expression profiles from IMPI-1 mice with single-cell RNA sequencing profiles from two genetically engineered mouse prostate cancer models. My results indicate that epithelial cells in IMPI-1 prostates that have been exposed to a prolonged inflammatory environment are enriched for genes that are expressed by Myc-expressing luminal cells and reactive basal and luminal cells in two independent mouse prostate cancer models. Myc-expressing luminal cells and reactive basal and luminal cells have been previously reported to be present in the early stages of prostate cancer development in these models. These data demonstrate that chronic inflammation in the mouse prostate leads to cellular and molecular changes that recapitulate features observed in precursor states of prostate cancer. This data provide strong experimental evidence in support of the longstanding hypothesis that chronic inflammation plays a causal role in the development of human prostate cancer. Future experiments will be required to identify other molecular and cellular alterations that permit precursor lesions to progress to overt adenocarcinoma
EVALUATING THE EFFECTS OF TISSUE ARCHITECTURE ON DROSOPHILA CHEMOTAXIS USING ADVANCED IMAGING AND ANALYSIS TECHNIQUES
(2024-01-01) George, Alexander; Starz-Gaiano, Michelle; Biological Sciences; Biological Sciences
Graded concentrations of diffusible signals, such as morphogens and chemoattractants, instruct important developmental processes, like cell specification and cell migration. However, signal distribution in complex tissue geometries in vivo has not been well characterized, which has implications in understanding concentration-dependent signaling effects. Using the border cells, which migrate collectively in the Drosophila egg chamber during oogenesis and are guided by chemoattractants, we can study these important issues in vivo. We find that distinct features in the tissue geometry along the migration route, specifically acellular gaps at multicellular intersections, disrupt local concentrations of secreted chemoattractants to affect directed border cell migration. In live-imaged wild-type egg chambers, we observed declines in posterior speed that occur specifically at intersections; trends that disappear in response to elevated levels of chemoattractant, suggesting that migratory cues differ in these regions, normally. We developed a mathematical model, informed by this data, to predict the migration changes in response to both chemical and architectural inputs. Our model indicates that in silico, border cells slow down in intersections due to local changes in the chemoattractant gradient, which matches our in vivo phenotypes. Importantly, we observed that migration delays in response to modified chemoattractant levels could be rescued by manipulating the tissue geometry, which strongly suggests that chemoattractant concentrations can be buffered by tissue architecture. In characterizing these phenotypes, I updated and improved upon published live-imaging methods to culture egg chambers and visualize border cells over the full course of migration. I also came up with novel mounting strategies that allowed for efficient and reproducible characterization of fluorescently-tagged signals in live egg chambers. These strategies allowed us to visualize the tagged chemoattractant, Platelet-Derived Growth Factor/Vascular Endothelial Growth Factor-Related Factor 1 (PVF1) and characterize its distribution in the border cell migratory domain of live egg chambers for the first time in the field. Finally, we demonstrate that the Heparan Sulfate Proteoglycan (HSPG) and Extracellular Matrix (ECM) component, Perlecan, plays a role in border cell migration, potentially by modulating PVF1 function. Overall, this body of work shows that in vivo tissue architecture can affect the distribution and function of important signaling molecules, with consequences for essential developmental processes, like cell migration. Funding: NSF-IOS 2303857 & NSF-NIGMS 1953423.
Delineating mechanisms of GPCR signaling: Studies on the Kinin receptors and GPR162
(2024-01-01) Darira, Shradha; Sutton, Laurie P; Biological Sciences; Biology, Molecular and Cell
G protein coupled receptors (GPCRs) are the largest class of membrane proteins. They act as signaling molecules that transmit extracellular signals into the cell, thereby regulating various physiological functions. Upon activation by an extracellular signal, GPCRs can initiate distinct intracellular events via interaction with G proteins. Given their role in regulating almost all physiological functions and their presence on the plasma membrane, GPCRs make for attractive therapeutic targets. Through my dissertation work, I have advanced our understanding of these prospects to aid the pursuit of GPCR based drug discovery. The major focus of my dissertation was understanding biased signaling. Bias is defined as the tendency of certain receptors to be able to activate to more than one G protein depending on the nature of the activating ligand. To understand these processes, we made use of the kinin receptor system as a model. These GPCRs namely, Bradykinin 1(B1R) and Bradykinin 2(B2R) are major regulators of aspects such as pain, inflammation and cardiovascular homeostasis. However, the molecular mechanisms underlying this regulation are not well understood. To better understand these mechanisms, we generated a comprehensive G protein activation map of these receptors when activated by each of the four different peptide ligands (bradykinin, kallidin, des-arg9-bradykinin and des-arg10-kallidin). Forming a major group of understudied GPCRs are the orphan GPCRs whose functions remain unknown, and their endogenous ligand have not been identified. GPR162 is one such orphan receptor that has been implicated in regulating hedonic tone or an individual’s liking of rewarding stimuli. This part of my dissertation project was focused on the design and use of two different chimeric GPCR constructs of GPR162. This approach enables us to activate these chimeric constructs using known ligands in vitro allowing us to discern these intracellular signaling events. Next, to understand the involvement of GPR162 in regulating hedonic tone, we created and validated a novel global GPR162 knock-out (KO) mouse model. Overall, this thesis is focused on understudied aspects of GPCR signaling through the development and optimization of novel molecular tools to understand the intracellular signaling capabilities of the orphan receptor GPR162 and provides novel insights into the unconventional signaling mechanisms of the kinin receptors.
Astrocyte-mediated mechanisms contribute to traumatic brain injury pathology
(Wiley, 2023) Munoz-Ballester, Carmen; Robel, Stefanie
Astrocytes respond to traumatic brain injury (TBI) with changes to their molecular make-up and cell biology, which results in changes in astrocyte function. These changes can be adaptive, initiating repair processes in the brain, or detrimental, causing secondary damage including neuronal death or abnormal neuronal activity. The response of astrocytes to TBI is often梑ut not always梐ccompanied by the upregulation of intermediate filaments, including glial fibrillary acidic protein (GFAP) and vimentin. Because GFAP is often upregulated in the context of nervous system disturbance, reactive astrogliosis is sometimes treated as an 揳ll-or-none� process. However, the extent of astrocytes' cellular, molecular, and physiological adjustments is not equal for each TBI type or even for each astrocyte within the same injured brain. Additionally, new research highlights that different neurological injuries and diseases result in entirely distinctive and sometimes divergent astrocyte changes. Thus, extrapolating findings on astrocyte biology from one pathological context to another is problematic. We summarize the current knowledge about astrocyte responses specific to TBI and point out open questions that the field should tackle to better understand how astrocytes shape TBI outcomes. We address the astrocyte response to focal versus diffuse TBI and heterogeneity of reactive astrocytes within the same brain, the role of intermediate filament upregulation, functional changes to astrocyte function including potassium and glutamate homeostasis, blood朾rain barrier maintenance and repair, metabolism, and reactive oxygen species detoxification, sex differences, and factors influencing astrocyte proliferation after TBI. This article is categorized under: Neurological Diseases > Molecular and Cellular Physiology
Mild Traumatic Brain Injury-Induced Disruption of the Blood-Brain Barrier Triggers an Atypical Neuronal Response
(Frontiers, 2022-02-18) Munoz-Ballester, Carmen; Mahmutovic, Dzenis; Rafiqzad, Yusuf; Korot, Alia; Robel, Stefanie
Mild TBI (mTBI), which affects 75% of TBI survivors or more than 50 million people worldwide each year, can lead to consequences including sleep disturbances, cognitive impairment, mood swings, and post-traumatic epilepsy in a subset of patients. To interrupt the progression of these comorbidities, identifying early pathological events is key. Recent studies have shown that microbleeds, caused by mechanical impact, persist for months after mTBI and are correlated to worse mTBI outcomes. However, the impact of mTBI-induced blood-brain barrier damage on neurons is yet to be revealed. We used a well-characterized mouse model of mTBI that presents with frequent and widespread but size-restricted damage to the blood-brain barrier to assess how neurons respond to exposure of blood-borne factors in this pathological context. We used immunohistochemistry and histology to assess the expression of neuronal proteins in excitatory and inhibitory neurons after mTBI. We observed that the expression of NeuN, Parvalbumin, and CamKII was lost within minutes in areas with blood-brain barrier disruption. Yet, the neurons remained alive and could be detected using a fluorescent Nissl staining even 6 months later. A similar phenotype was observed after exposure of neurons to blood-borne factors due to endothelial cell ablation in the absence of a mechanical impact, suggesting that entrance of blood-borne factors into the brain is sufficient to induce the neuronal atypical response. Changes in postsynaptic spines were observed indicative of functional changes. Thus, this study demonstrates That exposure of neurons to blood-borne factors causes a rapid and sustained loss of neuronal proteins and changes in spine morphology in the absence of neurodegeneration, a finding that is likely relevant to many neuropathologies.
Assessment of Blood-Brain Barrier Integrity Using Dyes and Tracers
(2024-09-05) Munoz-Ballester, Carmen; Robel, Stefanie; Golf, Samantha; Heithoff, Benjamin; George, Kijana; Robel, Stefanie
Under physiological conditions the blood-brain barrier (BBB) is required for regulating the passage of substances between the bloodstream and the brain. To date, disruption of the BBB has been associated with nearly all neurological diseases. Dye and tracer experiments have been used to assess BBB integrity for decades, yet quantitative assessment of these experiments has only recently been implemented. Further, interpretation of these results requires the consideration of tracer-specific properties. Here, we describe a protocol for evaluating BBB leakage using the small molecule cadaverine in quantitative way. We also cover advantages/disadvantages of using some reagents and highlight limitations in data interpretations based on assays used to assess BBB permeability.
Imaging Techniques for the Analysis of Blood-Brain Barrier and Gliovascular Unit Dysfunction
(2024-09-04) Robel, Stefanie; Munoz-Ballester, Carmen; Heithoff, Benjamin; George, Kijana; Robel, Stefanie
Proper blood-brain barrier (BBB) function is essential to maintain homeostasis keeping the central nervous system healthy. Disruption of the BBB has been described in nearly all neurological disease and injury contexts. Given the various physical and metabolic roles of the BBB and gliovascular unit (GVU), dysfunction should be assessed across multiple levels to pinpoint the exact nature of the impairment. Here we describe imaging techniques for evaluating various aspects of BBB and GVU integrity and function, tailored for use in mouse models with protocols for quantitative image analysis. These imaging techniques complement classical dye tracer experiments and reveal underlying molecular causes of BBB dysfunction.
Optimized Enrichment of Murine Blood-Brain Barrier Vessels with a Critical Focus on Network Hierarchy in Post-Collection Analysis
(2024-09-20) Abdelazim, Hanaa; Barnes, Audra; Stupin, James; Hasson, Ranah; Munoz-Ballester, Carmen ; Young, Kenneth L.; Robel, Stefanie; Smyth, James W.; Lamouille, Samy; Chappell, John C.
Cerebrovascular networks contain a unique region of interconnected capillaries known as the blood-brain barrier (BBB). Positioned between upstream arteries and downstream veins, these microvessels have unique structural features, such as the absence of vascular smooth muscle cells (vSMCs) and a relatively thin basement membrane, to facilitate highly efficient yet selective exchange between the circulation and the brain interstitium. This vital role in neurological health and function has garnered significant attention from the scientific community and inspired methodology for enriching BBB capillaries. Extensive characterization of the isolates from such protocols is essential for framing the results of follow-on experiments and analyses, providing the most accurate interpretation and assignment of BBB properties. Seeking to aid in these efforts, here we visually screened output samples using fluorescent labels and found considerable reduction of non-vascular cells following density gradient centrifugation (DGC) and subsequent filtration. Comparatively, this protocol enriched brain capillaries, though larger diameter vessels associated with vSMCs could not be fully excluded. Protein analysis further underscored the enrichment of vascular markers following DGC, with filtration preserving BBB-associated markers and reducing � though not fully removing � arterial/venous contributions. Transcriptional profiling followed similar trends of DGC plus filtration generating isolates with less non-vascular and non- capillary material included. Considering vascular network hierarchy inspired a more comprehensive assessment of the material yielded from brain microvasculature isolation protocols. This approach is important for providing an accurate representation of the cerebrovascular segments being used for data collection and assigning BBB properties specifically to capillaries relative to other regions of the brain vasculature.HIGHLIGHTS� We optimized a protocol for the enrichment of murine capillaries using density gradient centrifugation and follow-on filtration.� We offer an approach to analyzing post-collection cerebrovascular fragments and cells with respect to vascular network hierarchy.� Assessing arterial and venous markers alongside those associated with the BBB provides a more comprehensive view of material collected.� Enhanced insight into isolate composition is critical for a more accurate view of BBB biology relative to larger diameter cerebrovasculature.MOTIVATION The recent surge in studies investigating the cerebrovasculature, and the blood-brain barrier (BBB) in particular, has inspired a broad range of approaches to target and observe these specialized blood vessels within murine models. To capture transcriptional and molecular changes during a specific intervention or disease model, techniques have been developed to isolate brain capillary networks and collect their cellular constituents for downstream analysis. Here, we sought to highlight the benefits and cautions of isolating and enriching microvessels from murine brain tissue. Specifically, through rigorous assessment of the output material following application of specific protocols, we presented the benefits of specific approaches to reducing the inclusion of non-vascular cells and non-capillary vessel segments, verified by analysis of vascular-related proteins and transcripts. We also emphasized the levels of larger- caliber vessels (i.e. arteries/arterioles and veins/venules) that are collected alongside cerebral capillaries with each method. Distinguishing these vascular regions with greater precision is critical for attributing specific characteristics exclusively to the BBB where metabolic, ion, and waste exchange occurs. While the addition of larger vessels to molecular / transcriptional analyses or follow-on experiments may not be substantial for a given protocol, it is essential to gauge and report their level of inclusion, as their contributions may be inadvertently assigned to the BBB. Therefore, we present this optimized brain microvessel isolation protocol and associated evaluation methods to underscore the need for increased rigor in characterizing vascular regions that are collected and analyzed within a given study.Graphical Abstract Constructed using resources from BioRender.com.Download figureOpen in new tab
Astrocytic connexin43 phosphorylation contributes to seizure susceptibility after mild Traumatic Brain Injury
(2024-11-14) Muñoz-Ballester, Carmen; Leitzel, Owen; Golf, Samantha; Phillips, Chelsea M.; Zeitz, Michael J.; Pandit, Rahul; Smyth, James W.; Lamouille, Samy; Robel, Stefanie
Astrocytes play a crucial role in maintaining brain homeostasis through functional gap junctions (GJs) primarily formed by connexin43 (Cx43). These GJs facilitate electrical and metabolic coupling between astrocytes, allowing the passage of ions, glucose, and metabolites. Dysregulation of Cx43 has been implicated in various pathologies, including traumatic brain injury (TBI) and acquired epilepsy. We previously identified a subset of atypical astrocytes after mild TBI that exhibit reduced Cx43 expression and coupling and are correlated with the development of spontaneous seizures. Given that mild TBI affects millions globally and can lead to long-term complications, including post-traumatic epilepsy, understanding the molecular events post-TBI is critical for developing therapeutic strategies.In the present study, we assessed the heterogeneity of Cx43 protein expression after mild TBI. In accordance with our previous findings, a subset of astrocytes lost Cx43 expression. As previously reported after TBI, we also found a significant increase in total Cx43 protein expression after mild TBI, predominantly in the soluble form, suggesting that while junctional Cx43 protein levels remained stable, hemichannels and cytoplasmic Cx43 were increased. We then investigated the phosphorylation of Cx43 at serine 368 after TBI, which is known to influence GJ assembly and function. Phosphorylation of Cx43 at serine 368 is elevated following TBI and Cx43S368A mutant mice, lacking this phosphorylation, exhibited reduced susceptibility to seizures induced by pentylenetetrazol (PTZ). These findings suggest that TBI-induced Cx43 phosphorylation enhances seizure susceptibility, while inhibiting this modification presents a potential therapeutic avenue for mitigating neuronal hyperexcitability and seizure development.
AFLPs support deep relationships among darters (Percidae: Etheostomatinae) consistent with morphological hypotheses
(Springer, 2011-12) Smith, T. A.; Mendelson, T. C.; Page, L. M.
Recent attention has focused on the efficacy of amplified fragment length polymorphisms (AFLPs) for resolving deep evolutionary relationships. Here we show that AFLPs provide resolution of deep relationships within the family Percidae that are more consistent with previous morphological hypotheses than are relationships proposed by previous molecular analyses. Despite in silico predictions, we were able to resolve relatively ancient divergences, estimated at >25?MA. We show that the most distantly related species share the fewest fragments, but suggest that large data sets and extensive taxon sampling are sufficient to overcome this obstacle of the AFLP technique for deep divergences. We compare genetic distances estimated from mitochondrial DNA with those from AFLPs and contrast traditional PAUP* Nei朙i AFLP genetic distances with a recently proposed method utilizing the Dice equation with constraining nucleotides.
Implantation of Islets Co-Seeded with Tregs in a Novel Biomaterial Reverses Diabetes in the NOD Mouse Model
(Springer Nature, 2025-01-01) Elizondo, Diana M.; de Oliveira Rekowsky, Lais L.; de Sa Resende, Ayane; Seenarine, Jonathan; da Silva, Ricardo Luis Louzada; Ali, Jamel; Yang, Dazhi; de Moura, Tatiana; Lipscomb, Michael W.
BACKGROUND: Type 1 diabetes (T1D) results in autoreactive T cells chronically destroying pancreatic islets. This often results in irreplaceable loss of insulin-producing beta cells. To reverse course, a combinatorial strategy of employing glucose-responsive insulin restoration coupled with inhibiting autoreactive immune responses is required. METHODS: Non-obese diabetic mice received a single intraperitoneal implantation of a novel biomaterial co-seeded with insulin-producing islets and T regulatory cells (Tregs). Controls included biomaterial seeded solely with islets, or biomaterial only groups. Mice were interrogated for changes in inflammation and diabetes progression via blood glucose monitoring, multiplex serum cytokine profiling, flow cytometry and immunohistochemistry assessments. RESULTS: Islet and Tregs co-seeded biomaterial recipients had increased longevity, insulin secretion, and normoglycemia through 180 days post-implantation compared to controls. Serum profile revealed reduced TNFα, IFNγ, IL-1β and increased IL-10, insulin, C-Peptide, PP and PPY in recipients receiving co-seeded biomaterial. Evaluation of the resected co-seeded biomaterial revealed reduced infiltrating autoreactive CD8 + and CD4 + T cells concomitant with sustained presence of Foxp3 + Tregs; further analysis revealed that the few infiltrated resident effector CD4⁺ or CD8⁺ T cells were anergic, as measured by low levels of IFNγ and Granzyme-B upon stimulation when compared to controls. Interestingly, studies also revealed increased Tregs in the pancreas. However, there was no restoration of the pancreas beta cell compartment, suggesting normoglycemia and production of insulin levels were largely supported by the implanted co-seeded biomaterial. CONCLUSION: These studies show the efficacy of a combinatorial approach seeding Tregs with pancreatic islets in a novel self-assembling organoid for reversing T1D.
Flood Risk Assessment of the National Harbor at Maryland, United States
(2024-11-17) Negussie, Neftalem; Yesserie, Addis; Harris, Chinchu; Keita, Abou; Ashqar, Huthaifa
Over the past few decades, floods have become one of the costliest natural hazards and losses have sharply escalated. Floods are an increasing problem in urban areas due to increased residential settlement along the coastline and climate change is a contributing factor to this increased frequency. In order to analyze flood risk, a model is proposed to identify the factors associated with increased flooding at a local scale. The study area includes National Harbor, MD, and the surrounding area of Fort Washington. The objective is to assess flood risk due to an increase in sea level rise for the study area of interest. The study demonstrated that coastal flood risk increased with sea level rise even though the predicted level of impact is fairly insignificant for the study area. The level of impact from increased flooding is highly dependent on the location of the properties and other topographic information.
Functional analysis of regA paralog rlsD in Volvox carteri
(Wiley, 2024-10-22) Jiménez-Marín, Berenice; Ortega-Escalante, José A.; Tyagi, Antariksh; Seah, Jundhi; Olson, Bradley J. S. C.; Miller, Stephen M.
Volvox carteri is an excellent system for investigating the origins of cell differentiation because it possesses just two cell types, reproductive gonidia and motile somatic cells, which evolved relatively recently. The somatic phenotype depends on the regA gene, which represses cell growth and reproduction, preventing cells expressing it from growing large enough to become gonidia. regA encodes a putative transcription factor and was generated in an undifferentiated ancestor of V. carteri through duplication of a progenitor gene whose ortholog in V. carteri is named rlsD. Here we analyze the function of rlsD through knockdown, overexpression, and RNA-seq experiments, to gain clues into the function of a member of an understudied putative transcription factor family and to obtain insight into the origins of cell differentiation in the volvocine algae. rlsD knockdown was lethal, while rlsD overexpression dramatically reduced gonidial growth. rlsD overexpression led to differential expression of approximately one-fourth of the genome, with repressed genes biased for those typically overexpressed in gonidia relative to somatic cells, and upregulated genes biased toward expression in soma, where regA expression is high. Notably, rlsD overexpression affects accumulation of transcripts for genes/Pfam domains involved in ribosome biogenesis, photosynthetic light harvesting, and sulfate generation, functions related to organismal growth, and responses to resource availability. We also found that in the wild type, rlsD expression is induced by light deprivation. These findings are consistent with the idea that cell differentiation in V. carteri evolved when a resource-responsive, growth-regulating gene was amplified, and a resulting gene duplicate was co-opted to repress growth in a constitutive, spatial context.
System Change Evaluation of a State-System Approach to Faculty Diversification
(Understanding Interventions Journal, 2024-10-31) Carter-Veale, Wendy Y.; Cresiski, Robin H.; Sharp, Gwen
Women and people of color continue to be underrepresented among academic faculty in higher education, particularly in STEM fields. We use the Water Systems of Change theoretical framework and a qualitative document analysis to evaluate a case study of five institutions within a state university system that formed the NSF-funded AGEP PROMISE Academy Alliance (APAA) to address a shortage of faculty from minoritized backgrounds in the biomedical sciences. The APAA developed and implemented a novel intervention that focuses on minoritized postdoctoral scholar recruitment, development, and conversion into tenure-track faculty roles, while leveraging the state system as a collaborative body. We assess the program’s transformative influence on the university system and participating institutions, revealing changes at the structural, relational, and transformative levels.
Harnessing the AI/ML in Drug and Biological Products Discovery and Development: The Regulatory Perspective
(2024-10-30) Mirakhori, Fahimeh; Niazi, Sarfaraz K.
Artificial Intelligence (AI) has the disruptive potential to transform patients’ lives via innovations in pharmaceutical sciences, drug development, clinical trials, and manufacturing. However, it presents significant challenges, ethical concerns, and risks across sectors and societies. AI’s rapid advancement has revealed regulatory gaps as existing public policies struggle to keep pace with the challenges posed by these emerging technologies. The term AI itself has become commonplace to argue that greater “human oversight” for “machine intelligence” is needed to harness the power of this revolutionary technology for both potential and risk management, and hence to call for more practical regulatory guidelines, harmonized frameworks, and effective policies to ensure safety, scalability, data privacy, and governance, transparency, and equitable treatment. In this review paper, we employ a holistic multidisciplinary lens to overview the current regulatory landscape with a synopsis of the FDA workshop perspectives on the use of AI in drug and biological product development. We discuss the promises of responsible data-driven AI, challenges and related practices adopted to overcome limitations, and our practical reflections on regulatory oversight. Finally, the paper outlines a path forward and future opportunities for lawful ethical AI. This review highlights the importance of risk-based regulatory oversight, including diverging views in the field, in reaching a consensus.
Efficacy and Safety of GLP-1 Receptor Agonists in Patients With Metabolic Dysfunction-Associated Steatotic Liver Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
(Cureus, 2024-10-13) Njei, Basile; Al-Ajlouni, Yazan; Lemos, Samira Y.; Ugwendum, Derek; Ameyaw, Prince; Njei, Lea-Pearl; Boateng, Sarpong
Metabolic dysfunction-associated steatotic liver disease (MASLD) poses a major global health challenge. glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown potential therapeutic benefits for MASLD patients, including improvements in liver function, inflammation, and fibrosis. This study aims to systematically review and meta-analyze randomized controlled trials (RCTs) to evaluate the efficacy and safety of GLP-1RAs in MASLD patients, focusing on hepatic outcomes, cardiovascular outcomes, anthropometric measurements, and mortality. Following PRISMA guidelines, a comprehensive database search was conducted to include RCTs assessing GLP-1RAs' effects on MASLD. Quality assessment was conducted using the Revised Cochrane Risk of Bias tool. Our meta-analysis used a random-effects model, calculating standardized mean differences for continuous outcomes to determine the agents' efficacy and safety. Additionally, funnel plots were generated to assess publication bias, ensuring the integrity of our meta-analytical findings. The review included 27 trials, revealing GLP-1RAs significantly improved hepatic function markers (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, and liver fat content) and cardiovascular risk factors (fasting blood sugar, HbA1c levels, lipid profiles). Additionally, GLP-1RAs were associated with significant reductions in body weight, BMI, subcutaneous fat, and waist circumference. GLP-1RAs demonstrate a promising therapeutic role in managing MASLD, offering benefits that extend to improving liver function, mitigating cardiovascular risk, and promoting weight loss. Further research is needed to confirm these findings and optimize GLP-1RAs' usage in MASLD treatment.
The Use of Guided Reflections in Learning Proof Writing
(MDPI, 2024-10-04) Hoffman, Kathleen; Williams, Tory; Kephart, Kerrie
We investigated written self-reflections in an undergraduate proof-writing course designed to mitigate the difficulty of a subsequent introductory analysis course. Students wrote weekly self-reflections guided by mechanical, structural, creative, and critical thinking modalities. Our research was guided by three research questions focused on the impact of student self-reflections on student metacognition and performance in the interventional and follow-up class. To address these questions, we categorized the quality of the students’ reflections and calculated their average course grades within each category in the proof-writing, the prerequisite, and the introductory analysis courses. The results demonstrated that writing high-quality self-reflections was a statistically significant predictor of earning higher average course grades in the proof-writing course and the analysis course, but not in the prerequisite course. Convergence over the semester of the students’ self-evaluations toward an experts’ scorings on a modality rubric indicates that students improve in their understanding of the modalities. The repeated writing of guided self-reflections using the framework of the modalities seems to support growth in the students’ awareness of their proof-writing abilities.
Guanine nucleotide exchange factors and colon neoplasia
(Frontiers, 2024-10-17) Njei, Lea-Pearl; Sampaio Moura, Natalia; Schledwitz, Alyssa; Griffiths, Kelly; Cheng, Kunrong; Raufman, Jean-Pierre
Despite many diagnostic and therapeutic advances, colorectal cancer (CRC) remains the second leading cause of cancer death for men and women in the United States. Alarmingly, for reasons currently unknown, the demographics of this disease have shifted towards a younger population. Hence, understanding the molecular mechanisms underlying CRC initiation and progression and leveraging these findings for therapeutic purposes remains a priority. Here, we review critically the evidence that canonical and noncanonical actions of guanine nucleotide exchange factors (GEFs) play important roles in CRC evolution. Rho GEF GTPases, which switch between inactive GDP-bound and active GTP-bound states, are commonly overexpressed and activated in a variety of cancers, including CRC, and may be tractable therapeutic targets. In addition to comprehensively reviewing this field, we focus on Rho/Rac GEFs that are involved in regulating key functions of normal and neoplastic cells like cell polarity, vesicle trafficking, cell cycle regulation, and transcriptional dynamics. Prime examples of such Rho/Rac GEFs include βPak-interacting exchange factor (βPix), a Rho family GEF for Cdc42/Rac1, Tiam1, GEF-H1, RGNEF, and other GEFs implicated in CRC development and progression. Throughout this analysis, we explore how these findings fill key gaps in knowledge regarding the molecular basis of colon carcinogenesis and how they may be leveraged to treat advanced CRC. Lastly, we address potential future directions for research into the role of GEFs as CRC biomarkers and therapeutic targets. In this regard, leveraging the noncanonical actions of GEFs appears to provide a relatively unexplored opportunity requiring further investigation.

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