Digital Commons Network^™

State-Level Macro-Economic Factors Moderate The Association Of Low Income With Brain Structure And Mental Health In U.S. Children, David G Weissman, Mark L Hatzenbuehler, Mina Cikara, Deanna M Barch, Katie A Mclaughlin

2020-Current year OA Pubs

Macrostructural characteristics, such as cost of living and state-level anti-poverty programs relate to the magnitude of socioeconomic disparities in brain development and mental health. In this study we leveraged data from the Adolescent Brain and Cognitive Development (ABCD) study from 10,633 9-11 year old youth (5115 female) across 17 states. Lower income was associated with smaller hippocampal volume and higher internalizing psychopathology. These associations were stronger in states with higher cost of living. However, in high cost of living states that provide more generous cash benefits for low-income families, socioeconomic disparities in hippocampal volume were reduced by 34%, such that …

A Narrative Inquiry Of Selected Women’S Career Pathways To State-Level Leadership In Agriculture, Timothy Keown

All Dissertations

In this study, I used a qualitative narrative inquiry to examine stories from three individually selected state-level agricultural sector women leaders as they described their career paths to leadership roles. This purpose of the study was to address the problem of a lack of practical understanding of women leaders’ experiences in pursuing, achieving, and keeping leadership roles within the agricultural industry. The existing literature shows that women are less likely to hold an agriculture leadership role in their career. To establish the research question, I used feminist educational theory. This theoretical framework and the associated epistemology of narrative inquiry served …

Urinary Tract Infections Trigger Synucleinopathy Via The Innate Immune Response, Wouter Peelaerts, Scott J Hultgren, Tom J Hannan, Et Al.

2020-Current year OA Pubs

Symptoms in the urogenital organs are common in multiple system atrophy (MSA), also in the years preceding the MSA diagnosis. It is unknown how MSA is triggered and these observations in prodromal MSA led us to hypothesize that synucleinopathy could be triggered by infection of the genitourinary tract causing ɑ-synuclein (ɑSyn) to aggregate in peripheral nerves innervating these organs. As a first proof that peripheral infections could act as a trigger in MSA, this study focused on lower urinary tract infections (UTIs), given the relevance and high frequency of UTIs in prodromal MSA, although other types of infection might also …

Sex Differences In The Inflammatory Response To Stroke, Muhammad Bilal Tariq, Juneyoung Lee, Louise D Mccullough

Faculty, Staff and Student Publications

Ischemic stroke is a leading cause of morbidity and mortality and disproportionally affects women, in part due to their higher longevity. Older women have poorer outcomes after stroke with high rates of cognitive deficits, depression, and reduced quality of life. Post-stroke inflammatory responses are also sexually dimorphic and drive differences in infarct size and recovery. Factors that influence sex-specific immune responses can be both intrinsic and extrinsic. Differences in gonadal hormone exposure, sex chromosome compliment, and environmental/social factors can drive changes in transcriptional and metabolic profiles. In addition, how these variables interact, changes across the lifespan. After the onset of …

Ros-Mediated Srms Activation Confers Platinum Resistance In Ovarian Cancer, Yunhan Jiang, Lina Song, Yizhu Lin, Pawel Nowialis, Qiongmei Gao, Tao Li, Bin Li, Xiaobo Mao, Qianqian Song, Chengguo Xing, Guangrong Zheng, Shuang Huang, Lingtao Jin

Faculty, Staff and Student Publications

Ovarian cancer is the leading cause of death among gynecological malignancies. Checkpoint blockade immunotherapy has so far only shown modest efficacy in ovarian cancer and platinum-based chemotherapy remains the front-line treatment. Development of platinum resistance is one of the most important factors contributing to ovarian cancer recurrence and mortality. Through kinome-wide synthetic lethal RNAi screening combined with unbiased datamining of cell line platinum response in CCLE and GDSC databases, here we report that Src-Related Kinase Lacking C-Terminal Regulatory Tyrosine And N-Terminal Myristylation Sites (SRMS), a non-receptor tyrosine kinase, is a novel negative regulator of MKK4-JNK signaling under platinum treatment and …

Vestigial-Like 1 (Vgll1): An Ancient Co-Transcriptional Activator Linking Wing, Placenta, And Tumor Development, Heather M Sonnemann, Barbara Pazdrak, Dinler A Antunes, Jason Roszik, Gregory Lizée

Faculty, Staff and Student Publications

Vestigial-like 1 (VGLL1) is a recently discovered driver of proliferation and invasion that is expressed in many aggressive human malignancies and is strongly associated with poor prognosis. The VGLL1 gene encodes for a co-transcriptional activator that shows intriguing structural similarity to key activators in the hippo pathway, providing important clues to its functional role. VGLL1 binds to TEAD transcription factors in an analogous fashion to YAP1 but appears to activate a distinct set of downstream gene targets. In mammals, VGLL1 expression is found almost exclusively in placental trophoblasts, cells that share many hallmarks of cancer. Due to its role as …

Exploration Of Associations Among Dietary Tryptophan, Microbiome Composition And Function, And Symptom Severity In Irritable Bowel Syndrome, Anna M Plantinga, Kendra J Kamp, Qinglong Wu, Li Chen, Linda Yoo, Robert L Burr, Kevin C Cain, Daniel Raftery, Fausto Carnevale Neto, Shyam Badu, Sik Yu So, Tor Savidge, Robert J Shulman, Margaret M Heitkemper

Faculty, Staff and Students Publications

BACKGROUND: Imbalance of the tryptophan (TRP) pathway may influence symptoms among patients with irritable bowel syndrome (IBS). This study explored relationships among different components that contribute to TRP metabolism (dietary intake, stool metabolite levels, predicted microbiome metabolic capability) in females with IBS and healthy controls (HCs). Within the IBS group, we also investigated relationships between TRP metabolic determinants, Bifidobacterium abundance, and symptoms of IBS.

METHODS: Participants with IBS (Rome III) and HCs completed a 28-day diary of gastrointestinal symptoms and a 3-day food record for TRP intake. They provided a stool sample for shotgun metagenomics, 16 S rRNA analyses, and …

Cascade Testing After Exome Sequencing: Retrospective Analysis Of Linked Family Data At 2 Us Laboratories, Julie Stefka, Haley Streff, Pengfei Liu, Meghan Towne, Hadley Stevens Smith

Faculty, Staff and Students Publications

Purpose: Cascade testing, the process of testing a proband's at-risk relatives, is integral to realizing the full value of genomic sequencing. However, there is little empirical evidence on the uptake of cascade testing after a positive exome sequencing (ES) result in a population of probands with diverse clinical indications.

Methods: We retrospectively reviewed administrative data from 2 US clinical laboratories that perform ES. For each proband with a positive ES result, we used linked family data to describe the frequency of relatives' cascade testing performed at the same laboratory, variant detection yield of cascade tests, and characteristics of probands and …

Elevated Bile Acids Are Associated With Left Ventricular Structural Changes In Biliary Atresia, Manpreet K Virk, Muhammad Umair M Mian, Dalia A Bashir, John K Wilkes, Tobias Schlingman, Saul Flores, Curtis Kennedy, Fong Lam, Ayse A Arikan, Trung Nguyen, Krupa Mysore, Nhu Thao Nguyen Galvan, Jorge Coss-Bu, Saul J Karpen, Sanjiv Harpavat, Moreshwar S Desai

Faculty, Staff and Students Publications

BACKGROUND: In children with biliary atresia (BA), pathologic structural changes within the heart, which define cirrhotic cardiomyopathy, are associated with adverse perioperative outcomes. Despite their clinical relevance, little is known about the pathogenesis and triggers of pathologic remodeling. Bile acid excess causes cardiomyopathy in experimental cirrhosis, but its role in BA is poorly understood.

METHODS: Echocardiographic parameters of left ventricular (LV) geometry [LV mass (LVM), LVM indexed to height, left atrial volume indexed to BSA (LAVI), and LV internal diameter (LVID)] were correlated with circulating serum bile acid concentrations in 40 children (52% female) with BA listed for transplantation. A …

Margetuximab In Her2-Positive Metastatic Breast Cancer, William J Gradishar, Ruth O'Regan, Mothaffar F Rimawi, Jeffrey L Nordstrom, Minori K Rosales, Hope S Rugo

Faculty, Staff and Students Publications

Several anti-HER2 agents are approved for third-line treatment and beyond (after first-line and second-line); however, no specific treatment strategy is recommended for third-line and beyond. Although these agents improve disease outcomes, HER2-positive metastatic breast cancer remains incurable and there is an unmet need for effective therapies in the later line setting. This review focuses on the development of margetuximab-cmkb, a novel, Fc-engineered, anti-HER2 monoclonal antibody, and its role in the systemic treatment of adult patients with metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 regimens, at least one of which was for metastatic disease.

Propranolol Reduces Ifn-Γ Driven Pd-L1 Immunosuppression And Improves Anti-Tumour Immunity In Ovarian Cancer, M Falcinelli, G Al-Hity, S Baron, M Mampay, M C Allen, M Samuels, W Jones, C Cilibrasi, Renee L Flaherty, G Giamas, P H Thaker, M S Flint

2020-Current year OA Pubs

The immune system plays an important role in controlling epithelial ovarian cancer (EOC). EOC is considered to be a "cold tumour," a tumour that has not triggered a strong response by the immune system. However, tumour infiltrating lymphocytes (TILs) and the expression of programmed cell death ligand (PD-L1) are used as prognostic indicators in EOC. Immunotherapy such as PD-(L)1 inhibitors have shown limited benefit in EOC. Since the immune system is affected by behavioural stress and the beta-adrenergic signalling pathway, this study aimed to explore the impact of propranolol (PRO), a beta-blocker, on anti-tumour immunity in both in vitro and …

Hica Toxin-Based Counterselection Marker For Allelic Exchange Mutations In Fusobacterium Nucleatum, Bibek Gc, Peng Zhou, Chenggang Wu

Faculty, Staff and Student Publications

The study of fusobacterial virulence factors has dramatically benefited from the creation of various genetic tools for DNA manipulation, including galK-based counterselection for in-frame deletion mutagenesis in Fusobacterium nucleatum, which was recently developed. However, this method requires a host lacking the galK gene, which is an inherent limitation. To circumvent this limitation, we explored the possibility of using the hicA gene that encodes a toxin consisting of a HicAB toxin-antitoxin module in Fusobacterium periodonticum as a new counterselective marker. Interestingly, the full-length hicA gene is not toxic in F. nucleatum, but a truncated hicA gene version lacking the first …

Interspecies Interactions Within The Host: The Social Network Of Group B Streptococcus, Marlyd E Mejia, Clare M Robertson, Kathryn A Patras

Faculty, Staff and Students Publications

Group B Streptococcus (GBS) is a pervasive neonatal pathogen accounting for a combined half a million deaths and stillbirths annually. The most common source of fetal or neonatal GBS exposure is the maternal microbiota. GBS asymptomatically colonizes the gastrointestinal and vaginal mucosa of 1 in 5 individuals globally, although its precise role in these niches is not well understood. To prevent vertical transmission, broad-spectrum antibiotics are administered to GBS-positive mothers during labor in many countries. Although antibiotics have significantly reduced GBS early-onset neonatal disease, there are several unintended consequences, including an altered neonatal microbiota and increased risk for other microbial …

Rank Is A Poor Prognosis Marker And A Therapeutic Target In Er-Negative Postmenopausal Breast Cancer, Marina Ciscar, Eva M Trinidad, Gema Perez-Chacon, Mansour Alsaleem, Maria Jimenez, Maria J Jimenez-Santos, Hector Perez-Montoyo, Adrian Sanz-Moreno, Andrea Vethencourt, Michael Toss, Anna Petit, Maria T Soler-Monso, Victor Lopez, Jorge Gomez-Miragaya, Clara Gomez-Aleza, Lacey E Dobrolecki, Michael T Lewis, Alejandra Bruna, Silvana Mouron, Miguel Quintela-Fandino, Fatima Al-Shahrour, Antonio Martinez-Aranda, Angels Sierra, Andrew R Green, Emad Rakha, Eva Gonzalez-Suarez

Faculty, Staff and Students Publications

Despite strong preclinical data, the therapeutic benefit of the RANKL inhibitor, denosumab, in breast cancer patients, beyond the bone, is unclear. Aiming to select patients who may benefit from denosumab, we hereby analyzed RANK and RANKL protein expression in more than 2,000 breast tumors (777 estrogen receptor-negative, ER- ) from four independent cohorts. RANK protein expression was more frequent in ER- tumors, where it associated with poor outcome and poor response to chemotherapy. In ER- breast cancer patient-derived orthoxenografts (PDXs), RANKL inhibition reduced tumor cell proliferation and stemness, regulated tumor immunity and metabolism, and improved response to chemotherapy. Intriguingly, tumor …

Effect Of Angiotensin-Converting Enzyme Inhibitor And Angiotensin Receptor Blocker Initiation On Organ Support-Free Days In Patients Hospitalized With Covid-19: A Randomized Clinical Trial, Patrick R Lawler, Lennie P G Derde, Frank L Van De Veerdonk, Bryan J Mcverry, David T Huang, Lindsay R Berry, Elizabeth Lorenzi, Roland Van Kimmenade, Frank Gommans, Muthiah Vaduganathan, David E Leaf, Rebecca M Baron, Edy Y Kim, Claudia Frankfurter, Slava Epelman, Yvonne Kwan, Richard Grieve, Stephen O'Neill, Zia Sadique, Michael Puskarich, John C Marshall, Alisa M Higgins, Paul R Mouncey, Kathryn M Rowan, Farah Al-Beidh, Djillali Annane, Yaseen M Arabi, Carly Au, Abi Beane, Wilma Van Bentum-Puijk, Marc J M Bonten, Charlotte A Bradbury, Frank M Brunkhorst, Aidan Burrell, Adrian Buzgau, Meredith Buxton, Maurizio Cecconi, Allen C Cheng, Matthew Cove, Michelle A Detry, Lise J Estcourt, Justin Ezekowitz, Mark Fitzgerald, David Gattas, Lucas C Godoy, Herman Goossens, Rashan Haniffa, David A Harrison, Thomas Hills, Christopher M Horvat, Nao Ichihara, Francois Lamontagne, Kelsey M Linstrum, Daniel F Mcauley, Anna Mcglothlin, Shay P Mcguinness, Zoe Mcquilten, Srinivas Murthy, Alistair D Nichol, David R J Owen, Rachael L Parke, Jane C Parker, Katrina M Pollock, Luis Felipe Reyes, Hiroki Saito, Marlene S Santos, Christina T Saunders, Christopher W Seymour, Manu Shankar-Hari, Vanessa Singh, Alexis F Turgeon, Anne M Turner, Ryan Zarychanski, Cameron Green, Roger J Lewis, Derek C Angus, Scott Berry, Anthony C Gordon, Colin J Mcarthur, Steve A Webb

Faculty, Staff and Student Publications

IMPORTANCE: Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19.

OBJECTIVE: To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19.

DESIGN, SETTING, AND PARTICIPANTS: In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non-critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022).

INTERVENTIONS: Patients were randomized to receive open-label initiation of an ACE inhibitor …

Targeting The Mevalonate Pathway Suppresses Arid1a-Inactivated Cancers By Promoting Pyroptosis, Wei Zhou, Heng Liu, Zhe Yuan, Joseph Zundell, Martina Towers, Jianhuang Lin, Simona Lombardi, Hao Nie, Brennah Murphy, Tyler Yang, Chen Wang, Liping Liao, Aaron R Goldman, Toshitha Kannan, Andrew V Kossenkov, Ronny Drapkin, Luis J Montaner, Daniel T Claiborne, Nan Zhang, Shuai Wu, Rugang Zhang

Faculty, Staff and Student Publications

ARID1A, encoding a subunit of the SWI/SNF complex, is mutated in ∼50% of clear cell ovarian carcinoma (OCCC) cases. Here we show that inhibition of the mevalonate pathway synergizes with immune checkpoint blockade (ICB) by driving inflammasome-regulated immunomodulating pyroptosis in ARID1A-inactivated OCCCs. SWI/SNF inactivation downregulates the rate-limiting enzymes in the mevalonate pathway such as HMGCR and HMGCS1, which creates a dependence on the residual activity of the pathway in ARID1A-inactivated cells. Inhibitors of the mevalonate pathway such as simvastatin suppresses the growth of ARID1A mutant, but not wild-type, OCCCs. In addition, simvastatin synergizes with anti-PD-L1 antibody in a genetic OCCC …

Bi-Allelic Snapc4 Variants Dysregulate Global Alternative Splicing And Lead To Neuroregression And Progressive Spastic Paraparesis, F Graeme Frost, Marie Morimoto, Prashant Sharma, Lyse Ruaud, Newell Belnap, Daniel G Calame, Yuri Uchiyama, Naomichi Matsumoto, Machteld M Oud, Elise A Ferreira, Vinodh Narayanan, Sampath Rangasamy, Matt Huentelman, Lisa T Emrick, Ikuko Sato-Shirai, Satoko Kumada, Nicole I Wolf, Peter J Steinbach, Yan Huang, Undiagnosed Diseases Network, Barbara N Pusey, Sandrine Passemard, Jonathan Levy, Séverine Drunat, Marie Vincent, Agnès Guet, Emanuele Agolini, Antonio Novelli, Maria Cristina Digilio, Jill A Rosenfeld, Jennifer L Murphy, James R Lupski, Gilbert Vezina, Ellen F Macnamara, David R Adams, Maria T Acosta, Cynthia J Tifft, William A Gahl, May Christine V Malicdan

Faculty, Staff and Students Publications

The vast majority of human genes encode multiple isoforms through alternative splicing, and the temporal and spatial regulation of those isoforms is critical for organismal development and function. The spliceosome, which regulates and executes splicing reactions, is primarily composed of small nuclear ribonucleoproteins (snRNPs) that consist of small nuclear RNAs (snRNAs) and protein subunits. snRNA gene transcription is initiated by the snRNA-activating protein complex (SNAPc). Here, we report ten individuals, from eight families, with bi-allelic, deleterious SNAPC4 variants. SNAPC4 encoded one of the five SNAPc subunits that is critical for DNA binding. Most affected individuals presented with delayed motor development …

Age-Related Changes To Adipose Tissue And Peripheral Neuropathy In Genetically Diverse Het3 Mice Differ By Sex And Are Not Mitigated By Rapamycin Longevity Treatment., Jake W Willows, Morganne Robinson, Zahra Alshahal, Samantha K Morrison, Gargi Mishra, Harrison Cyr, Magdalena Blaszkiewicz, Gilian Gunsch, Sabrina Dipietro, Emma Paradie, Benjamin Tero, Anne Harrington, Larisa Ryzhova, Lucy Liaw, Peter C. Reifsnyder, David E Harrison, Kristy L Townsend

Faculty Research 2023

Neural communication between the brain and adipose tissues regulates energy expenditure and metabolism through modulation of adipose tissue functions. We have recently demonstrated that under pathophysiological conditions (obesity, diabetes, and aging), total subcutaneous white adipose tissue (scWAT) innervation is decreased ('adipose neuropathy'). With advanced age in the C57BL/6J mouse, small fiber peripheral nerve endings in adipose tissue die back, resulting in reduced contact with adipose-resident blood vessels and other cells. This vascular neuropathy and parenchymal neuropathy together likely pose a physiological challenge for tissue function. In the current work, we used the genetically diverse HET3 mouse model to investigate the …

Women In Sustainable Leadership: A Case Study On The Perspectives, Opportunities, And Challenges Of Biologist And Conservationist Estrela Matilde, Ella Lyons

Independent Study Project (ISP) Collection

Despite the relatively small population of 8,000 occupants and the minimal international recognition of the Island of Príncipe, located off of the Gulf of Guinea on the Western Coast of Central Africa, the region has increasingly become a leading example of sustainable practices to be taken on a global scale in the near future to combat our current climate crisis. This case study explores the sustainable practices that Príncipe has learned to embrace under the leadership of Portuguese conservation biologist and project manager for the NGO Fundação Príncipe, Estrela Matilde. Estrela integrates social, cultural, and environmental conservation to align with …

Probenecid Slows Disease Progression In A Murine Model Of Autosomal Dominant Polycystic Kidney Disease, Sergey N. Arkhipov, D'Anna L. Potter, Regina F. Sultanova, Daria V. Ilatovskaya, Peter C. Harris, Tengis S. Pavlov

Hypertension and Vascular Research Articles

Development of autosomal dominant polycystic kidney disease (ADPKD) involves renal epithelial cell abnormalities. Cystic fluid contains a high level of ATP that, among other effects, leads to a reduced reabsorption of electrolytes in cyst-lining cells, and thus results in cystic fluid accumulation. Earlier, we demonstrated that Pkd1(RC/RC) mice, a hypomorphic model of ADPKD, exhibit increased expression of pannexin-1, a membrane channel capable of ATP release. In the current study, we found that human ADPKD cystic epithelia have higher pannexin-1 abundance than normal collecting ducts. We hypothesized that inhibition of pannexin-1 function with probenecid can be used to attenuate ADPKD development. …

Resistance To Mild Cold Stress Is Greater In Both Wild-Type And Long-Lived Ghr-Ko Female Mice., Yimin Fang, David Medina, Robert Stockwell, Samuel Mcfadden, Erin R Hascup, Kevin N Hascup, Andrzej Bartke

Articles

Adapting to stress, including cold environmental temperature (eT), is crucial for the survival of mammals, especially small rodents. Long-lived mutant mice have enhanced stress resistance against oxidative and non-oxidative challenges. However, much less is known about the response of those long-lived mice to cold stress. Growth hormone receptor knockout (GHR-KO) mice are long-lived with reduced growth hormone signaling. We wanted to test whether GHR-KO mice have enhanced resistance to cold stress. To examine the response of GHR-KO mice to cold eT, GHR-KO mice were housed at mild cold eT (16 °C) immediately following weaning. Longevity results showed that female GHR-KO …

Loss Of Neuron Navigator 2 Impairs Brain And Cerebellar Development, Andrea Accogli, Shenzhao Lu, Ilaria Musante, Paolo Scudieri, Jill A Rosenfeld, Mariasavina Severino, Simona Baldassari, Michele Iacomino, Antonella Riva, Ganna Balagura, Gianluca Piccolo, Carlo Minetti, Denis Roberto, Fan Xia, Razaali Razak, Emily Lawrence, Mohamed Hussein, Emmanuel Yih-Herng Chang, Michelle Holick, Elisa Calì, Emanuela Aliberto, Rosalba De-Sarro, Antonio Gambardella, Undiagnosed Diseases Network, Synaps Study Group, Lisa Emrick, Peter J A Mccaffery, Margaret Clagett-Dame, Paul C Marcogliese, Hugo J Bellen, Seema R Lalani, Federico Zara, Pasquale Striano, Vincenzo Salpietro

Faculty, Staff and Students Publications

Cerebellar hypoplasia and dysplasia encompass a group of clinically and genetically heterogeneous disorders frequently associated with neurodevelopmental impairment. The Neuron Navigator 2 (NAV2) gene (MIM: 607,026) encodes a member of the Neuron Navigator protein family, widely expressed within the central nervous system (CNS), and particularly abundant in the developing cerebellum. Evidence across different species supports a pivotal function of NAV2 in cytoskeletal dynamics and neurite outgrowth. Specifically, deficiency of Nav2 in mice leads to cerebellar hypoplasia with abnormal foliation due to impaired axonal outgrowth. However, little is known about the involvement of the NAV2 gene in human disease phenotypes. In …

Dietary Intake Of Total, Heme And Non-Heme Iron And The Risk Of Colorectal Cancer In A European Prospective Cohort Study, Elom K Aglago, Amanda J Cross, Elio Riboli, Veronika Fedirko, David J Hughes, Agnes Fournier, Paula Jakszyn, Heinz Freisling, Marc J Gunter, Christina C Dahm, Kim Overvad, Anne Tjønneland, Cecilie Kyrø, Marie-Christine Boutron-Ruault, Joseph A Rothwell, Gianluca Severi, Verena Katzke, Bernard Srour, Matthias B Schulze, Clemens Wittenbecher, Domenico Palli, Sabina Sieri, Fabrizio Pasanisi, Rosario Tumino, Fulvio Ricceri, Bas Bueno-De-Mesquita, Jeroen W G Derksen, Guri Skeie, Torill Enget Jensen, Marko Lukic, Maria-Jose Sánchez, Pilar Amiano, Sandra Colorado-Yohar, Aurelio Barricarte, Ulrika Ericson, Bethany Van Guelpen, Keren Papier, Anika Knuppel, Corinne Casagrande, Inge Huybrechts, Alicia K Heath, Konstantinos K Tsilidis, Mazda Jenab

Faculty, Staff and Student Publications

BACKGROUND: Iron is an essential micronutrient with differing intake patterns and metabolism between men and women. Epidemiologic evidence on the association of dietary iron and its heme and non-heme components with colorectal cancer (CRC) development is inconclusive.

METHODS: We examined baseline dietary questionnaire-assessed intakes of total, heme, and non-heme iron and CRC risk in the EPIC cohort. Sex-specific multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were computed using Cox regression. We modelled substitution of a 1 mg/day of heme iron intake with non-heme iron using the leave one-out method.

RESULTS: Of 450,105 participants (318,680 women) followed for 14.2 …

Total Daily Energy Expenditure Has Declined Over The Past Three Decades Due To Declining Basal Expenditure, Not Reduced Activity Expenditure, John R Speakman, Jasper M A De Jong, Srishti Sinha, Klaas R Westerterp, Yosuke Yamada, Hiroyuki Sagayama, Philip N Ainslie, Liam J Anderson, Lenore Arab, Kweku Bedu-Addo, Stephane Blanc, Alberto G Bonomi, Pascal Bovet, Soren Brage, Maciej S Buchowski, Nancy F Butte, Stefan G J A Camps, Jamie A Cooper, Richard Cooper, Sai Krupa Das, Peter S W Davies, Lara R Dugas, Ulf Ekelund, Sonja Entringer, Terrence Forrester, Barry W Fudge, Melanie Gillingham, Santu Ghosh, Annelies H Goris, Michael Gurven, Lewis G Halsey, Catherine Hambly, Hinke H Haisma, Daniel Hoffman, Sumei Hu, Annemiek M Joosen, Jennifer L Kaplan, Peter Katzmarzyk, William E Kraus, Robert F Kushner, William R Leonard, Marie Löf, Corby K Martin, Eric Matsiko, Anine C Medin, Erwin P Meijer, Marian L Neuhouser, Theresa A Nicklas, Robert M Ojiambo, Kirsi H Pietiläinen, Jacob Plange-Rhule, Guy Plasqui, Ross L Prentice, Susan B Racette, David A Raichlen, Eric Ravussin, Leanne M Redman, Susan B Roberts, Michael C Rudolph, Luis B Sardinha, Albertine J Schuit, Analiza M Silva, Eric Stice, Samuel S Urlacher, Giulio Valenti, Ludo M Van Etten, Edgar A Van Mil, Brian M Wood, Jack A Yanovski, Tsukasa Yoshida, Xueying Zhang, Alexia J Murphy-Alford, Cornelia U Loechl, Anura Kurpad, Amy H Luke, Herman Pontzer, Matthew S Rodeheffer, Jennifer Rood, Dale A Schoeller, William W Wong

Faculty, Staff and Student Publications

Obesity is caused by prolonged positive energy balance1,2. Whether reduced energy expenditure stemming from reduced activity levels contributes, is debated3,4. Here we used the IAEA DLW database on energy expenditure of adults in the USA and Europe (n = 4799) to explore patterns in total (TEE: n=4799), basal (BEE: n = 1432) and physical activity energy expenditure (AEE: n = 1432) over time. In both sexes total energy expenditure (TEE) adjusted for body composition and age declined with time, while adjusted AEE increased over time. In males adjusted BEE decreased significantly, but …

Insulin-Like Growth Factor-1 Supplementation Promotes Brain Maturation In Preterm Pigs, Line I Christiansen, Bo Holmqvist, Xiaoyu Pan, Kristine Holgersen, Sandy E H Lindholm, Nicole L Henriksen, Douglas G Burrin, David Ley, Thomas Thymann, Per Torp Sangild, Stanislava Pankratova

Faculty, Staff and Students Publications

Very preterm infants show low levels of insulin-like growth factor-1 (IGF-1), which is associated with postnatal growth restriction and poor neurologic outcomes. It remains unknown whether supplemental IGF-1 may stimulate neurodevelopment in preterm neonates. Using cesarean-delivered preterm pigs as a model of preterm infants, we investigated the effects of supplemental IGF-1 on motor function and on regional and cellular brain development. Pigs were treated with 2.25 mg/kg/d recombinant human IGF-1/IGF binding protein-3 complex from birth until day 5 or 9 before the collection of brain samples for quantitative immunohistochemistry (IHC), RNA sequencing, and quantitative PCR analyses. Brain protein synthesis was …

Naive T Cells Inhibit The Outgrowth Of Intractable Antigen-Activated Memory T Cells: Implications For T-Cell Immunotherapy, Sandhya Sharma, Mae Woods, Naren U Mehta, Tim Sauer, Kathan S Parikh, Michael Schmuck-Henneresse, Huimin Zhang, Birju Mehta, Malcolm K Brenner, Helen E Heslop, Cliona M Rooney

Faculty, Staff and Students Publications

BACKGROUND: The wider application of T cells targeting viral tumor-antigens via their native receptors is hampered by the failure to expand potent tumor-specific T cells from patients. Here, we examine reasons for and solutions to this failure, taking as our model the preparation of Epstein-Barr virus (EBV)-specific T cells (EBVSTs) for the treatment of EBV-positive lymphoma. EBVSTs could not be manufactured from almost one-third of patients, either because they failed to expand, or they expanded, but lacked EBV specificity. We identified an underlying cause of this problem and established a clinically feasible approach to overcome it.

METHODS: CD45RO+CD45RA- memory compartment …

Baseline Characteristics Of The North American Prodromal Synucleinopathy Cohort, Jonathan E Elliott, Jennifer Mcleland, Susan R Criswell, Yo-El S Ju, Et Al.

2020-Current year OA Pubs

OBJECTIVE: Rapid eye movement (REM) sleep behavior disorder (RBD) is widely considered a prodromal synucleinopathy, as most with RBD develop overt synucleinopathy within ~10 years. Accordingly, RBD offers an opportunity to test potential treatments at the earliest stages of synucleinopathy. The North American Prodromal Synucleinopathy (NAPS) Consortium has created a multisite RBD participant, primarily clinic-based cohort to better understand characteristics at diagnosis, and in future work, identify predictors of phenoconversion, develop synucleinopathy biomarkers, and enable early stage clinical trial enrollment.

METHODS: Participants ≥18 years of age with overnight polysomnogram-confirmed RBD without Parkinson's disease, dementia, multiple system atrophy, or narcolepsy were …

A Learned Map For Places And Concepts In The Human Medial Temporal Lobe, Nora A. Herweg, Lukas Kunz, Daniel Schonhaut, Armin Brandt, Paul A. Wanda, Ashwini D. Sharan, Michael R. Sperling, Andreas Schulze-Bonhage, Michael J. Kahana

Department of Neurology Faculty Papers

Distinct lines of research in both humans and animals point to a specific role of the hippocampus in both spatial and episodic memory function. The discovery of concept cells in the hippocampus and surrounding medial temporal lobe (MTL) regions suggests that the MTL maps physical and semantic spaces with a similar neural architecture. Here, we studied the emergence of such maps using MTL microwire recordings from 20 patients (9 female, 11 male) navigating a virtual environment featuring salient landmarks with established semantic meaning. We present several key findings. The array of local field potentials in the MTL contains sufficient information …

Rare Variant Enrichment Analysis Supports Greb1l As A Contributory Driver Gene In The Etiology Of Mayer-Rokitansky-Küster-Hauser Syndrome, Angad Jolly, Haowei Du, Christelle Borel, Na Chen, Sen Zhao, Christopher M Grochowski, Ruizhi Duan, Jawid M Fatih, Moez Dawood, Sejal Salvi, Shalini N Jhangiani, Donna M Muzny, André Koch, Konstantinos Rouskas, Stavros Glentis, Efthymios Deligeoroglou, Flora Bacopoulou, Carol A Wise, Jennifer E Dietrich, Ignatia B Van Den Veyver, Antigone S Dimas, Sara Brucker, V Reid Sutton, Richard A Gibbs, Stylianos E Antonarakis, Nan Wu, Zeynep H Coban-Akdemir, Lan Zhu, Jennifer E Posey, James R Lupski

Faculty, Staff and Student Publications

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is characterized by aplasia of the female reproductive tract; the syndrome can include renal anomalies, absence or dysgenesis, and skeletal anomalies. While functional models have elucidated several candidate genes, only WNT4 (MIM: 603490) variants have been definitively associated with a subtype of MRKH with hyperandrogenism (MIM: 158330). DNA from 148 clinically diagnosed MRKH probands across 144 unrelated families and available family members from North America, Europe, and South America were exome sequenced (ES) and by family-based genomics analyzed for rare likely deleterious variants. A replication cohort consisting of 442 Han Chinese individuals with MRKH was …

Macrophages Promote Repair Of Inner Hair Cell Ribbon Synapses Following Noise-Induced Cochlear Synaptopathy, Vijayprakash Manickam, Dinesh Y Gawande, Andrew R Stothert, Anna C Clayman, Lyudmila Batalkina, Mark E Warchol, Kevin K Ohlemiller, Tejbeer Kaur

2020-Current year OA Pubs

Resident cochlear macrophages rapidly migrate into the inner hair cell synaptic region and directly contact the damaged synaptic connections after noise-induced synaptopathy. Eventually, such damaged synapses are spontaneously repaired, but the precise role of macrophages in synaptic degeneration and repair remains unknown. To address this, cochlear macrophages were eliminated using colony stimulating factor 1 receptor (CSF1R) inhibitor, PLX5622. Sustained treatment with PLX5622 in