Yu-Hua Chow, Cecilia López-Martínez, W. Conrad Liles, William A. Altemeier, Sina A. Gharib, Chi F. Hung
{"title":"Toll-interacting protein inhibits transforming growth factor beta signaling in mouse lung fibroblasts","authors":"Yu-Hua Chow, Cecilia López-Martínez, W. Conrad Liles, William A. Altemeier, Sina A. Gharib, Chi F. Hung","doi":"10.1096/fba.2023-00054","DOIUrl":"10.1096/fba.2023-00054","url":null,"abstract":"<p>Variations in the Toll-interacting protein (TOLLIP) gene have been identified in genome-wide association studies to correlate with risk of disease, mortality, and response to N-acetylcysteine therapy in idiopathic pulmonary fibrosis. Although TOLLIP is known to modulate innate immune responses, its relevance in organ fibrogenesis remains unknown. Prior work in the literature suggests TOLLIP dampens transforming growth factor beta (TGFβ) signaling in human cell lines. In this study, we examined the role of TOLLIP in mouse lung fibroblast (MLF) responses to TGFβ and in the bleomycin model of experimental lung fibrosis using <i>Tollip−/−</i> mice. We hypothesize that if TOLLIP negatively regulates TGFβ signaling, then <i>Tollip−/−</i> mouse lung fibroblasts (MLFs) would have enhanced response to TGFβ treatment, and <i>Tollip−/−</i> mice would develop increased fibrosis following bleomycin challenge. Primary MLFs were stimulated with TGFβ (1 ng/mL) for 24 h. RNA was obtained to assess global transcriptional responses by RNA-seq and markers of myofibroblast transition by qPCR. Functional assessment of TGFβ-stimulated MLFs included cell migration by scratch assay, cell proliferation, and matrix invasion through Matrigel. In the in vivo model of lung fibrosis, <i>Tollip−/−</i> mice and wild-type (WT) littermates were administered bleomycin intratracheally and assessed for fibrosis. We further examined TGFβ signaling in vivo after bleomycin injury by SMAD2, ERK1/2, and TGFβR1 Western blot. In response to TGFβ treatment, both WT and <i>Tollip−/−</i> MLFs exhibited global transcriptional changes consistent with myofibroblast differentiation. However, <i>Tollip−/−</i> MLFs showed greater number of differentially expressed genes compared to WT MLFs and greater upregulation of <i>Acta2</i> by qPCR. Functionally, <i>Tollip−/−</i> MLFs also exhibited increased migration and Matrigel invasiveness compared to WT. We found evidence of enhanced TGFβ signaling in <i>Tollip−/−</i> through SMAD2 in vitro and in vivo. <i>Tollip−/−</i> mice experienced lower survival using a standard weight-adjusted dosing without evidence of differences in fibrosis at Day 21. With adjustment of dosing for sex, no differences were observed in fibrosis at Day 21. However, <i>Tollip−/−</i> mice had greater weight loss and increased bronchoalveolar lavage fluid total protein during early resolution at Day 14 compared to WT without evidence of differences in acute lung injury at Day 7, suggesting impaired resolution of lung injury.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"6 1","pages":"12-25"},"PeriodicalIF":2.7,"publicationDate":"2023-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fba.2023-00054","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139211308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Charles J. Kim, Chanpreet Singh, Marina Kaczmarek, Madison O'Donnell, Christine Lee, Kevin DiMagno, Melody W. Young, William Letsou, Raddy L. Ramos, Michael C. Granatosky, Michael Hadjiargyrou
{"title":"Mustn1 ablation in skeletal muscle results in functional alterations","authors":"Charles J. Kim, Chanpreet Singh, Marina Kaczmarek, Madison O'Donnell, Christine Lee, Kevin DiMagno, Melody W. Young, William Letsou, Raddy L. Ramos, Michael C. Granatosky, Michael Hadjiargyrou","doi":"10.1096/fba.2023-00082","DOIUrl":"https://doi.org/10.1096/fba.2023-00082","url":null,"abstract":"<p><i>Mustn1</i>, a gene expressed exclusively in the musculoskeletal system, was shown in previous in vitro studies to be a key regulator of myogenic differentiation and myofusion. Other studies also showed <i>Mustn1</i> expression associated with skeletal muscle development and hypertrophy. However, its specific role in skeletal muscle function remains unclear. This study sought to investigate the effects of <i>Mustn1</i> in a conditional knockout (KO) mouse model in Pax7 positive skeletal muscle satellite cells. Specifically, we investigated the potential effects of <i>Mustn1</i> on myogenic gene expression, grip strength, alterations in gait, ex vivo investigations of isolated skeletal muscle isometric contractions, and potential changes in the composition of muscle fiber types. Results indicate that <i>Mustn1</i> KO mice did not present any substantial phenotypic changes or significant variations in genes related to myogenic differentiation and fusion. However, an approximately 10% decrease in overall grip strength was observed in the 2-month-old KO mice in comparison to the control wild type (WT), but this decrease was not significant when normalized by weight. KO mice also generated approximately 8% higher vertical force than WT at 4 months in the hindlimb. Ex vivo experiments revealed decreases in about 20 to 50% in skeletal muscle contractions and about 10%–20% fatigue in soleus of both 2- and 4-month-old KO mice, respectively. Lastly, immunofluorescent analyses showed a persistent increase of Type IIb fibers up to 15-fold in the KO mice while Type I fibers decreased about 20% and 30% at both 2 and 4 months, respectively. These findings suggest a potential adaptive or compensatory mechanism following <i>Mustn1</i> loss, as well as hinting at an association between <i>Mustn1</i> and muscle fiber typing. Collectively, <i>Mustn1</i>'s complex roles in skeletal muscle physiology requires further research, particularly in terms of understanding the potential role of <i>Mustn1</i> in muscle repair and regeneration, as well as with influence of exercise. Collectively, these will offer valuable insights into <i>Mustn1</i>'s key biological functions and regulatory pathways.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"5 12","pages":"541-557"},"PeriodicalIF":2.7,"publicationDate":"2023-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fba.2023-00082","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138571072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Elena Silva, Véronique Ferchaud-Roucher, Anita Kramer, Lana Madi, Priyadarshini Pantham, Stephanie Chassen, Thomas Jansson, Theresa L. Powell
{"title":"Oleic acid stimulation of amino acid uptake in primary human trophoblast cells is mediated by phosphatidic acid and mTOR signaling","authors":"Elena Silva, Véronique Ferchaud-Roucher, Anita Kramer, Lana Madi, Priyadarshini Pantham, Stephanie Chassen, Thomas Jansson, Theresa L. Powell","doi":"10.1096/fba.2023-00113","DOIUrl":"10.1096/fba.2023-00113","url":null,"abstract":"<p>Normal fetal development is critically dependent on optimal nutrient supply by the placenta, and placental amino acid transport has been demonstrated to be positively associated with fetal growth. Mechanistic target of rapamycin (mTOR) is a positive regulator of placental amino acid transporters, such as System A. Oleic acid (OA) has been previously shown to have a stimulatory role on placental mTOR signaling and System A amino acid uptake in primary human trophoblast (PHT) cells. We investigated the mechanistic link between OA and System A activity in PHT. We found that inhibition of mTOR complex 1 or 2, using small interfering RNA to knock down raptor or rictor, prevented OA-stimulated System A amino acid transport indicating the interaction of OA with mTOR. Phosphatidic acid (PA) is a key intermediary for phospholipid biosynthesis and a known regulator of the mTOR pathway; however, phospholipid biosynthetic pathways have not been extensively studied in placenta. We identified placental isoforms of acyl transferase enzymes involved in de novo phospholipid synthesis. Silencing of 1-acylglycerol-3-phosphate-O-acyltransferase-4, an enzyme in this pathway, prevented OA mediated stimulation of mTOR and System A amino acid transport. These data indicate that OA stimulates mTOR and amino acid transport in PHT cells mediated through de novo synthesis of PA. We speculate that fatty acids in the maternal circulation, such as OA, regulate placental functions critical for fetal growth by interaction with mTOR and that late pregnancy hyperlipidemia may be critical for increasing nutrient transfer to the fetus.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"6 1","pages":"1-11"},"PeriodicalIF":2.7,"publicationDate":"2023-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fba.2023-00113","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134991856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kelley L. Colvin, Robert J. Elliott, Desiree M. Goodman, Julie Harral, Edward G. Barrett, Michael E. Yeager
{"title":"Increased lethality of respiratory infection by Streptococcus pneumoniae in the Dp16 mouse model of Down syndrome","authors":"Kelley L. Colvin, Robert J. Elliott, Desiree M. Goodman, Julie Harral, Edward G. Barrett, Michael E. Yeager","doi":"10.1096/fba.2023-00091","DOIUrl":"10.1096/fba.2023-00091","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>We sought to investigate whether the Dp16 mouse model of Down syndrome (DS) is more susceptible to severe and lethal respiratory tract infection by <i>Streptococcus pneumoniae</i>.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Study Design</h3>\u0000 \u0000 <p>We infected controls and Dp16 mice with <i>Streptococcus pneumoniae</i> and measured survival rates. We compared cytokine production by primary lung cell cultures exposed to <i>Streptococcus pneumoniae</i>. We examined lung protein expression for interferon signaling related pathways. We characterized the histopathology and quantified the extent of bronchus-associated lymphoid tissue. Finally, we examined mouse tissues for the presence of oligomeric tau protein.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We found that the Dp16 mouse model of DS displayed significantly higher susceptibility to lethal respiratory infection with <i>Streptococcus pneumoniae</i> compared to control mice. Lung cells cultured from Dp16 mice displayed unique secreted cytokine profiles compared to control mice. The Dp16 mouse lungs were characterized by profound lobar pneumonia with massive diffuse consolidation involving nearly the entire lobe. Marked red hepatization was noted, and Dp16 mice lungs contained numerous bronchus-associated lymphoid tissues that were highly follicularized. Compared to uninfected mice, both control mice and Dp16 mice infected with <i>Streptococcus pneumoniae</i> showed evidence of oligomeric tau aggregates.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Increased susceptibility to severe respiratory tract infection with <i>Streptococcus pneumoniae</i> in Dp16 mice closely phenocopies infection in individuals with DS. The increase does not appear to be linked to overexpression of mouse interferon genes syntenic to human chromosome 21.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"5 12","pages":"528-540"},"PeriodicalIF":2.7,"publicationDate":"2023-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fba.2023-00091","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136104382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Antioxidants restore store-operated Ca2+ entry in patient-iPSC-derived myotubes with tubular aggregate myopathy-associated Ile484ArgfsX21 STIM1 mutation via upregulation of binding immunoglobulin protein","authors":"Fusako Sakai-Takemura, Fumiaki Saito, Ken'ichiro Nogami, Yusuke Maruyama, Ahmed Elhussieny, Kiichiro Matsumura, Shin'ichi Takeda, Yoshitsugu Aoki, Yuko Miyagoe-Suzuki","doi":"10.1096/fba.2023-00069","DOIUrl":"https://doi.org/10.1096/fba.2023-00069","url":null,"abstract":"<p>Store-operated Ca<sup>2+</sup> entry (SOCE) is indispensable for intracellular Ca<sup>2+</sup> homeostasis in skeletal muscle, and constitutive activation of SOCE causes tubular aggregate myopathy (TAM). To understand the pathogenesis of TAM, we induced pluripotent stem cells (iPSCs) from a TAM patient with a rare mutation (c.1450_1451insGA; p. Ile484ArgfsX21) in the <i>STIM1</i> gene. This frameshift mutation produces a truncated STIM1 with a disrupted C-terminal inhibitory domain (CTID) and was reported to diminish SOCE. Myotubes induced from the patient's-iPSCs (TAM myotubes) showed severely impaired SOCE, but antioxidants greatly restored SOCE partly via upregulation of an endoplasmic reticulum (ER) chaperone, BiP (GRP78), in the TAM myotubes. Our observation suggests that antioxidants are promising tools for treatment of TAM caused by reduced SOCE.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"5 11","pages":"453-469"},"PeriodicalIF":2.7,"publicationDate":"2023-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71982294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sara Raimondi, Giulia Faravelli, Paola Nocerino, Valentina Mondani, Alma Baruffaldi, Loredana Marchese, Maria Chiara Mimmi, Diana Canetti, Guglielmo Verona, Marianna Caterino, Margherita Ruoppolo, P. Patrizia Mangione, Vittorio Bellotti, Francesca Lavatelli, Sofia Giorgetti
{"title":"Human wild-type and D76N β2-microglobulin variants are significant proteotoxic and metabolic stressors for transgenic C. elegans","authors":"Sara Raimondi, Giulia Faravelli, Paola Nocerino, Valentina Mondani, Alma Baruffaldi, Loredana Marchese, Maria Chiara Mimmi, Diana Canetti, Guglielmo Verona, Marianna Caterino, Margherita Ruoppolo, P. Patrizia Mangione, Vittorio Bellotti, Francesca Lavatelli, Sofia Giorgetti","doi":"10.1096/fba.2023-00073","DOIUrl":"https://doi.org/10.1096/fba.2023-00073","url":null,"abstract":"<p>β<sub>2</sub>-microglobulin (β<sub>2</sub>-m) is a plasma protein derived from physiological shedding of the class I major histocompatibility complex (MHCI), causing human systemic amyloidosis either due to persistently high concentrations of the wild-type (WT) protein in hemodialyzed patients, or in presence of mutations, such as D76N β<sub>2</sub>-m, which favor protein deposition in the adulthood, despite normal plasma levels. Here we describe a new transgenic Caenorhabditis elegans (<i>C. elegans</i>) strain expressing human WT β<sub>2</sub>-m at high concentrations, mimicking the condition that underlies dialysis-related amyloidosis (DRA) and we compare it to a previously established strain expressing the highly amyloidogenic D76N β<sub>2</sub>-m at lower concentrations. Both strains exhibit behavioral defects, the severity of which correlates with β<sub>2</sub>-m levels rather than with the presence of mutations, being more pronounced in WT β<sub>2</sub>-m worms. β<sub>2</sub>-m expression also has a deep impact on the nematodes' proteomic and metabolic profiles. Most significantly affected processes include protein degradation and stress response, amino acids metabolism, and bioenergetics. Molecular alterations are more pronounced in worms expressing WT β<sub>2</sub>-m at high concentration compared to D76N β<sub>2</sub>-m worms. Altogether, these data show that β<sub>2</sub>-m is a proteotoxic protein in vivo also in its wild-type form, and that concentration plays a key role in modulating pathogenicity. Our transgenic nematodes recapitulate the distinctive features subtending DRA compared to hereditary β<sub>2</sub>-m amyloidosis (high levels of non-mutated β<sub>2</sub>-m vs. normal levels of variant β<sub>2</sub>-m) and provide important clues on the molecular bases of these human diseases.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"5 11","pages":"484-505"},"PeriodicalIF":2.7,"publicationDate":"2023-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72001853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Eunyoung Lee, Daedong Kim, Hyo-Deok Seo, Jeong-Hoon Hahm, Jae-Gu Seo, Sang-Nam Lee, Do-Hak Kim, Jiyun Ahn, Chang Hwa Jung
{"title":"Akkermansia muciniphila promotes testosterone-mediated hair growth inhibition in mice","authors":"Eunyoung Lee, Daedong Kim, Hyo-Deok Seo, Jeong-Hoon Hahm, Jae-Gu Seo, Sang-Nam Lee, Do-Hak Kim, Jiyun Ahn, Chang Hwa Jung","doi":"10.1096/fba.2023-00056","DOIUrl":"10.1096/fba.2023-00056","url":null,"abstract":"<p>The beneficial effects of <i>Akkermansia muciniphila</i> (<i>Akk</i>) on gut health and inflammation reduction have been demonstrated; however, scientific evidence of hair growth enhancement by <i>Akk</i> has not been reported. Therefore, this study was undertaken to investigate the effect of <i>Akk</i> on improving testosterone-mediated hair growth inhibition. Hair growth inhibition was induced through subcutaneous injection of testosterone into the shaved dorsal skin of C57BL/6 male mice. Live and pasteurized <i>Akk</i> were orally administered at a concentration of 1 × 10<sup>8</sup> colony-forming unit. After 5 weeks, hair length and skin tissues were analyzed. The live and pasteurized <i>Akk</i> significantly stimulated hair growth, countering the inhibitory effect of testosterone compared to the testosterone-alone group. Hematoxylin and eosin staining revealed a significant increase in hair follicle size in the <i>Akk</i>-treated group. An increase in β-catenin levels, which are associated with hair growth and cell cycle progression, was also observed. Moreover, the <i>Akk</i>-treated group exhibited increased levels of fibroblast growth factors, including <i>Fgf7</i>, <i>Igf1</i>, <i>Fgf7</i>, <i>Fgf10</i>, and <i>Fgf21</i>. However, no significant difference was observed between the live and pasteurized <i>Akk</i> groups. These results underscore the potential of live and pasteurized <i>Akk</i> in improving testosterone-mediated hair growth inhibition.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"5 12","pages":"521-527"},"PeriodicalIF":2.7,"publicationDate":"2023-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fba.2023-00056","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135112305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xiao Sun, Jun Kong, Shuangshan Dong, Hiroki Kato, Hiroshi Sato, Yuta Hirofuji, Yosuke Ito, Lu Wang, Takahiro A. Kato, Michiko Torio, Yasunari Sakai, Shouichi Ohga, Satoshi Fukumoto, Keiji Masuda
{"title":"TRPV4-mediated Ca2+ deregulation causes mitochondrial dysfunction via the AKT/α-synuclein pathway in dopaminergic neurons","authors":"Xiao Sun, Jun Kong, Shuangshan Dong, Hiroki Kato, Hiroshi Sato, Yuta Hirofuji, Yosuke Ito, Lu Wang, Takahiro A. Kato, Michiko Torio, Yasunari Sakai, Shouichi Ohga, Satoshi Fukumoto, Keiji Masuda","doi":"10.1096/fba.2023-00057","DOIUrl":"10.1096/fba.2023-00057","url":null,"abstract":"<p>Mutations in the gene encoding the transient receptor potential vanilloid member 4 (TRPV4), a Ca<sup>2+</sup> permeable nonselective cation channel, cause TRPV4-related disorders. TRPV4 is widely expressed in the brain; however, the pathogenesis underlying TRPV4-mediated Ca<sup>2+</sup> deregulation in neurodevelopment remains unresolved and an effective therapeutic strategy remains to be established. These issues were addressed by isolating mutant dental pulp stem cells from a tooth donated by a child diagnosed with metatropic dysplasia with neurodevelopmental comorbidities caused by a gain-of-function TRPV4 mutation, c.1855C > T (p.L619F). The mutation was repaired using CRISPR/Cas9 to generate corrected isogenic stem cells. These stem cells were differentiated into dopaminergic neurons and the pharmacological effects of folic acid were examined. In mutant neurons, constitutively elevated cytosolic Ca<sup>2+</sup> augmented AKT-mediated α-synuclein (α-syn) induction, resulting in mitochondrial Ca<sup>2+</sup> accumulation and dysfunction. The TRPV4 antagonist, AKT inhibitor, or α-syn knockdown, normalizes the mitochondrial Ca<sup>2+</sup> levels in mutant neurons, suggesting the importance of mutant TRPV4/Ca<sup>2+</sup>/AKT-induced α-syn in mitochondrial Ca<sup>2+</sup> accumulation. Folic acid was effective in normalizing mitochondrial Ca<sup>2+</sup> levels via the transcriptional repression of α-syn and improving mitochondrial reactive oxygen species levels, adenosine triphosphate synthesis, and neurite outgrowth of mutant neurons. This study provides new insights into the neuropathological mechanisms underlying TRPV4-related disorders and related therapeutic strategies.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"5 12","pages":"507-520"},"PeriodicalIF":2.7,"publicationDate":"2023-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fba.2023-00057","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136213609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Abigail M. Brown, Lindsay C. Meyers, Janani Varadarajan, Nicholas J. Ward, Jean-Philippe Cartailler, Roger G. Chalkley, Kathleen L. Gould, Kimberly A. Petrie
{"title":"From goal to outcome: Analyzing the progression of biomedical sciences PhD careers in a longitudinal study using an expanded taxonomy","authors":"Abigail M. Brown, Lindsay C. Meyers, Janani Varadarajan, Nicholas J. Ward, Jean-Philippe Cartailler, Roger G. Chalkley, Kathleen L. Gould, Kimberly A. Petrie","doi":"10.1096/fba.2023-00072","DOIUrl":"10.1096/fba.2023-00072","url":null,"abstract":"<p>Biomedical sciences PhDs pursue a wide range of careers inside and outside academia. However, there is little data regarding how career interests of PhD students relate to the decision to pursue postdoctoral training or to their eventual career outcomes. Here, we present the career goals and career outcomes of 1452 biomedical sciences PhDs who graduated from Vanderbilt University between 1997 and 2021. We categorized careers using an expanded three-tiered taxonomy and flags that delineate key career milestones. We also analyzed career goal changes between matriculation and doctoral defense, and the reasons why students became more- or less-interested in research-intensive faculty careers. We linked students' career goal at doctoral defense to whether they did a postdoc, the duration of time between doctoral defense and the first non-training position, the career area of the first non-training position, and the career area of the job at 10 years after graduation. Finally, we followed individual careers for 10 years after graduation to characterize movement between different career areas over time. We found that most students changed their career goal during graduate school, declining numbers of alumni pursued postdoctoral training, many alumni entered first non-training positions in a different career area than their goal at doctoral defense, and the career area of the first non-training position was a good indicator of the job that alumni held 10 years after graduation. Our findings emphasize that students need a wide range of career development opportunities and career mentoring during graduate school to prepare them for futures in research and research-related professions.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"5 11","pages":"427-452"},"PeriodicalIF":2.7,"publicationDate":"2023-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71479809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Wil J. Reynolds, Ndubuisi Eje, Paul Christensen, Wen-Hwa Li, Susan M. Daly, Ramine Parsa, Bhaven Chavan, Mark A. Birch-Machin
{"title":"Biological effects of air pollution on the function of human skin equivalents","authors":"Wil J. Reynolds, Ndubuisi Eje, Paul Christensen, Wen-Hwa Li, Susan M. Daly, Ramine Parsa, Bhaven Chavan, Mark A. Birch-Machin","doi":"10.1096/fba.2023-00068","DOIUrl":"10.1096/fba.2023-00068","url":null,"abstract":"<p>The World Health Organization reports that 99% of the global population are exposed to pollution levels higher than the recommended air quality guidelines. Pollution-induced changes in the skin have begun to surface; however, the effects require further investigation so that effective protective strategies can be developed. This study aimed to investigate some of the aging-associated effects caused by ozone and particulate matter (PM) on human skin equivalents. Full-thickness skin equivalents were exposed to 0.01 μg/μL PM, 0.05 μg/μL PM, 0.3 ppm ozone, or a combination of 0.01 μg/μL PM and 0.3 ppm ozone, before skin equivalents and culture medium were harvested for histological/immunohistochemical staining, gene and protein expression analysis using qPCR, Western blotting, and ELISA. Markers include MMP-1, MMP-3, <i>COL1A1</i>, collagen-I, 4-HNE, HMGCR, and PGE2. PM was observed to induce a decrease in epidermal thickness and an enhanced matrix building phenotype, with increases in <i>COL1A1</i> and an increase in collagen-I protein expression. By contrast, ozone induced an increase in epidermal thickness and was found to induce a matrix-degrading phenotype, with decreases in collagen-I gene/protein expression and increases in MMP-1 and MMP-3 gene/protein expression. Ozone was also found to induce changes in lipid homeostasis and inflammation induction. Some synergistic damage was also observed when combining ozone and 0.01 μg/μL PM. The results presented in this study identify distinct pollutant-induced effects and show how pollutants may act synergistically to augment damage; given individuals are rarely only exposed to one pollutant type, exposure to multiple pollutant types should be considered to develop effective protective interventions.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"5 11","pages":"470-483"},"PeriodicalIF":2.7,"publicationDate":"2023-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71479808","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}