Digital Commons Network^™

Development Of Pullulan/Chitosan/Salvianolic Acid Ternary Fibrous Membranes And Their Potential For Chemotherapeutic Applications, Salahuddin Ahmed, Megan Keniry, Victoria Padilla, Narcedalia Anaya-Barbosa, Md Noushad Javed, Robert Gilkerson, Kithzia Gomez, Acharan S. Narula, Karen Lozano

Mechanical Engineering Faculty Publications

This study investigates the feasibility of centrifugal spinning for producing fibrous membranes containing pullulan, chitosan, and danshen extract. The danshen extract is composed of 20 wt% salvianolic acid B (SA). Citric acid was added to the mixture as a crosslinking agent to promote its use in the aqueous medium. The influence of the danshen concentration (25 wt% and 33 wt%) on fiber morphology, thermal behavior, and the biochemical effect was analyzed. Developed fiber-based membranes consist of long, continuous, and uniform fibers with a sparse scattering of beads. Fiber diameter analysis shows values ranging from 384 ± 123 nm to 644 …

Subcellular Proteomics For Determining Iron-Limited Remodeling Of Plastids In The Model Diatom Thalassiosira Pseudonana (Bacillariophyta), Kristofer M. Gomes, Brook L. Nunn, P. Dreux Chappell, Bethany D. Jenkins

Graduate School of Oceanography Faculty Publications

Diatoms are important primary producers in the world's oceans, yet their growth is constrained in large regions by low bioavailable iron (Fe). Low-Fe stress-induced limitation of primary production is due to requirements for Fe in components of essential metabolic pathways including photosynthesis and other chloroplast plastid functions. Studies have shown that under low-Fe stress, diatoms alter plastid-specific processes, including components of electron transport. These physiological changes suggest changes of protein content and in protein abundances within the diatom plastid. While in silico predictions provide putative information on plastid-localized proteins, knowledge of diatom plastid proteins remains limited in comparison to well-studied …

The Graphical User Interface For Bounded Addition Fuzzy Splicing, Mathuri Selvarajoo, Mohd Pawiro Santono, Fong Wan Heng, Nor Haniza Sarmin

Malaysian Journal of Computing (MJoC)

A splicing system is one of the early theoretical proposals of the DNA-based computation device. The splicing operation starts when two DNA molecules are cut at specific subsequences with the presence of restriction enzymes: the first part is then connected to the second part of the other molecule, or vice versa, to produce splicing languages. Fuzzy with bounded-addition operation has been introduced as a restriction in splicing systems to increase the generative power of the languages generated. In this research, a graphical user interface is developed to generate all the splicing languages generated by bounded-addition fuzzy splicing systems and their …

Revised Draft Final Quarterly Operations And Maintenance Report Butte Treatment Lagoon System – First Quarter 2022, Pioneer Technical Services, Inc.

Silver Bow Creek/Butte Area Superfund Site

No abstract provided.

Enhancing Autism Education: Exploring Interactive Videos And Ai Integration For Effective Teaching, Fatima Ahmed Alraeesi

Theses

This research focuses on enhancing autism education by integrating interactive videos and AI solutions to improve teacher training. As the number of autistic students rises, it becomes crucial for special education teachers to employ effective teaching strategies tailored to individual needs. The most effective teaching methods for autistic students involve understanding the condition and incorporating customized instruction strategies, such as adapting assignments to suit the student's needs, assisting those with difficulty speaking, and employing visual aids for better organization. The proposed solution involves utilizing interactive video technology to train teachers, bridging the gap between research and practical implementation of educational …

The Vcam1-Apoe Pathway Directs Microglial Chemotaxis And Alleviates Alzheimer's Disease Pathology, Shun-Fat Lau, Wei Wu, Hiu Yi Wong, Li Ouyang, Yi Qiao, Jiahui Xu, Jessica Hiu-Yan Lau, Carlton Wong, Yuanbing Jiang, David M Holtzman, Amy K Y Fu, Nancy Y Ip

2020-Current year OA Pubs

In Alzheimer's disease (AD), sensome receptor dysfunction impairs microglial danger-associated molecular pattern (DAMP) clearance and exacerbates disease pathology. Although extrinsic signals, including interleukin-33 (IL-33), can restore microglial DAMP clearance, it remains largely unclear how the sensome receptor is regulated and interacts with DAMP during phagocytic clearance. Here, we show that IL-33 induces VCAM1 in microglia, which promotes microglial chemotaxis toward amyloid-beta (Aβ) plaque-associated ApoE, and leads to Aβ clearance. We show that IL-33 stimulates a chemotactic state in microglia, characterized by Aβ-directed migration. Functional screening identified that VCAM1 directs microglial Aβ chemotaxis by sensing Aβ plaque-associated ApoE. Moreover, we found …

Clinical Classification Of Variants In The Valosin-Containing Protein Gene Associated With Multisystem Proteinopathy, Marianela Schiava, Jil Daw, Conrad Chris Weihl, Et Al.

2020-Current year OA Pubs

BACKGROUND AND OBJECTIVES: Pathogenic variants in the valosin-containing protein (

METHODS: A 6-item clinical score was developed to evaluate the phenotypic level of evidence to support the pathogenicity of the novel variants. Each item is allocated a value, a score ranging from 0.5 to 5.5 points. A receiver-operating characteristic curve was used to identify a cutoff value of 3 to consider a variant as high likelihood disease associated. The scoring system results were confronted with results of in vitro ATPase activity assays and with in silico analysis.

RESULTS: All variants were missense, except for one small deletion-insertion, 18 led to …

Conservation Agriculture Assists Smallholder Farmers And Their Agroecosystem In The Democratic Republic Of The Congo, Willy Mulimbi, Kristofor R. Brye, Lawton L. Nalley, Damas R. Birindwa

Agricultural Economics and Agribusiness Faculty Publications and Presentations

onservation agriculture, a sustainable farming practice combining no or minimum soil disturbance, crop diversification, and soil cover, can benefit humans and the biophysical environment. However, less than half of Sub-Saharan African countries implement conservation agriculture, and the majority of smallholder farmers are using unsustainable practices. Research and field trials on conservation agriculture adaptation to soil and agroecological conditions are vital for increasing adoption of conservation agriculture in Sub-Saharan Africa. The objectives of this study were to (i) evaluate the change in soil chemical properties and soil biology from implementation of conservation agriculture, (ii) assess cowpea (Vigna unguiculata L. Walp.) …

Best Practices For Effective Management Of Point Of Care Testing, Anil K Chokkalla, Brandy D Recio, Sridevi Devaraj

Faculty, Staff and Students Publications

With the recent COVID-19 pandemic, point-of-care testing has gained tremendous attention, particularly in acute care settings. The point-of-care testing landscape is rapidly expanding and being contemplated for any crucial test with a central laboratory turnaround time >25% of the clinical decision time. A typical point-of-care testing program within a large hospital system encompasses a multitude of operators utilizing a wide range of devices across multiple testing sites. Thus, managing a large point-of-care testing network remains a daunting task with challenges related to staffing, standardization, quality management, training and competency assessment, and data management. This review will focus on understanding the …

Bronchopulmonary Dysplasia – Associated Pulmonary Hypertension: An Updated Review, Ahmed El-Saie, Nidhy P Varghese, Melissa K Webb, Natalie Villafranco, Bheru Gandhi, Milenka Cuevas Guaman, Binoy Shivanna

Faculty, Staff and Students Publications

Bronchopulmonary dysplasia (BPD) is the leading cause of chronic lung disease in infants and the commonest complication of prematurity. Advances in respiratory and overall neonatal care have increased the survival of extremely low gestational age newborns, leading to the continued high incidence of BPD. Pulmonary hypertension (PH) represents the severe form of the pulmonary vascular disease associated with BPD, and affects almost one-third of infants with moderate to severe BPD. PH responds suboptimally to pulmonary vasodilators and increases morbidity and mortality in BPD infants. An up-to-date knowledge of the pathogenesis, pathophysiology, diagnosis, treatment, and outcomes of BPD-PH can be helpful …

A Novel Pathogenic Mutation Of Mecp2 Impairs Chromatin Association Independent Of Protein Levels, Jian Zhou, Claudia Cattoglio, Yingyao Shao, Harini P Tirumala, Carlo Vetralla, Sameer S Bajikar, Yan Li, Hu Chen, Qi Wang, Zhenyu Wu, Bing Tang, Mahla Zahabiyon, Aleksandar Bajic, Xiangling Meng, Jack J Ferrie, Anel Lagrone, Ping Zhang, Jean J Kim, Jianrong Tang, Zhandong Liu, Xavier Darzacq, Nathaniel Heintz, Robert Tjian, Huda Y Zoghbi

Faculty, Staff and Students Publications

Loss-of-function mutations in MECP2 cause Rett syndrome (RTT), a severe neurological disorder that mainly affects girls. Mutations in MECP2 do occur in males occasionally and typically cause severe encephalopathy and premature lethality. Recently, we identified a missense mutation (c.353G>A, p.Gly118Glu [G118E]), which has never been seen before in MECP2, in a young boy who suffered from progressive motor dysfunction and developmental delay. To determine whether this variant caused the clinical symptoms and study its functional consequences, we established two disease models, including human neurons from patient-derived iPSCs and a knock-in mouse line. G118E mutation partially reduces MeCP2 abundance …

A Cross-Species Proteomic Map Reveals Neoteny Of Human Synapse Development, Li Wang, Kaifang Pang, Li Zhou, Arantxa Cebrián-Silla, Susana González-Granero, Shaohui Wang, Qiuli Bi, Matthew L White, Brandon Ho, Jiani Li, Tao Li, Yonatan Perez, Eric J Huang, Ethan A Winkler, Mercedes F Paredes, Rothem Kovner, Nenad Sestan, Alex A Pollen, Pengyuan Liu, Jingjing Li, Xianhua Piao, José Manuel García-Verdugo, Arturo Alvarez-Buylla, Zhandong Liu, Arnold R Kriegstein

Faculty, Staff and Students Publications

The molecular mechanisms and evolutionary changes accompanying synapse development are still poorly understood1,2. Here we generate a cross-species proteomic map of synapse development in the human, macaque and mouse neocortex. By tracking the changes of more than 1,000 postsynaptic density (PSD) proteins from midgestation to young adulthood, we find that PSD maturation in humans separates into three major phases that are dominated by distinct pathways. Cross-species comparisons reveal that human PSDs mature about two to three times slower than those of other species and contain higher levels of Rho guanine nucleotide exchange factors (RhoGEFs) in the …

Time To Establish An International Vaccine Candidate Pool For Potential Highly Infectious Respiratory Disease: A Community’S View, Lan Yao, Hiam Chemaitelly, Emanuel Goldman, Esayas Kebede Gudina, Asma Khalil, Rahaman Ahmed, Ayorinde Babatunde James, Anna Roca, Mosoka Papa Fallah, Andrew Macnab, William C Cho, John Eikelboom, Farah Naz Qamar, Peter Kremsner, Miquel Oliu-Barton, Ivan Sisa, Birkneh Tilahun Tadesse, Florian Marks, Lishi Wang, Jerome H Kim, Xia Meng, Yongjun Wang, Alyce D Fly, Cong-Yi Wang, Sara W Day, Scott C Howard, J Carolyn Graff, Marcello Maida, Kunal Ray, Carlos Franco-Paredes, Tapfumanei Mashe, Ngashi Ngongo, Jean Kaseya, Nicaise Ndembi, Yu Hu, Maria Elena Bottazzi, Peter J Hotez, Ken J Ishii, Gang Wang, Dianjun Sun, Lotfi Aleya, Weikuan Gu

Faculty, Staff and Students Publications

In counteracting highly infectious and disruptive respiratory diseases such as COVID-19, vaccination remains the primary and safest way to prevent disease, reduce the severity of illness, and save lives. Unfortunately, vaccination is often not the first intervention deployed for a new pandemic, as it takes time to develop and test vaccines, and confirmation of safety requires a period of observation after vaccination to detect potential late-onset vaccine-associated adverse events. In the meantime, nonpharmacologic public health interventions such as mask-wearing and social distancing can provide some degree of protection. As climate change, with its environmental impacts on pathogen evolution and international …

A Recombinant Protein Xbb15 Rbd/Alum/Cpg Vaccine Elicits High Neutralizing Antibody Titers Against Omicron Subvariants Of Sars-Cov-2, Syamala Rani Thimmiraju, Rakesh Adhikari, Maria Jose Villar, Jungsoon Lee, Zhuyun Liu, Rakhi Kundu, Yi-Lin Chen, Suman Sharma, Karm Ghei, Brian Keegan, Leroy Versteeg, Portia M Gillespie, Allan Ciciriello, Nelufa Y Islam, Cristina Poveda, Nestor Uzcategui, Wen-Hsiang Chen, Jason T Kimata, Bin Zhan, Ulrich Strych, Maria Elena Bottazzi, Peter J Hotez, Jeroen Pollet

Faculty, Staff and Students Publications

(1) Background: We previously reported the development of a recombinant protein SARS-CoV-2 vaccine, consisting of the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein, adjuvanted with aluminum hydroxide (alum) and CpG oligonucleotides. In mice and non-human primates, our wild-type (WT) RBD vaccine induced high neutralizing antibody titers against the WT isolate of the virus, and, with partners in India and Indonesia, it was later developed into two closely resembling human vaccines, Corbevax and Indovac. Here, we describe the development and characterization of a next-generation vaccine adapted to the recently emerging XBB variants of SARS-CoV-2. (2) Methods: We conducted preclinical studies …

N7-Methylguanosine Methylation Of Trnas Regulates Survival To Stress In Cancer, Raquel García-Vílchez, Ana M Añazco-Guenkova, Judith López, Sabine Dietmann, Mercedes Tomé, Sonia Jimeno, Mikel Azkargorta, Félix Elortza, Laura Bárcena, Monika Gonzalez-Lopez, Ana M Aransay, Manuel A Sánchez-Martín, Pablo Huertas, Raúl V Durán, Sandra Blanco

2020-Current year OA Pubs

Tumour progression and therapy tolerance are highly regulated and complex processes largely dependent on the plasticity of cancer cells and their capacity to respond to stress. The higher plasticity of cancer cells highlights the need for identifying targetable molecular pathways that challenge cancer cell survival. Here, we show that N

Second International Consensus Report On Gaps And Opportunities For The Clinical Translation Of Precision Diabetes Medicine, Deirdre K Tobias, Jordi Merino, Abrar Ahmad, Catherine Aiken, Jamie L Benham, Dhanasekaran Bodhini, Amy L Clark, Kevin Colclough, Rosa Corcoy, Sara J Cromer, Daisy Duan, Jamie L Felton, Ellen C Francis, Pieter Gillard, Véronique Gingras, Romy Gaillard, Eram Haider, Alice Hughes, Jennifer M Ikle, Laura M Jacobsen, Anna R Kahkoska, Jarno L T Kettunen, Raymond J Kreienkamp, Lee-Ling Lim, Jonna M E Männistö, Robert Massey, Niamh-Maire Mclennan, Rachel G Miller, Mario Luca Morieri, Jasper Most, Rochelle N Naylor, Bige Ozkan, Kashyap Amratlal Patel, Scott J Pilla, Katsiaryna Prystupa, Sridharan Raghavan, Mary R Rooney, Martin Schön, Zhila Semnani-Azad, Magdalena Sevilla-Gonzalez, Pernille Svalastoga, Wubet Worku Takele, Claudia Ha-Ting Tam, Anne Cathrine B Thuesen, Mustafa Tosur, Amelia S Wallace, Caroline C Wang, Jessie J Wong, Jennifer M Yamamoto, Katherine Young, Chloé Amouyal, Mette K Andersen, Maxine P Bonham, Mingling Chen, Feifei Cheng, Tinashe Chikowore, Sian C Chivers, Christoffer Clemmensen, Dana Dabelea, Adem Y Dawed, Aaron J Deutsch, Laura T Dickens, Linda A Dimeglio, Monika Dudenhöffer-Pfeifer, Carmella Evans-Molina, María Mercè Fernández-Balsells, Hugo Fitipaldi, Stephanie L Fitzpatrick, Stephen E Gitelman, Mark O Goodarzi, Jessica A Grieger, Marta Guasch-Ferré, Nahal Habibi, Torben Hansen, Chuiguo Huang, Arianna Harris-Kawano, Heba M Ismail, Benjamin Hoag, Randi K Johnson, Angus G Jones, Robert W Koivula, Aaron Leong, Gloria K W Leung, Ingrid M Libman, Kai Liu, S Alice Long, William L Lowe, Robert W Morton, Ayesha A Motala, Suna Onengut-Gumuscu, James S Pankow, Maleesa Pathirana, Sofia Pazmino, Dianna Perez, John R Petrie, Camille E Powe, Alejandra Quinteros, Rashmi Jain, Debashree Ray, Mathias Ried-Larsen, Zeb Saeed, Vanessa Santhakumar, Sarah Kanbour, Sudipa Sarkar, Gabriela S F Monaco, Denise M Scholtens, Elizabeth Selvin, Wayne Huey-Herng Sheu, Cate Speake, Maggie A Stanislawski, Nele Steenackers, Andrea K Steck, Norbert Stefan, Julie Støy, Rachael Taylor, Sok Cin Tye, Gebresilasea Gendisha Ukke, Marzhan Urazbayeva, Bart Van Der Schueren, Camille Vatier, John M Wentworth, Wesley Hannah, Sara L White, Gechang Yu, Yingchai Zhang, Shao J Zhou, Jacques Beltrand, Michel Polak, Ingvild Aukrust, Elisa De Franco, Sarah E Flanagan, Kristin A Maloney, Andrew Mcgovern, Janne Molnes, Mariam Nakabuye, Pål Rasmus Njølstad, Hugo Pomares-Millan, Michele Provenzano, Cécile Saint-Martin, Cuilin Zhang, Yeyi Zhu, Sungyoung Auh, Russell De Souza, Andrea J Fawcett, Chandra Gruber, Eskedar Getie Mekonnen, Emily Mixter, Diana Sherifali, Robert H Eckel, John J Nolan, Louis H Philipson, Rebecca J Brown, Liana K Billings, Kristen Boyle, Tina Costacou, John M Dennis, Jose C Florez, Anna L Gloyn, Maria F Gomez, Peter A Gottlieb, Siri Atma W Greeley, Kurt Griffin, Andrew T Hattersley, Irl B Hirsch, Marie-France Hivert, Korey K Hood, Jami L Josefson, Soo Heon Kwak, Lori M Laffel, Siew S Lim, Ruth J F Loos, Ronald C W Ma, Chantal Mathieu, Nestoras Mathioudakis, James B Meigs, Shivani Misra, Viswanathan Mohan, Rinki Murphy, Richard Oram, Katharine R Owen, Susan E Ozanne, Ewan R Pearson, Wei Perng, Toni I Pollin, Rodica Pop-Busui, Richard E Pratley, Leanne M Redman, Maria J Redondo, Rebecca M Reynolds, Robert K Semple, Jennifer L Sherr, Emily K Sims, Arianne Sweeting, Tiinamaija Tuomi, Miriam S Udler, Kimberly K Vesco, Tina Vilsbøll, Robert Wagner, Stephen S Rich, Paul W Franks

Faculty, Staff and Students Publications

Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, …

The Improving Medication Adherence In Adolescents And Young Adults Following Liver Transplantation (Imalt) Multisite Trial: Design And Trial Implementation Considerations, Eyal Shemesh, Sarah Duncan-Park, George Mazariegos, Rachel Annunziato, Ravinder Anand, Miguel Reyes-Mugica, Jeff Mitchell, Benjamin L Shneider

Faculty, Staff and Students Publications

BACKGROUND/AIMS: Medication non-adherence is a leading cause of transplant rejection, organ loss, and death; yet no rigorous controlled study to date has shown compelling clinical benefits from an adherence-improving intervention. Non-adherent patients are less likely to participate in trials, and therefore, most studies enroll a majority of adherent patients who do not stand to benefit from the intervention, as they do not have the condition (non-adherence) under investigation. The improving Medication Adherence in adolescent Liver Transplant recipients trial specifically targets non-adherent patients to investigate whether a remote intervention to improve adherence results in reduced incidence of biopsy-confirmed rejection.

METHODS: Improving …

A Pilot Genome-Wide Association Study Meta-Analysis Of Gastroparesis, Leticia Camargo Tavares, Tenghao Zheng, Madeline Kwicklis, Emily Mitchell, Anita Pandit, Suraj Pullapantula, Cheryl Bernard, Maris Teder-Laving, Francine Z Marques, Tonu Esko, Braden Kuo, Robert J Shulman, Bruno P Chumpitazi, Kenneth L Koch, Irene Sarosiek, Thomas L Abell, Richard W Mccallum, Henry P Parkman, Pankaj J Pasricha, Frank A Hamilton, James Tonascia, Matthew Zawistowski, Gianrico Farrugia, Madhusudan Grover, Mauro D'Amato

Faculty, Staff and Students Publications

BACKGROUND: Gastroparesis (GP) is characterized by delayed gastric emptying in the absence of mechanical obstruction.

OBJECTIVE: Genetic predisposition may play a role; however, investigation at the genome-wide level has not been performed.

METHODS: We carried out a genome-wide association study (GWAS) meta-analysis on (i) 478 GP patients from the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium (GpCRC) compared to 9931 population-based controls from the University of Michigan Health and Retirement Study; and (ii) 402 GP cases compared to 48,340 non-gastroparesis controls from the Michigan Genomics Initiative. Associations for 5,811,784 high-quality SNPs were tested on …

Age-Related Differences In The Contribution Of Systolic Blood Pressure And Biomarkers To Cardiovascular Disease Risk Prediction: The Atherosclerosis Risk In Communities (Aric) Study, Mahmoud Al Rifai, George E Taffet, Kunihiro Matsushita, Salim S Virani, James De Lemos, Amit Khera, Jarrett Berry, Chiadi Ndumele, David Aguilar, Caroline Sun, Ron C Hoogeveen, Elizabeth Selvin, Christie M Ballantyne, Vijay Nambi

Faculty, Staff and Students Publications

We sought to determine how biomarkers known to be associated with hypertension-induced end-organ injury complement the use of systolic blood pressure (SBP) for cardiovascular disease (CVD) risk prediction at different ages. Using data from visits 2 (1990 to 1992) and 5 (2011 to 2013) of the Atherosclerosis Risk in Communities (ARIC) study, 3 models were used to predict CVD (composite of coronary heart disease, stroke, and heart failure). Model A included traditional risk factors (TRFs) except SBP, model B-TRF plus SBP, and model C-TRF plus biomarkers (high-sensitivity troponin T [hsTnT] and N-terminal pro-B-type natriuretic peptide [NT-proBNP]). Harrel's C-statistics were used …

A Novel Prediction Model Of The Risk Of Pancreatic Cancer Among Diabetes Patients Using Multiple Clinical Data And Machine Learning, Shih-Min Chen, Phan Thanh Phuc, Phung-Anh Nguyen, Whitney Burton, Shwu-Jiuan Lin, Weei-Chin Lin, Christine Y Lu, Min-Huei Hsu, Chi-Tsun Cheng, Jason C Hsu

Faculty, Staff and Students Publications

INTRODUCTION: Pancreatic cancer is associated with poor prognosis. Considering the increased global incidence of diabetes cases and that individuals with diabetes are considered a high-risk subpopulation for pancreatic cancer, it is critical to detect the risk of pancreatic cancer within populations of person living = with diabetes. This study aimed to develop a novel prediction model for pancreatic cancer risk among patients with diabetes, using = a real-world database containing clinical features and employing numerous artificial intelligent approach algorithms.

METHODS: This retrospective observational study analyzed data on patients with Type 2 diabetes from a multisite Taiwanese EMR database between 2009 …

A Pancreatic Player In Dementia: Pathological Role For Islet Amyloid Polypeptide Accumulation In The Brain, Angelina S Bortoletto, Ronald J Parchem

Faculty, Staff and Students Publications

Type 2 diabetes mellitus patients have a markedly higher risk of developing dementia. While multiple factors contribute to this predisposition, one of these involves the increased secretion of amylin, or islet amyloid polypeptide, that accompanies the pathophysiology of type 2 diabetes mellitus. Islet amyloid polypeptide accumulation has undoubtedly been implicated in various forms of dementia, including Alzheimer’s disease and vascular dementia, but the exact mechanisms underlying islet amyloid polypeptide’s causative role in dementia are unclear. In this review, we have summarized the literature supporting the various mechanisms by which islet amyloid polypeptide accumulation may cause neuronal damage, ultimately leading to …

Mammalian Aging Driven By Transcription Going Awry, Brenna S Mccauley, Weiwei Dang

Faculty, Staff and Students Publications

The mechanisms that underlie increased cryptic transcription during senescence and aging have been poorly understood. Sen et al. recently identified cryptic transcription start sites (cTSSs) and chromatin state changes that may contribute to cTSS activation in mammals. Their results indicate that enhancer-promoter conversion may drive cryptic transcription in senescence.

Prevalence Of Pathogenic Germline Variants In Adult-Type Diffuse Glioma, Malcolm F Mcdonald, Lyndsey L Prather, Cassandra R Helfer, Ethan B Ludmir, Alfredo E Echeverria, Shlomit Yust-Katz, Akash J Patel, Benjamin Deneen, Ganesh Rao, Ali Jalali, Shweta U Dhar, Chris I Amos, Jacob J Mandel

Faculty, Staff and Students Publications

BACKGROUND: No consensus germline testing guidelines currently exist for glioma patients, so the prevalence of germline pathogenic variants remains unknown. This study aims to determine the prevalence and type of pathogenic germline variants in adult glioma.

METHODS: A retrospective review at a single institution with paired tumor/normal sequencing from August 2018-April 2022 was performed and corresponding clinical data were collected.

RESULTS: We identified 152 glioma patients of which 15 (9.8%) had pathogenic germline variants. Pathogenic germline variants were seen in 11/84 (13.1%) of Glioblastoma, IDH wild type; 3/42 (7.1%) of Astrocytoma, IDH mutant; and 1/26 (3.8%) of Oligodendroglioma, IDH mutant, …

Human Glp1r Variants Affecting Glp1r Cell Surface Expression Are Associated With Impaired Glucose Control And Increased Adiposity, Wenwen Gao, Lei Liu, Eunna Huh, Florence Gbahou, Erika Cecon, Masaya Oshima, Ludivine Houzé, Panagiotis Katsonis, Alan Hegron, Zhiran Fan, Guofei Hou, Guillaume Charpentier, Mathilde Boissel, Mehdi Derhourhi, Michel Marre, Beverley Balkau, Philippe Froguel, Raphael Scharfmann, Olivier Lichtarge, Julie Dam, Amélie Bonnefond, Jianfeng Liu, Ralf Jockers

Faculty, Staff and Students Publications

The glucagon-like peptide 1 receptor (GLP1R) is a major drug target with several agonists being prescribed in patients with type 2 diabetes (T2D) and obesity 1, 2. The impact of genetic variability of GLP1R on receptor function and its association with metabolic traits are unclear with conflicting reports. Here, we performed a functional profiling of 60 GLP1R variants across four signaling pathways and revealed an unexpected diversity of phenotypes ranging from defective cell surface expression to complete or pathway-specific gain- (GoF) and loss-of-functions (LoF). The defective insulin secretion of GLP1R LoF variants was rescued by allosteric GLP1R ligands …

Scalable Nanopore Sequencing Of Human Genomes Provides A Comprehensive View Of Haplotype-Resolved Variation And Methylation, Mikhail Kolmogorov, Kimberley J Billingsley, Mira Mastoras, Melissa Meredith, Jean Monlong, Ryan Lorig-Roach, Mobin Asri, Pilar Alvarez Jerez, Laksh Malik, Ramita Dewan, Xylena Reed, Rylee M Genner, Kensuke Daida, Sairam Behera, Kishwar Shafin, Trevor Pesout, Jeshuwin Prabakaran, Paolo Carnevali, Jianzhi Yang, Arang Rhie, Sonja W Scholz, Bryan J Traynor, Karen H Miga, Miten Jain, Winston Timp, Adam M Phillippy, Mark Chaisson, Fritz J Sedlazeck, Cornelis Blauwendraat, Benedict Paten

Faculty, Staff and Students Publications

Long-read sequencing technologies substantially overcome the limitations of short-reads but have not been considered as a feasible replacement for population-scale projects, being a combination of too expensive, not scalable enough or too error-prone. Here we develop an efficient and scalable wet lab and computational protocol, Napu, for Oxford Nanopore Technologies long-read sequencing that seeks to address those limitations. We applied our protocol to cell lines and brain tissue samples as part of a pilot project for the National Institutes of Health Center for Alzheimer's and Related Dementias. Using a single PromethION flow cell, we can detect single nucleotide polymorphisms with …

Neurodevelopmental Deficits And Cell-Type-Specific Transcriptomic Perturbations In A Mouse Model Of Hnrnpu Haploinsufficiency, Sarah A Dugger, Ryan S Dhindsa, Gabriela De Almeida Sampaio, Andrew K Ressler, Elizabeth E Rafikian, Sabrina Petri, Verity A Letts, Jiajie Teoh, Junqiang Ye, Sophie Colombo, Yueqing Peng, Mu Yang, Michael J Boland, Wayne N Frankel, David B Goldstein

Faculty, Staff and Students Publications

Heterozygous de novo loss-of-function mutations in the gene expression regulator HNRNPU cause an early-onset developmental and epileptic encephalopathy. To gain insight into pathological mechanisms and lay the potential groundwork for developing targeted therapies, we characterized the neurophysiologic and cell-type-specific transcriptomic consequences of a mouse model of HNRNPU haploinsufficiency. Heterozygous mutants demonstrated global developmental delay, impaired ultrasonic vocalizations, cognitive dysfunction and increased seizure susceptibility, thus modeling aspects of the human disease. Single-cell RNA-sequencing of hippocampal and neocortical cells revealed widespread, yet modest, dysregulation of gene expression across mutant neuronal subtypes. We observed an increased burden of differentially-expressed genes in mutant excitatory …

Germline Pathogenic Smarca4 Variants In Neuroblastoma, Leora Witkowski, Kim E Nichols, Marjolijn Jongmans, Nienke Van Engelen, Ronald R De Krijger, Jennifer Herrera-Mullar, Lieve Tytgat, Armita Bahrami, Helen Mar Fan, Aimee L Davidson, Thomas Robertson, Michael Anderson, Martin Hasselblatt, Sharon E Plon, William D Foulkes

Faculty, Staff and Students Publications

Heterozygous germline pathogenic variants (GPVs) in SMARCA4, the gene encoding the ATP-dependent chromatin remodeling protein SMARCA4 (previously known as BRG1), predispose to several rare tumour types, including small cell carcinoma of the ovary, hypercalcemic type, atypical teratoid and malignant rhabdoid tumor, and uterine sarcoma. The increase in germline testing of SMARCA4 in recent years has revealed putative GPVs affecting SMARCA4 in patients with other cancer types. Here we describe 11 patients with neuroblastoma, including four previously unreported cases, all of whom were found to harbour heterozygous germline variants in SMARCA4. Median age at diagnosis was 5 years (range 2 …

Views Of Adolescents And Young Adults With Cancer And Their Oncologists Toward Patients' Participation In Genomic Research, Amanda M Gutierrez, Jill O Robinson, Robin Raesz-Martinez, Isabel Canfield, Mary A Majumder, Sarah Scollon, Lauren R Desrosiers, Rebecca L Hsu, Wendy Allen-Rhoades, D Williams Parsons, Sharon E Plon, Amy L Mcguire, Janet Malek

Faculty, Staff and Students Publications

Purpose:

With increased use of genomic testing in cancer research and clinical care, it is important to understand the perspectives and decision-making preferences of adolescents and young adults (AYAs) with cancer and their treating oncologists.

Methods:

We conducted an interview substudy of the BASIC3 Study, which enrolled newly diagnosed cancer patients <18 years of age with assent. Of 32 young adults (YAs) with cancer who reached the age of majority (AOM; 18 years) while on study, 12 were successfully approached and all consented to study continuation at AOM. Of those, seven completed an interview. Patients' oncologists, who enrolled and participated in return of clinical genomic results, were also interviewed (n = 12). Interviews were transcribed, deidentified, and analyzed using thematic analysis.

Results:

YAs cited the possibility of helping others and advancing science as major reasons for their assent to initial study enrollment and their willingness to consent at AOM. YAs thought obtaining informed consent from research participants for …

Fatigue In Patients Receiving Maintenance Hemodialysis: A Review, Maurizio Bossola, S Susan Hedayati, Astrid D H Brys, L Parker Gregg

Faculty, Staff and Students Publications

Fatigue surrounding hemodialysis treatments is a common and often debilitating symptom that impacts patients' quality of life. Intradialytic fatigue develops or worsens immediately before hemodialysis and persists through the dialysis treatment. Little is known about associated risk factors or pathophysiology, although it may relate to a classic conditioning response. Postdialysis fatigue (PDF) develops or worsens after hemodialysis and may persist for hours. There is no consensus on how to measure PDF. Estimates for the prevalence of PDF range from 20%-86%, likely due to variation in methods of ascertainment and participant characteristics. Several hypotheses seek to explain the pathophysiology of PDF, …

The Pre-Adaptation Of A Stroke-Specific Self-Management Program Among Older Adults, Timothy Reistetter, Kimberly Hreha, Julianna M Dean, Monique R Pappadis, Rachel R Deer, Chih-Ying Li, Ickpyo Hong, Annalisa Na, Sara Nowakowski, Hashem M Shaltoni, Suresh K Bhavnani

Faculty, Staff and Students Publications

Objectives:

Managing multimorbidity as aging stroke patients is complex; standard self-management programs necessitate adaptations. We used visual analytics to examine complex relationships among aging stroke survivors’ comorbidities. These findings informed pre-adaptation of a component of the Chronic Disease Self-Management Program.

Methods:

Secondary analysis of 2013–2014 Medicare claims with stroke as an index condition, hospital readmission within 90 days (n=42,938), and 72 comorbidities. Visual analytics identified patient subgroups and co-occurring comorbidities. Guided by the framework for reporting adaptations and modifications to evidence-based interventions (FRAME), an interdisciplinary team developed vignettes that highlighted multimorbidity to customize the self-management program.

Results:

There were five …