Medicine and Health Sciences Commons^™

Characterization And Localization Of Antigens For Serodiagnosis Of Human Paragonimiasis, Kurt C Curtis, Kerstin Fischer, Young-Jun Choi, Makedonka Mitreva, Gary J Weil, Peter U Fischer

2020-Current year OA Pubs

Paragonimiasis is a foodborne trematode infection that affects 23 million people, mainly in Asia. Lung fluke infections lead frequently to chronic cough with fever and hemoptysis, and are often confused with lung cancer or tuberculosis. Paragonimiasis can be efficiently treated with praziquantel, but diagnosis is often delayed, and patients are frequently treated for other conditions. To improve diagnosis, we selected five Paragonimus kellicotti proteins based on transcriptional abundance, recognition by patient sera, and conservation among trematodes and expressed them as His-fusion proteins in Escherichia coli. Sequences for these proteins have 76-99% identity with amino acid sequences for orthologs in the …

Absent B Cells, Agammaglobulinemia, And Hypertrophic Cardiomyopathy In Folliculin-Interacting Protein 1 Deficiency, Francesco Saettini, Cecilia Poli, Jaime Vengoechea, Sonia Bonanomi, Julio C Orellana, Grazia Fazio, Fred H Rodriguez, Loreani P Noguera, Claire Booth, Valentina Jarur-Chamy, Marissa Shams, Maria Iascone, Maja Vukic, Serena Gasperini, Manuel Quadri, Amairelys Barroeta Seijas, Elizabeth Rivers, Mario Mauri, Raffaele Badolato, Gianni Cazzaniga, Cristina Bugarin, Giuseppe Gaipa, Wilma G M Kroes, Daniele Moratto, Monique M Van Oostaijen-Ten Dam, Frank Baas, Silvère Van Der Maarel, Rocco Piazza, Zeynep H Coban-Akdemir, James R Lupski, Bo Yuan, Ivan K Chinn, Lucia Daxinger, Andrea Biondi

Journal Articles

Agammaglobulinemia is the most profound primary antibody deficiency that can occur due to an early termination of B-cell development. We here investigated 3 novel patients, including the first known adult, from unrelated families with agammaglobulinemia, recurrent infections, and hypertrophic cardiomyopathy (HCM). Two of them also presented with intermittent or severe chronic neutropenia. We identified homozygous or compound-heterozygous variants in the gene for folliculin interacting protein 1 (FNIP1), leading to loss of the FNIP1 protein. B-cell metabolism, including mitochondrial numbers and activity and phosphatidylinositol 3-kinase/AKT pathway, was impaired. These defects recapitulated the Fnip1-/- animal model. Moreover, we identified either uniparental disomy …

Structural Insights Into The Disruption Of Tnf-Tnfr1 Signalling By Small Molecules Stabilising A Distorted Tnf, David Mcmillan, Carlos Martinez-Fleites, John Porter, David Fox, Rachel E. Davis, Prashant Mori, Tom Ceska, Bruce Carrington, Alastair Lawson, Tim Bourne, James O'Connell

Faculty Publications

Tumour necrosis factor (TNF) is a trimeric protein which signals through two membrane receptors, TNFR1 and TNFR2. Previously, we identified small molecules that inhibit human TNF by stabilising a distorted trimer and reduce the number of receptors bound to TNF from three to two. Here we present a biochemical and structural characterisation of the small molecule-stabilised TNF-TNFR1 complex, providing insights into how a distorted TNF trimer can alter signalling function. We demonstrate that the inhibitors reduce the binding affinity of TNF to the third TNFR1 molecule. In support of this, we show by X-ray crystallography that the inhibitor-bound, distorted, TNF …

Implications Of Oligomeric Amyloid-Beta (Oaβ42) Signaling Through Α7Β2-Nicotinic Acetylcholine Receptors (Nachrs) On Basal Forebrain Cholinergic Neuronal Intrinsic Excitability And Cognitive Decline, Andrew A George, Jaime M Vieira, Cameron Xavier-Jackson, Michael T Gee, John R Cirrito, Heather A Bimonte-Nelson, Marina R Picciotto, Ronald J Lukas, Paul Whiteaker

2020-Current year OA Pubs

Neuronal and network-level hyperexcitability is commonly associated with increased levels of amyloid-β (Aβ) and contribute to cognitive deficits associated with Alzheimer's disease (AD). However, the mechanistic complexity underlying the selective loss of basal forebrain cholinergic neurons (BFCNs), a well-recognized characteristic of AD, remains poorly understood. In this study, we tested the hypothesis that the oligomeric form of amyloid-β (oAβ

Multiwalled Carbon Nanotubes Co-Delivering Sorafenib And Epidermal Growth Factor Receptor Sirna Enhanced Tumor-Suppressing Effect On Liver Cancer., Zhili Wen, Yuliang Feng, Youwen Hu, Lingyan Lian, Hongyan Huang, Li Guo, Shanwen Chen, Qian Yang, Moran Zhang, Lijun Wan, Kedong Xu, Degejirifu, Xiaohua Yan

Faculty Research 2021

OBJECTIVE: This study aimed to investigate the effects of multiwalled carbon nanotubes (MWNTs) co-delivering sorafenib (Sor) and epidermal growth factor receptor (EGFR) siRNA (MWNT/Sor/siRNA) on tumor growth in liver cancer (LC).

RESULTS: MWNT/Sor/siRNA was proved to possess increased Sor release, high siRNA stability, and enhanced cellular uptake. In addition, MWNT treatment has few effects on cell proliferation and apoptosis in HepG2 cells; however, MWNT/Sor/siRNA treatment significantly inhibited clone number and induced cell apoptosis, which shows a more favorable antitumor effect than MWNT/Sor and free Sor and free siRNA in HepG2 cells. Moreover MWNT/Sor/siRNA treatment has the most significant antitumor effect …

The Gene Ontology Resource: Enriching A Gold Mine., Gene Ontology Consortium, Judith A. Blake, Mary E. Dolan, Harold J. Drabkin, David P. Hill

Faculty Research 2021

The Gene Ontology Consortium (GOC) provides the most comprehensive resource currently available for computable knowledge regarding the functions of genes and gene products. Here, we report the advances of the consortium over the past two years. The new GO-CAM annotation framework was notably improved, and we formalized the model with a computational schema to check and validate the rapidly increasing repository of 2838 GO-CAMs. In addition, we describe the impacts of several collaborations to refine GO and report a 10% increase in the number of GO annotations, a 25% increase in annotated gene products, and over 9,400 new scientific articles …

Mouse Genome Database (Mgd): Knowledgebase For Mouse-Human Comparative Biology., Judith A. Blake, Richard M. Baldarelli, James A. Kadin, Joel E Richardson, Cynthia Smith, Carol J Bult, Mouse Genome Database Group

Faculty Research 2021

The Mouse Genome Database (MGD; http://www.informatics.jax.org) is the community model organism knowledgebase for the laboratory mouse, a widely used animal model for comparative studies of the genetic and genomic basis for human health and disease. MGD is the authoritative source for biological reference data related to mouse genes, gene functions, phenotypes and mouse models of human disease. MGD is the primary source for official gene, allele, and mouse strain nomenclature based on the guidelines set by the International Committee on Standardized Nomenclature for Mice. MGD's biocuration scientists curate information from the biomedical literature and from large and small datasets contributed …

Effects Of Maternal Obesity And Gestational Diabetes Mellitus On The Placenta: Current Knowledge And Targets For Therapeutic Interventions, Samantha Bedell, Janine Hutson, Barbra De Vrijer, Genevieve Eastabrook

Obstetrics & Gynaecology Publications

Obesity and gestational diabetes mellitus (GDM) are becoming more common among pregnant women worldwide and are individually associated with a number of placenta-mediated obstetric complications, including preeclampsia, macrosomia, intrauterine growth restriction and stillbirth. The placenta serves several functions throughout pregnancy and is the main exchange site for the transfer of nutrients and gas from mother to fetus. In pregnancies complicated by maternal obesity or GDM, the placenta is exposed to environmental changes, such as increased inflammation and oxidative stress, dyslipidemia, and altered hormone levels. These changes can affect placental development and function and lead to abnormal fetal growth and development …

Self And Microbiota-Derived Epitopes Induce Cd4⁺ T Cell Anergy And Conversion Into Cd4⁺Foxp3⁺ Regulatory Cells, Michal P. Kuczma, Edyta A. Szurek, Anna Cebula, Vu L. Ngo, Maciej Pietrzak, Piotr Kraj, Timothy L. Denning, Leszek Ignatowicz

Biological Sciences Faculty Publications

The physiological role of T cell anergy induction as a key mechanism supporting self-tolerance remains undefined, and natural antigens that induce anergy are largely unknown. In this report, we used TCR sequencing to show that the recruitment of CD4⁺CD44⁺Foxp3⁻CD73⁺FR4⁺ anergic (Tan) cells expands the CD4⁺Foxp3⁺ (Tregs) repertoire. Next, we report that blockade in peripherally-induced Tregs (pTregs) formation due to mutation in CNS1 region of Foxp3 or chronic exposure to a selecting self-peptide result in an accumulation of Tan cells. Finally, we show that microbial antigens from Akkermansia muciniphila …

Regen Med Therapeutic Opportunities For Fighting Covid-19., Anthony Atala, Alicia Henn, Martha Lundberg, Taby Ahsan, Jordan Greenberg, Jeff Krukin, Steven Lynum, Cathleen Lutz, Kyle Cetrulo, Mohammad Albanna, Taciana Pereira, Shannon Eaker, Joshua Hunsberger

Faculty Research 2021

This perspective from a Regenerative Medicine Manufacturing Society working group highlights regenerative medicine therapeutic opportunities for fighting COVID-19. This article addresses why SARS-CoV-2 is so different from other viruses and how regenerative medicine is poised to deliver new therapeutic opportunities to battle COVID-19. We describe animal models that depict the mechanism of action for COVID-19 and that may help identify new treatments. Additionally, organoid platforms that can recapitulate some of the physiological properties of human organ systems, such as the lungs and the heart, are discussed as potential platforms that may prove useful in rapidly screening new drugs and identifying …

Oral Versus Gastrointestinal Mucosal Immune Niches In Homeostasis And Allostasis, Lina J Suárez, Silie Arboleda, Nikola Angelov, Roger M Arce

Journal Articles

Different body systems (epidermis, respiratory tract, cornea, oral cavity, and gastrointestinal tract) are in continuous direct contact with innocuous and/or potentially harmful external agents, exhibiting dynamic and highly selective interaction throughout the epithelia, which function as both a physical and chemical protective barrier. Resident immune cells in the epithelia are constantly challenged and must distinguish among antigens that must be either tolerated or those to which a response must be mounted for. When such a decision begins to take place in lymphoid foci and/or mucosa-associated lymphoid tissues, the epithelia network of immune surveillance actively dominates both oral and gastrointestinal compartments, …

Molecular Characterization Of Cryptosporidium Spp. From Humans In Ethiopia, Ambachew W. Hailu, Abraham Degarege, Haileeyesus Adamu, Damien Costa, Venceslas Villier, Abdelmounaim Mouhajir, Loic Favennec, Romy Razakandrainibe, Beyene Petros

Journal Articles: Epidemiology

Data on the distribution and genotype of Cryptosporidium species is limited in Ethiopia. This study examined the presence and genetic diversity of Cryptosporidium species circulating in Ethiopian human population. Stool samples collected from patients who visited rural (n = 94) and urban (n = 93) health centers in Wurgissa and Hawassa district, respectively, were examined for the presence of Cryptosporidium spp. using microscopy, nested PCR and real-time PCR. To detect infection with PCR, analysis of 18S ribosomal RNA was performed. Subtyping was performed by sequencing a fragment of GP60 gene. The overall prevalence of infection was 46% (n = 86) …

Isolation And Characterization Of A Novel Bacteriophage Wo From Allonemobius Socius Crickets In Missouri, Jonah Kupritz, John Martin, Kerstin Fischer, Kurt C. Curtis, Joseph R. Fauver, Yuefang Huang, Young-Jun Choi, Wandy L. Beatty, Makedonka Mitreva, Peter U. Fischer

Journal Articles: Epidemiology

Wolbachia are endosymbionts of numerous arthropod and some nematode species, are important for their development and if present can cause distinct phenotypes of their hosts. Prophage DNA has been frequently detected in Wolbachia, but particles of Wolbachia bacteriophages (phage WO) have been only occasionally isolated. Here, we report the characterization and isolation of a phage WO of the southern ground cricket, Allonemobius socius, and provided the first whole-genome sequence of phage WO from this arthropod family outside of Asia. We screened A. socius abdomen DNA extracts from a cricket population in eastern Missouri by quantitative PCR for Wolbachia surface protein …

Megf10 Deficiency Impairs Skeletal Muscle Stem Cell Migration And Muscle Regeneration, Chengcheng Li, Dorianmarie Vargas-Franco, Madhurima Saha, Rachel M. Davis, Kelsey A. Manko, Isabelle Draper, Christina A. Pacak, Peter B. Kang

Faculty Publications

Biallelic loss-of-function MEGF10 mutations lead to MEGF10 myopathy, also known as early onset myopathy with areflexia, respiratory distress, and dysphagia (EMARDD). MEGF10 is expressed in muscle satellite cells, but the contribution of satellite cell dysfunction to MEGF10 myopathy is unclear. Myofibers and satellite cells were isolated and examined from Megf10 and wild-type mice. A separate set of mice underwent repeated intramuscular barium chloride injections. Megf10 muscle satellite cells showed reduced proliferation and migration, while Megf10 mouse skeletal muscles showed impaired regeneration. Megf10 deficiency is associated with impaired muscle regeneration, due in part to defects in satellite cell function. Efforts to …

Patient-Derived Induced Pluripotent Stem Cell Models For Phenotypic Screening In The Neuronal Ceroid Lipofuscinoses, Ahmed Morsy, Angelica V. Carmona, Paul C. Trippier

Journal Articles: Pharmaceutical Sciences

Batten disease or neuronal ceroid lipofuscinosis (NCL) is a group of rare, fatal, inherited neurodegenerative lysosomal storage disorders. Numerous genes (CLN1-CLN8, CLN10-CLN14) were identified in which mutations can lead to NCL; however, the underlying pathophysiology remains elusive. Despite this, the NCLs share some of the same features and symptoms but vary in respect to severity and onset of symptoms by age. Some common symptoms include the progressive loss of vision, mental and motor deterioration, epileptic seizures, premature death, and in the rare adult-onset, dementia. Currently, all forms of NCL are fatal, and no curative treatments are available. Induced pluripotent stem …

Empathy, Animals, And Deadly Vices, Kathie Jenni

Animal Studies Journal

In Deadly Vices, Gabriele Taylor provides a secular analysis of vices which in Christian theology were thought to bring death to the soul: sloth, envy, avarice, pride, anger, lust, and gluttony. She argues that these vices are appropriately singled out and grouped together in that ‘they are destructive of the self and prevent its flourishing’. Using a related approach, I offer a secular analysis of gluttony and cowardice, examining their roles in common failures to empathise with animals. I argue that these vices constitute serious moral failings, for they enable continuing complicity in animal abuse and undermine integrity. While Taylor …

Ifn-Β Acts On Monocytes To Ameliorate Cns Autoimmunity By Inhibiting Proinflammatory Cross-Talk Between Monocytes And Th Cells., Javad Rasouli, Giacomo Casella, Larissa Ishikawa, Rodolfo Thome, Alexandra Boehm, Adam Ertel, Carolina R Melo-Silva, Elisabeth R. Mari, Patrizia Porazzi, Weifeng Zhang, Dan Xiao, Luis J. Sigal, Paolo Fortina, Guang-Xian Zhang, A M Rostami, Bogoljub Ciric

Department of Neurology Faculty Papers

IFN-β has been the treatment for multiple sclerosis (MS) for almost three decades, but understanding the mechanisms underlying its beneficial effects remains incomplete. We have shown that MS patients have increased numbers of GM-CSF+ Th cells in circulation, and that IFN-β therapy reduces their numbers. GM-CSF expression by myelin-specific Th cells is essential for the development of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. These findings suggested that IFN-β therapy may function via suppression of GM-CSF production by Th cells. In the current study, we elucidated a feedback loop between monocytes and Th cells that amplifies autoimmune neuroinflammation, …

Inhibition Of Nox1 Mitigates Blood Pressure Increases In Elastin Insufficiency, Angela Troia, Russell H Knutsen, Carmen M Halabi, Daniela Malide, Zu Xi Yu, Amanda Wardlaw-Pickett, Elise K Kronquist, Kit Man Tsang, Attila Kovacs, Robert P Mecham, Beth A Kozel

2020-Current year OA Pubs

Elastin (ELN) insufficiency leads to the cardiovascular hallmarks of the contiguous gene deletion disorder, Williams-Beuren syndrome, including hypertension and vascular stiffness. Previous studies showed that Williams-Beuren syndrome deletions, which extended to include the

Mir-9-1 Suppresses Cell Proliferation And Promotes Apoptosis By Targeting Uhrf1 In Lung Cancer, Cheng-You Jia, Wei Xiang, Ji-Bin Liu, Geng-Xi Jiang, Feng Sun, Jian-Jun Wu, Xiao-Li Yang, Rui Xin, Yi Shi, Dan-Dan Zhang, Wen Li, Zavuga Zuberi, Jie Zhang, Gai-Xia Lu, Hui-Min Wang, Pei-Yao Wang, Fei Yu, Zhong-Wei Lv, Yu-Shui Ma, Da Fu

Journal Articles

Lung cancer is listed as the most common reason for cancer-related death all over the world despite diagnostic improvements and the development of chemotherapy and targeted therapies. MicroRNAs control both physiological and pathological processes including development and cancer. A microRNA-9 to 1 (miR-9 to 1) overexpression model in lung cancer cell lines was established and miR-9 to 1 was found to significantly suppress the proliferation rate in lung cancer cell lines, colony formation in vitro, and tumorigenicity in nude mice of A549 cells. Ubiquitin-like containing PHD and RING finger domains 1 (UHRF1) was then identified to direct target of miR-9 …