Biomedical Sciences
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Biomedical Sciences is composed of two basic science departments: Anatomy, Physiology and Pharmacology; and Biochemistry, Microbiology and Immunology.
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Item Acute stress, but not corticosterone, facilitates acquisition of paired associates learning in rats using touchscreen-equipped operant conditioning chambers(Elsevier, 2018) Roebuck, Andrew; Liu, Max; Lins, Brittney; Scott, Gavin; Howland, John G.Item Cancer Cell’s Achilles Heels: Considerations for Design of Anti-Cancer Drug Combinations(International Journal of Molecular Sciences, 2024-12) Gahramanov, Valid; Vizeacoumar, Frederick Sagayaraj; Morales, Alain Morejon; Bonham, Keith; Sakharkar, Meena K.; Kumar, Santosh; Vizeacoumar, Franco; Freywald, Andrew; Sherman, MichaelLoss of function screens using shRNA (short hairpin RNA) and CRISPR (clustered regularly interspaced short palindromic repeats) are routinely used to identify genes that modulate responses of tumor cells to anti-cancer drugs. Here, by integrating GSEA (Gene Set Enrichment Analysis) and CMAP (Connectivity Map) analyses of multiple published shRNA screens, we identified a core set of pathways that affect responses to multiple drugs with diverse mechanisms of action. This suggests that these pathways represent “weak points” or “Achilles heels”, whose mild disturbance should make cancer cells vulnerable to a variety of treatments. These “weak points” include proteasome, protein synthesis, RNA splicing, RNA synthesis, cell cycle, Akt-mTOR, and tight junction-related pathways. Therefore, inhibitors of these pathways are expected to sensitize cancer cells to a variety of drugs. This hypothesis was tested by analyzing the diversity of drugs that synergize with FDA-approved inhibitors of the proteasome, RNA synthesis, and Akt-mTOR pathways. Indeed, the quantitative evaluation indicates that inhibitors of any of these signaling pathways can synergize with a more diverse set of pharmaceuticals, compared to compounds inhibiting targets distinct from the “weak points” pathways. Our findings described here imply that inhibitors of the “weak points” pathways should be considered as primary candidates in a search for synergistic drug combinations.Item Chronic maternal hyperglycemia induced during mid-pregnancy in rats increases RAGE expression, augments hippocampal excitability, and alters behavior of the offspring(Elsevier, 2015) Chandna, Andrew; Kuhlmann, Naila; Bryce, Courtney; Greba, Quentin; Campanucci, Veronica; Howland, John GItem Dissociable effects of the d- and l- enantiomers of govadine on the disruption of prepulse inhibition by MK-801 and apomorphine in male Long-Evans rats(2017) Lins, Brittney; Marks, Wendie; Phillips, Anthony; Howland, JohnItem Effects of stress on behavioral flexibility in rodents(Elsevier, 2017) Hurtubise, Jessica; Howland, JohnItem Effects of the metabotropic glutamate receptor 5 positive allosteric modulator CDPPB on rats tested with the paired associates learning task in touchscreen-equipped operant conditioning chambers(Elsevier, 2016) Lins, Brittney; Howland, John G.Item Evidence for altered insulin signaling in the brains of Genetic Absence Epilepsy Rats from Strasbourg(2020) Sekar, Sathiya; Marks, Wendie; Gopalakrishnan, Venkat; Greba, Quentin; Snutch, Terrance; Howland, John; Taghibiglou, ChangizItem Evolutionary repression of chondrogenic genes in the vertebrate osteoblast(Wiley, 2020-01-28) Nguyen, Jason; eames, brianGene expression in extant animals might reveal how skeletal cells have evolved over the past 500 million years. The cells that make up cartilage (chondrocytes) and bone (osteoblasts) express many of the same genes, but they also have important molecular differences that allow us to distinguish them as separate cell types. For example, traditional studies of later-diverged vertebrates, such as mouse and chick, defined the genes Col2a1 and sex-determining region Y-box 9 as cartilage-specific. However, recent studies have shown that osteoblasts of earlier-diverged vertebrates, such as frog, gar, and zebrafish, express these 'chondrogenic' markers. In this review, we examine the resulting hypothesis that chondrogenic gene expression became repressed in osteoblasts over evolutionary time. The amphibian is an underexplored skeletal model that is uniquely positioned to address this hypothesis, especially given that it diverged when life transitioned from water to land. Given the relationship between phylogeny and ontogeny, a novel discovery for skeletal cell evolution might bolster our understanding of skeletal cell development.Item Exosome-associated mitochondrial DNA in late-life depression: Implications for cognitive decline in older adults(Journal of Affective Disorders, 2024-06) Mendes-Silva, Ana Paula; Nikolova, Yuliya S.; Rajji, Tarek K.; Kennedy, James; Diniz, Breno; Gonçalves, Vanessa F.; Vieira, EricaBackground: Disrupted cellular communication, inflammatory responses and mitochondrial dysfunction are consistently observed in late-life depression (LLD). Exosomes (EXs) mediate cellular communication by transporting molecules, including mitochondrial DNA (EX-mtDNA), playing critical role in immunoregulation alongside tumor necrosis factor (TNF). Changes in EX-mtDNA are indicators of impaired mitochondrial function and might increase vulnerability to adverse health outcomes. Our study examined EX-mtDNA levels and integrity, exploring their associations with levels of TNF receptors I and II (TNFRI and TNFRII), and clinical outcomes in LLD. Methods: Ninety older adults (50 LLD and 40 controls (HC)) participated in the study. Blood was collected and exosomes were isolated using size-exclusion chromatography. DNA was extracted and EX-mtDNA levels and deletion were assessed using qPCR. Plasma TNFRI and TNFRII levels were quantified by multiplex immunoassay. Correlation analysis explored relationships between EX-mtDNA, clinical outcomes, and inflammatory markers. Results: Although no differences were observed in EX-mtDNA levels between groups, elevated levels correlated with poorer cognitive performance (r = − 0.328, p = 0.002) and increased TNFRII levels (r = 0.367, p = 0.004). LLD exhibited higher deletion rates (F(83,1) = 4.402, p = 0.039), with a trend remaining after adjusting for covariates (p = 0.084). Deletion correlated with poorer cognitive performance (r = − 0.335, p = 0.002). No other associations were found. Limitation: Cross-sectional study with a small number of participants from a specialized geriatric psychiatry treatment center. Conclusion: Our findings suggest that EX-mtDNA holds promise as an indicator of cognitive outcomes in LLD. Additional research is needed to further comprehend the role of EX-mtDNA levels/integrity in LLD, paving the way for its clinical application in the future.Item Generation of a plasmid series for rapid sub-cloning and use in various Enterobacteriaceae(Journal of Bioscience and Bioengineering, 2024-09-06) Braun, Hannah G.; Kanwal, Nabeela; Rivera Lopez, Luisa F.; Thomassin, Jenny-LeePlasmids are molecular genetic tools used for trans-complementation and gene expression in bacteria. Challenges faced by researchers include limited repertoire of antibiotic resistance of plasmids, issues related to plasmid compatibility and restricted or incompatible multiple cloning sites when needing to change plasmid copy number to tune production of their protein of interest. In this study, a series of plasmids were generated with compatible multiple cloning sites and homologous DNA regions to allow for modular cloning for rapid exchange of antibiotic resistance and plasmid origin. Plasmids generated in this series have options for high, mid, and low plasmid copy number, and have either an integrated FLAG epitope in the multiple cloning site or possess an uninterrupted multiple cloning site with the option of using the common LacZ-based blue/white screening method. Low copy plasmids also have one of five antibiotic selection markers. To demonstrate functionality of these plasmids, a representative FLAG tagged protein and mCherry were cloned into the low copy plasmids and expressed in various bacteria belonging to the Enterobacteriaceae family. In conclusion, by creating a new plasmid series, we have expanded the toolkit of available molecular biology tools for bacterial work.Item The Genetic Absence Epilepsy Rats from Strasbourg model of absence epilepsy exhibits alterations in fear conditioning and latent inhibition consistent with psychiatric comorbidities in humans(Wiley, 2016) Marks, Wendie; Cavanagh, Mary; Greba, Quentin; Cain, Stuart; Snutch, Terrance; Howland, John G.Item Maternal immune activation during pregnancy in rats impairs working memory capacity of the offspring(Elsevier, 2017) Murray, Brendan; Davies, Don; Molder, Joel; Howland, John G.Item NMDA receptors in visual and olfactory sensory integration in male Long Evans rats: a role for the orbitofrontal cortex(2020) Sandini, Thaisa; Marks, Wendie; Tahir, Nimra; Song, Yen; Greba, Quentin; Howland, JohnItem Performance of the odour span task is not impaired following inactivations of parietal cortex in rats(2018) Scott, Gavin; Zabder, Nadine; Greba, Quentin; Howland, JohnItem Performance of the trial-unique, delayed non-matching-to-location (TUNL) task depends on AMPA/Kainate, but not NMDA, ionotropic glutamate receptors in the rat posterior parietal cortex(Elsevier, 2019) Scott, Gavin; Roebuck, Andrew; Greba, Quentin; Howland, John G.Item Sex differences in exploratory behavior of rats successfully performing the object-in-place recognition memory test(Behavioural Brain Research, 2024-10) McElroy, Dan L.; Howland, JohnMale and female rodents display unique search strategies when exploring new and familiar environments. Sex differences are well-documented in the literature and may be observed in tasks that rely on spontaneous exploration (e.g., recognition memory tests). Therefore, we assessed patterns of male and female rat behavior in the object-in-place (OiP) test, a common recognition memory paradigm involving object-location associations. Twelve male and 12 female adult Long Evans rats were tested four times in the 1-h OiP test and exploratory behaviors were compared during habituation, sample, and test phases. Results revealed that females moved faster and farther than males, showed increased immobility frequency and reduced immobility duration, reduced outer zone mobility duration, and increased inner zone entrances, compared to males during habituations. During sample phases, female rats moved faster than males, displayed reduced immobility frequency in the inner zone, and demonstrated consistent distance travelled across repeated sessions; conversely, male rats moved less in later sessions and exhibited increased mobility frequency in the outer zone. Analyses comparing test phase behavior revealed females continued to move faster than males; however, no other sex differences were observed. These findings are consistent with previous literature highlighting unique sex differences in explorative behaviors during recognition testing. Sex differences in locomotion and mobility state behaviors may be more indicative of individual motivation and search strategy between the sexes and less indicative of recognition memory.Item Sociability impairments in Genetic Absence Epilepsy Rats from Strasbourg: Reversal by the T-type calcium channel antagonist Z944(Elsevier, 2017) Henbid, Mark; Marks, Wendie; Collins, Madeline; Cain, Stuart; Snutch, Terrance; Howland, John G.Item Synaptic plasticity in learning and memory: stress effects in the hippocampus(Elsevier, 2008) Wang, Yu Tian; Howland, JohnItem The T-type calcium channel antagonist Z944 disrupts prepulse inhibition in both epileptic and non-epileptic rats(Elsevier, 2016) Marks, Wendie; Greba, Quentin; Cain, Stuart; Snutch, Terrance; Howland, John G.Item The T-type calcium channel antagonist Z944 rescues impairments in crossmodal and visual recognition memory in Genetic Absence Epilepsy Rats from Strasbourg(Elsevier, 2016) Marks, Wendie; Cain, Stuart; Snutch, Terrance; Howland, John G.