Browsing by Subject "Biological sciences"
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Item Asparagine starvation suppresses histone demethylation through iron depletion(Elsevier, 2023-03-16) Jiang, Jie; Srivastava, Sankalp; Liu, Sheng; Seim, Gretchen; Claude, Rodney; Zhong, Minghua; Cao, Sha; Davé, Utpal; Kapur, Reuben; Mosley, Amber L.; Zhang, Chi; Wan, Jun; Fan, Jing; Zhang, Ji; Pediatrics, School of MedicineIntracellular α-ketoglutarate is an indispensable substrate for the Jumonji family of histone demethylases (JHDMs) mediating most of the histone demethylation reactions. Since α-ketoglutarate is an intermediate of the tricarboxylic acid cycle and a product of transamination, its availability is governed by the metabolism of several amino acids. Here, we show that asparagine starvation suppresses global histone demethylation. This process is neither due to the change of expression of histone-modifying enzymes nor due to the change of intracellular levels of α-ketoglutarate. Rather, asparagine starvation reduces the intracellular pool of labile iron, a key co-factor for the JHDMs to function. Mechanistically, asparagine starvation suppresses the expression of the transferrin receptor to limit iron uptake. Furthermore, iron supplementation to the culture medium restores histone demethylation and alters gene expression to accelerate cell death upon asparagine depletion. These results suggest that suppressing iron-dependent histone demethylation is part of the cellular adaptive response to asparagine starvation.Item Bibliometric and authorship trends over a 30 year publication history in two representative US sports medicine journals(Elsevier, 2020-03-31) Dynako, Joseph; Owens, Garrett W.; Loder, Randall T.; Frimpong, Tony; Gerena, Rolando Gabriel; Hasnain, Fawaz; Snyder, Dayton; Freiman, Serena; Hart, Kyle; Kacena, Melissa A.; Whipple, Elizabeth C.; Orthopaedic Surgery, School of MedicineBibliometric studies are important to understand changes and improvement opportunities in academia. This study compared bibliometric trends for two major sports medicine/arthroscopy journals, the American Journal of Sports Medicine® (AJSM®) and Arthroscopy® over the past 30 years. Trends over time and comparisons between both journals were noted for common bibliometric variables (number of authors, references, pages, citations, and corresponding author position) as well as author gender and continental origin. Appropriate statistical analyses were performed. A p < 0.001 was considered statistically significant. One representative year per decade was used. There were 814 manuscripts from AJSM® and 650 from Arthroscopy®. For AJSM® the number of manuscripts steadily increased from 86 in 1986 to 350 in 2016; for Arthroscopy® the number of manuscripts increased from 73 in 1985/1986, to 267 in 2006, but then dropped to 229 in 2016. There were significant increases in all bibliometric variables, except for the number of citations which decreased in Arthroscopy®. There were significant differences in manuscript region of origin by journal (p = 0.000002). Arthroscopy® had a greater percentage of manuscripts from Asia than AJSM® (19.3% vs 11.5%) while AJSM® had a greater percentage from North America (70.3% vs 59.2%); both journals had similar percentages from Europe (18.2% for AJSM® and 21.6% for Arthroscopy®). For AJSM® the average percentage of female first authors was 13.3%, increasing from 4.7% in 1986 to 19.3% in 2016; the average percentage of female corresponding authors was 7.3%. For Arthroscopy®, the average percentage of female first authors was 8.1%, increasing from 2.8% in 1985/1986 to 15.7% in 2016 (p = 0.00007). In conclusion, AJSM® and Arthroscopy® showed an increase in most variables analyzed. Although Arthroscopy® is climbing at a higher rate than AJSM® for female authors, AJSM® has an overall greater percentage of female authors.Item Extracellular matrix protein composition dynamically changes during murine forelimb development(Elsevier, 2024-01-09) Jacobson, Kathryn R.; Saleh, Aya M.; Lipp, Sarah N.; Tian, Chengzhe; Watson, Audrey R.; Luetkemeyer, Callan M.; Ocken, Alexander R.; Spencer, Sabrina L.; Kinzer-Ursem, Tamara L.; Calve, Sarah; Medicine, School of MedicineThe extracellular matrix (ECM) is an integral part of multicellular organisms, connecting different cell layers and tissue types. During morphogenesis and growth, tissues undergo substantial reorganization. While it is intuitive that the ECM remodels in concert, little is known regarding how matrix composition and organization change during development. Here, we quantified ECM protein dynamics in the murine forelimb during appendicular musculoskeletal morphogenesis (embryonic days 11.5-14.5) using tissue fractionation, bioorthogonal non-canonical amino acid tagging, and mass spectrometry. Our analyses indicated that ECM protein (matrisome) composition in the embryonic forelimb changed as a function of development and growth, was distinct from other developing organs (brain), and was altered in a model of disease (osteogenesis imperfecta murine). Additionally, the tissue distribution for select matrisome was assessed via immunohistochemistry in the wild-type embryonic and postnatal musculoskeletal system. This resource will guide future research investigating the role of the matrisome during complex tissue development.Item Tangent functional connectomes uncover more unique phenotypic traits(Elsevier, 2023-08-12) Abbas, Kausar; Liu, Mintao; Wang, Michael; Duong-Tran, Duy; Tipnis, Uttara; Amico, Enrico; Kaplan, Alan D.; Dzemidzic, Mario; Kareken, David; Ances, Beau M.; Harezlak, Jaroslaw; Goñi, Joaquín; Neurology, School of MedicineFunctional connectomes (FCs) containing pairwise estimations of functional couplings between pairs of brain regions are commonly represented by correlation matrices. As symmetric positive definite matrices, FCs can be transformed via tangent space projections, resulting into tangent-FCs. Tangent-FCs have led to more accurate models predicting brain conditions or aging. Motivated by the fact that tangent-FCs seem to be better biomarkers than FCs, we hypothesized that tangent-FCs have also a higher fingerprint. We explored the effects of six factors: fMRI condition, scan length, parcellation granularity, reference matrix, main-diagonal regularization, and distance metric. Our results showed that identification rates are systematically higher when using tangent-FCs across the “fingerprint gradient” (here including test-retest, monozygotic and dizygotic twins). Highest identification rates were achieved when minimally (0.01) regularizing FCs while performing tangent space projection using Riemann reference matrix and using correlation distance to compare the resulting tangent-FCs. Such configuration was validated in a second dataset (resting-state).Item TIGIT contributes to the regulation of 4-1BB and does not define NK cell dysfunction in glioblastoma(Elsevier, 2023-10-28) Lupo, Kyle B.; Torregrosa-Allen, Sandra; Elzey, Bennett D.; Utturkar, Sagar; Lanman, Nadia A.; Cohen-Gadol, Aaron A.; Slivova, Veronika; McIntosh, MacKenzie; Pollok, Karen E.; Matosevic, Sandro; Urology, School of MedicineTIGIT is a receptor on human natural killer (NK) cells. Here, we report that TIGIT does not spontaneously induce inhibition of NK cells in glioblastoma (GBM), but rather acts as a decoy-like receptor, by usurping binding partners and regulating expression of NK activating ligands and receptors. Our data show that in GBM patients, one of the underpinnings of unresponsiveness to TIGIT blockade is that by targeting TIGIT, NK cells do not lose an inhibitory signal, but gains the potential for new interactions with other, shared, TIGIT ligands. Therefore, TIGIT does not define NK cell dysfunction in GBM. Further, in GBM, TIGIT+ NK cells are hyperfunctional. In addition, we discovered that 4-1BB correlates with TIGIT expression, the agonism of which contributes to TIGIT immunotherapy. Overall, our data suggest that in GBM, TIGIT acts as a regulator of a complex network, and provide new clues about its use as an immunotherapeutic target.Item Translatomic analysis of regenerating and degenerating spinal motor neurons in injury and ALS(Elsevier, 2021-06-08) Shadrach, Jennifer L.; Stansberry, Wesley M.; Milen, Allison M.; Ives, Rachel E.; Fogarty, Elizabeth A.; Antonellis, Anthony; Pierchala, Brian A.; Anatomy and Cell Biology, School of MedicineThe neuromuscular junction is a synapse critical for muscle strength and coordinated motor function. Unlike CNS injuries, motor neurons mount robust regenerative responses after peripheral nerve injuries. Conversely, motor neurons selectively degenerate in diseases such as amyotrophic lateral sclerosis (ALS). To assess how these insults affect motor neurons in vivo, we performed ribosomal profiling of mouse motor neurons. Motor neuron-specific transcripts were isolated from spinal cords following sciatic nerve crush, a model of acute injury and regeneration, and in the SOD1G93A ALS model. Of the 267 transcripts upregulated after nerve crush, 38% were also upregulated in SOD1G93A motor neurons. However, most upregulated genes in injured and ALS motor neurons were context specific. Some of the most significantly upregulated transcripts in both paradigms were chemokines such as Ccl2 and Ccl7, suggesting an important role for neuroimmune modulation. Collectively these data will aid in defining pro-regenerative and pro-degenerative mechanisms in motor neurons.