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Item 445 The effects of dietary fiber based on fermentability and viscosity on phosphorus absorption and the gut microbiome in chronic kidney disease-mineral and bone disorder(Cambridge University Press, 2023-04-24) Biruete, Annabel; Chen, Neal X.; Srinivasan, Shruthi; O'Neill, Kalisha; Nelson, David; Hill Gallant, Kathleen M.; Moe, Sharon M.; Medicine, School of MedicineOBJECTIVES/GOALS: To compare the effects of dietary fiber supplementation based on fermentability and viscosity on phosphorus fractional absorption and the gut microbiome in a rat model of chronic kidney disease-mineral and bone disorder (CKD-MBD). METHODS/STUDY POPULATION: 25-week-old Cy/+ male rats (CKD hereafter) will be randomly assigned to receive one of four fiber treatments (10% w/w each) based on fermentability and viscosity: 1) Cellulose (-fermentability, -viscosity), 2) inulin (+fermentability, -viscosity), 3) psyllium husk (-fermentability, +viscosity), or 4) pectin (+ fermentability, +viscosity). Diets will be formulated with a semipurified diet containing 0.7% phosphorus. Treatments will last for 10 weeks, and rats will be euthanized at 35 weeks of age, where animals have reached kidney failure. Intravenous and oral 33P will be used for intestinal phosphorus fractional absorption and cecal/fecal samples will be obtained at euthanasia for microbiome assessment using shotgun metagenomics. RESULTS/ANTICIPATED RESULTS: Our preliminary data show that fermentable dietary fiber (inulin) impacted phosphorus homeostasis by increasing the circulating levels of fibroblast growth factor-23 (a bone-derived hormone that increases phosphorus excretion in urine) and lowering circulating levels of phosphorus in the Cy/+ male rat model of progressive chronic kidney disease. We hypothesize that dietary fiber impacts phosphorus absorption in gut microbiome-dependent and independent mechanisms. For example, fermentable fiber enhances the production of short-chain fatty acids, lowering the intraluminal pH, and enhancing mineral solubility and absorption. Meanwhile, viscous fibers may encapsulate minerals limiting their absorption if these fibers are non-fermentable. DISCUSSION/SIGNIFICANCE: Hyperphosphatemia, or high circulating phosphorus, is a major factor in the pathogenesis of CKD-MBD. Treatment of hyperphosphatemia is focused on reducing intestinal absorption. However, available therapies vary in their efficacy and focus on phosphorus absorption in the small intestine, ignoring the possible impact of the large intestine.Item Decreased microbial co-occurrence network stability and SCFA receptor level correlates with obesity in African-origin women(Nature Research, 2018-11-20) Dugas, Lara R.; Bernabé, Beatriz Peñalver; Priyadarshini, Medha; Fei, Na; Park, Seo Jin; Brown, Laquita; Plange-Rhule, Jacob; Nelson, David; Toh, Evelyn C.; Gao, Xiang; Dong, Qunfeng; Sun, Jun; Kliethermes, Stephanie; Gottel, Neil; Luke, Amy; Gilbert, Jack A.; Layden, Brian T.; Microbiology and Immunology, School of MedicineWe compared the gut microbial populations in 100 women, from rural Ghana and urban US [50% lean (BMI < 25 kg/m2) and 50% obese (BMI ≥ 30 kg/m2)] to examine the ecological co-occurrence network topology of the gut microbiota as well as the relationship of short chain fatty acids (SCFAs) with obesity. Ghanaians consumed significantly more dietary fiber, had greater microbial alpha-diversity, different beta-diversity, and had a greater concentration of total fecal SCFAs (p-value < 0.002). Lean Ghanaians had significantly greater network density, connectivity and stability than either obese Ghanaians, or lean and obese US participants (false discovery rate (FDR) corrected p-value ≤ 0.01). Bacteroides uniformis was significantly more abundant in lean women, irrespective of country (FDR corrected p < 0.001), while lean Ghanaians had a significantly greater proportion of Ruminococcus callidus, Prevotella copri, and Escherichia coli, and smaller proportions of Lachnospiraceae, Bacteroides and Parabacteroides. Lean Ghanaians had a significantly greater abundance of predicted microbial genes that catalyzed the production of butyric acid via the fermentation of pyruvate or branched amino-acids, while obese Ghanaians and US women (irrespective of BMI) had a significantly greater abundance of predicted microbial genes that encoded for enzymes associated with the fermentation of amino-acids such as alanine, aspartate, lysine and glutamate. Similar to lean Ghanaian women, mice humanized with stool from the lean Ghanaian participant had a significantly lower abundance of family Lachnospiraceae and genus Bacteroides and Parabacteroides, and were resistant to obesity following 6-weeks of high fat feeding (p-value < 0.01). Obesity-resistant mice also showed increased intestinal transcriptional expression of the free fatty acid (Ffa) receptor Ffa2, in spite of similar fecal SCFAs concentrations. We demonstrate that the association between obesity resistance and increased predicted ecological connectivity and stability of the lean Ghanaian microbiota, as well as increased local SCFA receptor level, provides evidence of the importance of robust gut ecologic network in obesity.Item Fecal bile acids, fecal short-chain fatty acids, and the intestinal microbiota in patients with irritable bowel syndrome (IBS) and control volunteers(Cambridge University Press, 2018-06) Shin, Andrea; Nelson, David; Wo, John; Camilleri, Michael; James-Stevenson, Toyia; Siwiec, Robert; Bohm, Matthew; Gupta, Anita; Medicine, School of MedicineOBJECTIVES/SPECIFIC AIMS: Objectives and goals of this study will be to: (1) compare fecal microbiota and fecal organic acids in irritable bowel syndrome (IBS) patients and controls and (2) investigate the association between colonic transit and fecal microbiota in IBS patients and controls. METHODS/STUDY POPULATION: We propose an investigation of fecal organic acids, colonic transit and fecal microbiota in 36 IBS patients and 18 healthy controls. The target population will be adults ages 18–65 years meeting Rome IV criteria for IBS (both diarrhea- and constipation-predominant, IBS-D and IBS-C) and asymptomatic controls. Exclusion criteria are: (a) history of microscopic colitis, inflammatory bowel disease, celiac disease, visceral cancer, chronic infectious disease, immunodeficiency, uncontrolled thyroid disease, liver disease, or elevated AST/ALT>2.0× the upper limit of normal, (b) prior radiation therapy of the abdomen or abdominal surgeries with the exception of appendectomy or cholecystectomy >6 months before study initiation, (c) ingestion of prescription, over the counter, or herbal medications affecting gastrointestinal transit or study interpretation within 6 months of study initiation for controls or within 2 days before study initiation for IBS patients, (d) pregnant females, (e) antibiotic usage within 3 months before study participation, (f) prebiotic or probiotic usage within the 2 weeks before study initiation, (g) tobacco users. Primary outcomes will be fecal bile acid excretion and profile, short-chain fatty acid excretion and profile, colonic transit, and fecal microbiota. Secondary outcomes will be stool characteristics based on responses to validated bowel diaries. Stool samples will be collected from participants during the last 2 days of a 4-day 100 g fat diet and split into 3 samples for fecal microbiota, SCFA, and bile acid analysis and frozen. Frozen aliquots will be shipped to the Metabolite Profiling Facility at Purdue University and the Mayo Clinic Department of Laboratory Medicine and Pathology for SCFA and bile acid measurements, respectively. Analysis of fecal microbiota will be performed in the research laboratory of Dr David Nelson in collaboration with bioinformatics expertise affiliated with the Nelson lab. Colonic transit time will be measured with the previously validated method using radio-opaque markers. Generalized linear models will be used as the analysis framework for comparing study endpoints among groups. RESULTS/ANTICIPATED RESULTS: This study seeks to examine the innovative concept that specific microbial signatures are associated with increased fecal excretion of organic acids to provide unique insights on a potential mechanistic link between altered intraluminal organic acids and fecal microbiota. DISCUSSION/SIGNIFICANCE OF IMPACT: Results may lead to development of targets for novel therapies and diagnostic biomarkers for IBS, emphasizing the role of the fecal metabolome.Item Identifying Factors Controlling Cell Shape and Virulence Gene Expression in Borrelia Burgdorferi(2019-08) Grothe, Amberly Nicole; Yang, X. Frank; Gilk, Stacey; Nelson, DavidLyme disease is a multi-system inflammatory disorder that is currently the fastest growing arthropod-borne disease in the United States. The Lyme disease pathogen, Borrelia burgdorferi, exists within an enzootic cycle consisting of Ixodes tick vectors and a variety of vertebrate hosts. Borrelia lies within a distinct clade of microorganisms known as spirochetes which exhibit a unique spiral morphology. The underlying genetic mechanisms controlling for borrelial morphologies are still being discovered. One flagellar protein, FlaB, has been indicated to affect both spiral shape and motility of the organisms and significantly impacts the organism’s ability to establish infection. Due to the potential connection between morphological characteristics and pathogenesis, we sought to screen and identify morphological mutants in an attempt to identify genes associated with morphological phenotypes of Borrelia burgdorferi. Among Borrelia’s unique features is the presence of abundant lipoproteins making up its cellular membrane as opposed to the typical lipopolysaccharides. These proteins confer a wide variety of functions to the microorganism, among which include the abilities to circulate between widely differing hosts and to establish infection. Two important outer surface proteins, OspC and OspA, are found to be inversely expressed throughout the borrelial life cycle. OspC, in particular, becomes highly expressed during tick-feeding and transmission to the mammalian host. It has been found to be essential for establishment of infection. A global regulatory pathway has been shown to control for OspC, however there are missing links in this pathway between the external stimuli (such as temperature, pH, and cell density) and the regulatory pathway. We have performed a screening process to identify OspC expression mutants in order to identify novel genes associated with this pathway.Item Proceedings of the 8th Annual Conference on the Science of Dissemination and Implementation(BioMed Central, 2016-08-01) Chambers, David; Simpson, Lisa; Hill-Briggs, Felicia; Neta, Gila; Vinson, Cynthia; Beidas, Rinad; Marcus, Steven; Aarons, Gregory; Hoagwood, Kimberly; Schoenwald, Sonja; Evans, Arthur; Hurford, Matthew; Rubin, Ronnie; Hadley, Trevor; Barg, Frances; Walsh, Lucia; Adams, Danielle; Mandell, David; Martin, Lindsey; Mignogna, Joseph; Mott, Juliette; Hundt, Natalie; Kauth, Michael; Kunik, Mark; Naik, Aanand; Cully, Jeffrey; McGuire, Alan; White, Dominique; Bartholomew, Tom; McGrew, John H.; Luther, Lauren; Rollins, Angie; Salyers, Michelle P.; Cooper, Brittany; Funaiole, Angie; Richards, Julie; Lee, Amy; Lapham, Gwen; Caldeiro, Ryan; Lozano, Paula; Gildred, Tory; Achtmeyer, Carol; Ludman, Evette; Addis, Megan; Marx, Larry; Bradley, Katharine; VanDeinse, Tonya; Wilson, Amy Blank; Stacey, Burgin; Powell, Byron; Bunger, Alicia; Cuddeback, Gary; Barnett, Miya; Stadnick, Nicole; Brookman-Frazee, Lauren; Lau, Anna; Dorsey, Shannon; Pullmann, Michael; Mitchell, Shannon; Schwartz, Robert; Kirk, Arethusa; Dusek, Kristi; Oros, Marla; Hosler, Colleen; Gryczynski, Jan; Barbosa, Carolina; Dunlap, Laura; Lounsbury, David; O'Grady, Kevin; Brown, Barry; Damschroder, Laura; Waltz, Thomas; Powell, Byron; Ritchie, Mona; Waltz, Thomas; Atkins, David; Imel, Zac E.; Xiao, Bo; Can, Doğan; Georiou, Panayiotis; Narayanan, Shrikanth; Berkel, Cady; Gallo, Carlos; Sandler, Irwin; Brown, C. Hendricks; Wolcik, Sharlene; Mauricio, Anne Marie; Gallo, Carlos; Mehrota, Sanjay; Chandurkar, Dharmendra; Bora, Siddhartha; Das, Arup; Tripathi, Anand; Saggurti, Nirajan; Raj, Anita; Hughes, Eric; Jacobs, Brian; Kirkendall, Eric; Loeb, Danielle; Trinkley, Katy; Yang, Michael; Sprowell, Andrew; Nease, Donald; Lyon, Aaron; Lewis, Cara; Boyd, Meredith; Melvin, Abigail; Nicodimos, Semret; Liu, Freda; Jungbluth, Nathanial; Lyon, Aaron; Landis-Lewis, Zach; Sales, Anne; Baloh, Jure; Ward, Marcia; Zhu, Xi; Bennett, Ian; Unutzer, Jurgen; Mao, Johnny; Proctor, Enola; Vredevoogd, Mindy; Chan, Ya-Fen; Williams, Nathaniel; Green, Phillip; Bernstein, Steven; Rosner, June-Marie; DeWitt, Michelle; Tetrault, Jeanette; Dziura, James; Hsiao, Allen; Sussman, Scott; O'Connor, Patrick; Toll, Benjamin; Jones, Michael; Gassaway, Julie; Tobin, Jonathan; Zatzick, Douglas; Bradbury, Angela R.; Patrick-Miller, Linda; Egleston, Brian; Olopade, Olufunmilayo I.; Hall, Michael J.; Daly, Mary B.; Fleisher, Linda; Grana, Generosa; Ganschow, Pamela; Fetzer, Dominique; Brandt, Amanda; Farengo-Clark, Dana; Forman, Andrea; Gaber, Rikki S.; Gulden, Cassandra; Horte, Janice; Long, Jessica; Chambers, Rachelle Lorenz; Lucas, Terra; Madaan, Shreshtha; Mattie, Kristin; McKenna, Danielle; Montgomery, Susan; Nielsen, Sarah; Powers, Jacquelyn; Rainey, Kim; Rybak, Christina; Savage, Michelle; Seelaus, Christina; Stoll, Jessica; Stopfer, Jill; Yao, Shirley; Domchek, Susan; Hahn, Erin; Munoz-Plaza, Corrine; Wang, Jianjin; Delgadillo, Jazmine Garcia; Mittman, Brian; Gould, Michael; Liang, Shuting (Lily); Kegler, Michelle C.; Cotter, Megan; Philips, Emily; Hermstad, April; Morton, Rentonia; Beasley, Derrick; Martinez, Jeremy; Riehman, Kara; Gustafson, David; Marsch, Lisa; Mares, Louise; Quanbeck, Andrew; McTavish, Fiona; McDowell, Helene; Brown, Randall; Thomas, Chantelle; Glass, Joseph; Isham, Joseph; Shah, Dhavan; Liebschutz, Jane; Lasser, Karen; Watkins, Katherine; Ober, Allison; Hunter, Sarah; Lamp, Karen; Ewing, Brett; Iwelunmor, Juliet; Gyamfi, Joyce; Blackstone, Sarah; Quakyi, Nana Kofi; Plange-Rhule, Jacob; Ogedegbe, Gbenga; Kumar, Pritika; Devanter, Nancy Van; Nguyen, Nam; Nguyen, Linh; Nguyen, Trang; Phuong, Nguyet; Shelley, Donna; Rudge, Sian; Langlois, Etienne; Tricco, Andrea; Ball, Sherry; Lambert-Kerzner, Anne; Sulc, Christine; Simmons, Carol; Shell-Boyd, Jeneen; Oestreich, Taryn; O'Connor, Ashley; Neely, Emily; McCreight, Marina; Labebue, Amy; DiFiore, Doreen; Brostow, Diana; Ho, P. Michael; Aron, David; Harvey, Jillian; McHugh, Megan; Scanon, Dennis; Lee, Rebecca; Soltero, Erica; Parker, Nathan; McNeill, Lorna; Ledoux, Tracey; McIsaac, Jessie-Lee; MacLeod, Kate; Ata, Nicole; Jarvis, Sherry; Kirk, Sara; Purtle, Jonathan; Dodson, Elizabeth; Brownson, Ross; Mittman, Brian; Curran, Geoffrey; Pyne, Jeffrey; Aarons, Gregory; Ehrhart, Mark; Torres, Elisa; Miech, Edward; Stevens, Kathleen; Hamilton, Alison; Cohen, Deborah; Padgett, Deborah; Morshed, Alexandra; Patel, Rupa; Prusaczyk, Beth; Aron, David C.; Gupta, Divya; Ball, Sherry; Hand, Rosa; Abram, Jenica; Wolfram, Taylor; Hastings, Molly; Moreland-Russell, Sarah; Tabek, Rachel; Ramsey, Alex; Baumann, Ana; Kryzer, Emily; Montgomery, Katherine; Lewis, Ericka; Padek, Margaret; Brownson, Ross; Mamaril, Cezar Brian; Mays, Glen; Branham, Keith; Timsina, Lava; Mays, Glen; Hogg, Rachel; Fagan, Abigail; Shapiro, Valerie; Brown, Eric; Haggerty, Kevin; Hawkins, David; Oesterle, Sabrina; Hawkins, David; Catalano, Richard; McKay, Virginia; Dolcini, M. Margaret; Hoffer, Lee; Moin, Tannaz; Li, Jinnan; Duru, O. Kenrik; Ettner, Susan; Turk, Norman; Chan, Charles; Keckhafer, Abigail; Luchs, Robert; Ho, Sam; Mangione, Carol; Selby, Peter; Zawertailo, Laurie; Minian, Nadia; Balliunas, Dolly; Dragonetti, Rosa; Hussain, Sarwar; Lecce, Julia; Chinman, Matthew; Acosta, Joie; Ebener, Patricia; Malone, Patrick S.; Slaughter, Mary; Freedman, Darcy; Flocke, Susan; Lee, Eunlye; Matlack, Kristen; Trapl, Erika; Ohri-Vachaspati, Punam; Taggart, Morgan; Borawski, Elaine; Parrish, Amanda; Harris, Jeffrey; Kohn, Marlana; Hammerback, Kristen; McMilan, Becca; Hannon, Peggy; Swindle, Taren; Curran, Geoffrey; Whiteside-Mansell, Leanne; Ward, Wendy; Holt, Cheryl; Santos, Sheri Lou; Tagai, Erin; Scheirer, Mary Ann; Carter, Roxanne; Bowie, Janice; Haider, Muhiuddin; Slade, Jimmie; Wang, Min Qi; Masica, Andrew; Ogola, Gerald; Berryman, Candice; Richter, Kathleen; Shelton, Rachel; Jandorf, Lina; Erwin, Deborah; Truong, Khoa; Javier, Joyce R.; Coffey, Dean; Schrager, Sheree; Palinkas, Lawrence; Miranda, Jeanne; Johnson, Veda; Hutcherson, Valerie; Ellis, Ruth; Kharmats, Anna; Marshall-King, Sandra; LaPradd, Monica; Fonseca-Becker, Fannie; Kepka, Deanna; Bodson, Julia; Warner, Echo; Fowler, Brynn; Shenkman, Elizabeth; Hogan, William; Odedina, Folakami; Leon, Jessica De; Hooper, Monica; Carrasquillo, Olveen; Reams, Renee; Hurt, Myra; Smit, Steven; Szapocznik, Jose; Nelson, David; Mandal, Prabir; Teufel, James; Department of Psychology, School of ScienceItem Recruitment and function of ORP1L on the Coxiella burnetii parasitophorous vacuole(2017-12-07) Justis, Anna Victoria; Gilk, Stacey D.; Spinola, Stanley M.; Nelson, David; Arrizabalaga, Gustavo A.; Harrington, Maureen A.Coxiella burnetii, the zoonotic agent of human Q fever and chronic endocarditis, is an obligate intracellular bacterial pathogen. The Coxiella intracellular niche, a large, lysosome-like parasitophorous vacuole (PV), is essential for bacterial survival and replication. There is growing evidence that host cell cholesterol trafficking plays a critical role in PV development and maintenance, prompting an examination of the role of cholesterol-binding host protein ORP1L (Oxysterol binding protein-Related Protein 1, Long) during infection. ORP1L is a multi-functional cholesterol-binding protein involved in late endosome/lysosome (LEL) trafficking, formation of membrane contact sites between LEL and the endoplasmic reticulum (ER), and cholesterol transfer from LEL to the ER. ORP1L localizes to the PV at novel membrane contact sites between the ER and the PV membrane. Ectopically expressed ORP1L in Coxiella-infected cells localizes to the PV membrane early during infection, before significant PV expansion and independent of other PV-localized proteins. Further, the N-terminal ORP1L Ankyrin repeats are both necessary and sufficient for PV localization, suggesting that protein-protein interactions, and not protein-lipid interactions, are primarily involved in PV association. Coxiella employs a Type IVB Secretion System (T4BSS) to translocate effector proteins into the host cytoplasm and manipulate various cellular functions. ORP1L is not found on the PV of a Coxiella mutant lacking a functional T4BSS, indicating a secreted bacterial protein is likely responsible for ORP1L recruitment. We identified a Coxiella mutant with a transposon insertion in CBU_0352 that exhibits a 50% decrease in ORP1L recruitment, suggesting that Coxiella CBU_0352 interacts directly or indirectly with ORP1L. Finally, we found that ORP1L depletion using siRNA alters PV dynamics, resulting in smaller yet more fusogenic Coxiella PVs. Together, these data suggest that ORP1L is specifically recruited to the PV, where it plays a novel role in Coxiella PV development and interactions between the PV and the host cell.Item Risk factors associated with upper aerodigestive tract or coliform bacterial overgrowth of the small intestine in symptomatic patients(Wolters Kluwer, 2020-02) Bohm, Matthew; Shin, Andrea; Teagarden, Sean; Xu, Huiping; Gupta, Anita; Siwiec, Robert; Nelson, David; Wo, John M.; Biostatistics, School of Public HealthIntroduction: The clinical relevance of bacterial types identified in small bowel aspirate cultures during diagnostic evaluation of small intestinal bacterial overgrowth (SIBO) is unclear. Aim: The main purpose of this study was to assess associations between risk factors for upper aerodigestive tract (UAT) or coliform SIBO and SIBO diagnosis by culture. Materials and methods: Small bowel aspirates were cultured in patients with suspected SIBO, defined as ≥10 colony-forming units/mL coliform or ≥10 colony-forming units/mL UAT bacteria. History was reviewed for risk factors and potential SIBO complications. Symptoms, quality of life, psychological traits, and laboratory values were assessed. We compared groups by 2-sample t test, Wilcoxon rank sum test, and the Fisher exact test. Overall associations of primary and secondary endpoints with type of bacterial overgrowth were assessed by analysis of variance F-test, Kruskal-Wallis test, and the Fisher exact tests. Associations of risk factors with type of overgrowth were explored using multinomial logistic regression. Results: Among 76 patients, 37 had SIBO (68% coliform, 33% UAT) and 39 did not. Conditions (P=0.02) and surgery (P<0.01) associated with decreased gastric acid were associated with SIBO. In multinomial logistic regression, conditions of decreased acid was associated with UAT SIBO [odds ratio (OR), 5.8; 95% confidence interval, 1.4-33.3]. Surgery causing decreased acid was associated with UAT [OR, 9.5 (1.4-106)] and coliform SIBO [OR, 8.4 (1.6-86.4)]. Three patients with discontinuous small bowel had coliform SIBO [OR, 17.4 (1.2-2515)]. There were no differences in complications, overall symptoms, quality of life, or psychological traits. Conclusions: Conditions or surgeries associated with decreased gastric acid are associated with SIBO diagnosis by culture.Item Role of a putative bacterial lipoprotein in Pseudomonas aeruginosa-mediated cytotoxicity toward airway cells(2014) Akhand, Saeed Salehin; Anderson, Gregory G.; Chang, Hua-Chen; Nelson, David; Atkinson, SimonThe patients with Cystic fibrosis (CF), an inherent genetic disorder, suffer from chronic bacterial infection in the lung. In CF, modification of epithelial cells leads to alteration of the lung environment, such as inhibition of ciliary bacterial clearance and accumulation of thickened mucus in the airways. Exploiting these conditions, opportunistic pathogens like Pseudomonas aeruginosa cause lifelong persistent infection in the CF lung by forming into antibiotic-resistant aggregated communities called biofilms. Airway infections as well as inflammation are the two major presentations of CF lung disease. P. aeruginosa strains isolated from CF lungs often contain mutations in the mucA gene, and this mutation results in higher level expression of bacterial polysaccharides and toxic lipoproteins. In a previous work, we have found a putative lipoprotein gene (PA4326) which is overexpressed in antibiotic-induced biofilm formed on cultured CF-derived airway cells. In the current work, we speculated that this particular putative lipoprotein affects cellular cytotoxicity and immune-stimulation in the epithelial cells. We found that mutation of this gene (ΔPA4326) results in reduced airway cell killing without affecting other common virulence factors.Moreover, we observed that this gene was able to stimulate secretion of the proinflammatory cytokine IL-8 from host cells. Interestingly, we also found that ΔPA4326 mutant strains produced less pyocyanin exotoxin compared to the wild type. Furthermore, our results suggest that PA4326 regulates expression of the pyocyanin biosynthesis gene phzM, leading to the reduced pyocyanin phenotype. Overall, these findings implicate PA4326 as a virulence factor in Pseudomonas aeruginosa. In the future, understating the molecular interplay between the epithelial cells and putative lipoproteins like PA4326 may lead to development of novel anti-inflammatory therapies that would lessen the suffering of CF patients.Item The Role of Chlamydia Protein TC0600 in Gastrointestinal Tract Infection(2021-12) Alrebdi, Waleed; Nelson, David; Bauer, Margaret; Yang, X. FrankChlamydia is the most frequently reported bacterial sexually transmitted infection in the world. Most urogenital chlamydia infections in men and women are asymptomatic, but these infections can lead to irreparable damage in the reproductive system and other tissues. Apart from the urogenital chlamydial infections, we know that chlamydia infects the gastrointestinal tract (GIT) in humans and can colonize the GIT for extended intervals without eliciting pathology. We are interested in investigating tissue tropism determinants in Chlamydia spp. because these could be targeted to development live-attenuated vaccines. Recently, we generated mutagenized isolates of the mouse pathogen Chlamydia muridarum, a close relative of the human pathogen Chlamydia trachomatis which causes chlamydia. One mutant that we isolated is significantly attenuated in murine gastrointestinal tissues compared to wild type, but retains its pathogenicity in the murine urogenital tract. Using novel genetic techniques, whole-genome sequencing, and complementation using newly developed vector systems we identified a chromosomal factor, tc0600, that we believe mediates the altered tissue tropism phenotype of this mutant in mice. Notably, the Chlamydia trachomatis ortholog of tc0600 has been linked to chlamydial GIT tropism in humans.Item Traumatic brain injury: progress and challenges in prevention, clinical care, and research(Elsevier, 2022) Maas, Andrew I. R.; Menon, David K.; Manley, Geoffrey T.; Abrams, Mathew; Åkerlund, Cecilia; Andelic, Nada; Aries, Marcel; Bashford, Tom; Bell, Michael J.; Bodien, Yelena G.; Brett, Benjamin L.; Büki, András; Chesnut, Randall M.; Citerio, Giuseppe; Clark, David; Clasby, Betony; Cooper, D. Jamie; Czeiter, Endre; Czosnyka, Marek; Dams-O'Connor, Kristen; De Keyser, Véronique; Diaz-Arrastia, Ramon; Ercole, Ari; van Essen, Thomas A.; Falvey, Éanna; Ferguson, Adam R.; Figaji, Anthony; Fitzgerald, Melinda; Foreman, Brandon; Gantner, Dashiell; Gao, Guoyi; Giacino, Joseph; Gravesteijn, Benjamin; Guiza, Fabian; Gupta, Deepak; Gurnell, Mark; Haagsma, Juanita A.; Hammond, Flora M.; Hawryluk, Gregory; Hutchinson, Peter; van der Jagt, Mathieu; Jain, Sonia; Jain, Swati; Jiang, Ji-Yao; Kent, Hope; Kolias, Angelos; Kompanje, Erwin J. O.; Lecky, Fiona; Lingsma, Hester F.; Maegele, Marc; Majdan, Marek; Markowitz, Amy; McCrea, Michael; Meyfroidt, Geert; Mikolić, Ana; Mondello, Stefania; Mukherjee, Pratik; Nelson, David; Nelson, Lindsay D.; Newcombe, Virginia; Okonkwo, David; Orešič, Matej; Peul, Wilco; Pisică, Dana; Polinder, Suzanne; Ponsford, Jennie; Puybasset, Louis; Raj, Rahul; Robba, Chiara; Røe, Cecilie; Rosand, Jonathan; Schueler, Peter; Sharp, David J.; Smielewski, Peter; Stein, Murray B.; von Steinbüchel, Nicole; Stewart, William; Steyerberg, Ewout W.; Stocchetti, Nino; Temkin, Nancy; Tenovuo, Olli; Theadom, Alice; Thomas, Ilias; Torres Espin, Abel; Turgeon, Alexis F.; Unterberg, Andreas; Van Praag, Dominique; van Veen, Ernest; Verheyden, Jan; Vande Vyvere, Thijs; Wang, Kevin K. W.; Wiegers, Eveline J. A.; Williams, W. Huw; Wilson, Lindsay; Wisniewski, Stephen R.; Younsi, Alexander; Yue, John K.; Yuh, Esther L.; Zeiler, Frederick A.; Zeldovich, Marina; Zemek, Roger; InTBIR Participants and Investigators; Physical Medicine and Rehabilitation, School of MedicineTraumatic brain injury (TBI) has the highest incidence of all common neurological disorders, and poses a substantial public health burden. TBI is increasingly documented not only as an acute condition but also as a chronic disease with long-term consequences, including an increased risk of late-onset neurodegeneration. The first Lancet Neurology Commission on TBI, published in 2017, called for a concerted effort to tackle the global health problem posed by TBI. Since then, funding agencies have supported research both in high-income countries (HICs) and in low-income and middle-income countries (LMICs). In November 2020, the World Health Assembly, the decision-making body of WHO, passed resolution WHA73.10 for global actions on epilepsy and other neurological disorders, and WHO launched the Decade for Action on Road Safety plan in 2021. New knowledge has been generated by large observational studies, including those conducted under the umbrella of the International Traumatic Brain Injury Research (InTBIR) initiative, established as a collaboration of funding agencies in 2011. InTBIR has also provided a huge stimulus to collaborative research in TBI and has facilitated participation of global partners. The return on investment has been high, but many needs of patients with TBI remain unaddressed. This update to the 2017 Commission presents advances and discusses persisting and new challenges in prevention, clinical care, and research. In LMICs, the occurrence of TBI is driven by road traffic incidents, often involving vulnerable road users such as motorcyclists and pedestrians. In HICs, most TBI is caused by falls, particularly in older people (aged ≥65 years), who often have comorbidities. Risk factors such as frailty and alcohol misuse provide opportunities for targeted prevention actions. Little evidence exists to inform treatment of older patients, who have been commonly excluded from past clinical trials—consequently, appropriate evidence is urgently required. Although increasing age is associated with worse outcomes from TBI, age should not dictate limitations in therapy. However, patients injured by low-energy falls (who are mostly older people) are about 50% less likely to receive critical care or emergency interventions, compared with those injured by high-energy mechanisms, such as road traffic incidents. Mild TBI, defined as a Glasgow Coma sum score of 13–15, comprises most of the TBI cases (over 90%) presenting to hospital. Around 50% of adult patients with mild TBI presenting to hospital do not recover to pre-TBI levels of health by 6 months after their injury. Fewer than 10% of patients discharged after presenting to an emergency department for TBI in Europe currently receive follow-up. Structured follow-up after mild TBI should be considered good practice, and urgent research is needed to identify which patients with mild TBI are at risk for incomplete recovery. The selection of patients for CT is an important triage decision in mild TBI since it allows early identification of lesions that can trigger hospital admission or life-saving surgery. Current decision making for deciding on CT is inefficient, with 90–95% of scanned patients showing no intracranial injury but being subjected to radiation risks. InTBIR studies have shown that measurement of blood-based biomarkers adds value to previously proposed clinical decision rules, holding the potential to improve efficiency while reducing radiation exposure. Increased concentrations of biomarkers in the blood of patients with a normal presentation CT scan suggest structural brain damage, which is seen on MR scanning in up to 30% of patients with mild TBI. Advanced MRI, including diffusion tensor imaging and volumetric analyses, can identify additional injuries not detectable by visual inspection of standard clinical MR images. Thus, the absence of CT abnormalities does not exclude structural damage—an observation relevant to litigation procedures, to management of mild TBI, and when CT scans are insufficient to explain the severity of the clinical condition. Although blood-based protein biomarkers have been shown to have important roles in the evaluation of TBI, most available assays are for research use only. To date, there is only one vendor of such assays with regulatory clearance in Europe and the USA with an indication to rule out the need for CT imaging for patients with suspected TBI. Regulatory clearance is provided for a combination of biomarkers, although evidence is accumulating that a single biomarker can perform as well as a combination. Additional biomarkers and more clinical-use platforms are on the horizon, but cross-platform harmonisation of results is needed. Health-care efficiency would benefit from diversity in providers. In the intensive care setting, automated analysis of blood pressure and intracranial pressure with calculation of derived parameters can help individualise management of TBI. Interest in the identification of subgroups of patients who might benefit more from some specific therapeutic approaches than others represents a welcome shift towards precision medicine. Comparative-effectiveness research to identify best practice has delivered on expectations for providing evidence in support of best practices, both in adult and paediatric patients with TBI. Progress has also been made in improving outcome assessment after TBI. Key instruments have been translated into up to 20 languages and linguistically validated, and are now internationally available for clinical and research use. TBI affects multiple domains of functioning, and outcomes are affected by personal characteristics and life-course events, consistent with a multifactorial bio-psycho-socio-ecological model of TBI, as presented in the US National Academies of Sciences, Engineering, and Medicine (NASEM) 2022 report. Multidimensional assessment is desirable and might be best based on measurement of global functional impairment. More work is required to develop and implement recommendations for multidimensional assessment. Prediction of outcome is relevant to patients and their families, and can facilitate the benchmarking of quality of care. InTBIR studies have identified new building blocks (eg, blood biomarkers and quantitative CT analysis) to refine existing prognostic models. Further improvement in prognostication could come from MRI, genetics, and the integration of dynamic changes in patient status after presentation. Neurotrauma researchers traditionally seek translation of their research findings through publications, clinical guidelines, and industry collaborations. However, to effectively impact clinical care and outcome, interactions are also needed with research funders, regulators, and policy makers, and partnership with patient organisations. Such interactions are increasingly taking place, with exemplars including interactions with the All Party Parliamentary Group on Acquired Brain Injury in the UK, the production of the NASEM report in the USA, and interactions with the US Food and Drug Administration. More interactions should be encouraged, and future discussions with regulators should include debates around consent from patients with acute mental incapacity and data sharing. Data sharing is strongly advocated by funding agencies. From January 2023, the US National Institutes of Health will require upload of research data into public repositories, but the EU requires data controllers to safeguard data security and privacy regulation. The tension between open data-sharing and adherence to privacy regulation could be resolved by cross-dataset analyses on federated platforms, with the data remaining at their original safe location. Tools already exist for conventional statistical analyses on federated platforms, however federated machine learning requires further development. Support for further development of federated platforms, and neuroinformatics more generally, should be a priority. This update to the 2017 Commission presents new insights and challenges across a range of topics around TBI: epidemiology and prevention (section 1); system of care (section 2); clinical management (section 3); characterisation of TBI (section 4); outcome assessment (section 5); prognosis (Section 6); and new directions for acquiring and implementing evidence (section 7). Table 1 summarises key messages from this Commission and proposes recommendations for the way forward to advance research and clinical management of TBI.