Digital Commons Network^™

Oleoylethanolamide Facilitates Pparα And Tfeb Signaling And Attenuates Aβ Pathology In A Mouse Model Of Alzheimer’S Disease, Michele M Comerota, Manasee Gedam, Wen Xiong, Feng Jin, Lisheng Deng, Meng C Wang, Jin Wang, Hui Zheng

Faculty, Staff and Students Publications

BACKGROUND: Age is the strongest risk factor for the development of Alzheimer's disease (AD). Besides the pathological hallmarks of β-amyloid (Aβ) plaques and neurofibrillary tangles, emerging evidence demonstrates a critical role of microglia and neuroinflammation in AD pathogenesis. Oleoylethanolamide (OEA) is an endogenous lipid amide that has been shown to promote lifespan and healthspan in C. elegans through regulation of lysosome-to-nucleus signaling and cellular metabolism. The goal of our study was to determine the role of OEA in the mediation of microglial activity and AD pathology using its stable analog, KDS-5104.

METHODS: We used primary microglial cultures and genetic and …

Spatial Organization Of The Mouse Retina At Single Cell Resolution By Merfish, Jongsu Choi, Jin Li, Salma Ferdous, Qingnan Liang, Jeffrey R Moffitt, Rui Chen

Faculty, Staff and Students Publications

The visual signal processing in the retina requires the precise organization of diverse neuronal types working in concert. While single-cell omics studies have identified more than 120 different neuronal subtypes in the mouse retina, little is known about their spatial organization. Here, we generated the single-cell spatial atlas of the mouse retina using multiplexed error-robust fluorescence in situ hybridization (MERFISH). We profiled over 390,000 cells and identified all major cell types and nearly all subtypes through the integration with reference single-cell RNA sequencing (scRNA-seq) data. Our spatial atlas allowed simultaneous examination of nearly all cell subtypes in the retina, revealing …

Insight Into The Mechanism Of H+-Coupled Nucleobase Transport, Jun Weng, Xiaoming Zhou, Pattama Wiriyasermkul, Zhenning Ren, Kehan Chen, Eva Gil-Iturbe, Ming Zhou, Matthias Quick

Faculty, Staff and Students Publications

The nucleobase/ascorbic acid transporter (NAT) family comprises proteins in all kingdoms of life. Their substrates, nucleobases and their analogs, have special attention in therapeutic applications, such as the treatment of solid tumors, lymphoproliferative diseases, viral infections, and inflammatory diseases. Here, we present the crystal structure of a bacterial NAT member, PurT of Colwellia psychrerythraea (PurTCp) at 2.80 Å resolution that, together with functional data, provide insight into the transport mechanism of NAT family members.

Proteogenomic Data And Resources For Pan-Cancer Analysis, Yize Li, Yongchao Dou, Felipe Da Veiga Leprevost, Yifat Geffen, Anna P Calinawan, François Aguet, Yo Akiyama, Shankara Anand, Chet Birger, Song Cao, Rekha Chaudhary, Padmini Chilappagari, Marcin Cieslik, Antonio Colaprico, Daniel Cui Zhou, Corbin Day, Marcin J Domagalski, Myvizhi Esai Selvan, David Fenyö, Steven M Foltz, Alicia Francis, Tania Gonzalez-Robles, Zeynep H Gümüş, David Heiman, Michael Holck, Runyu Hong, Yingwei Hu, Eric J Jaehnig, Jiayi Ji, Wen Jiang, Lizabeth Katsnelson, Karen A Ketchum, Robert J Klein, Jonathan T Lei, Wen-Wei Liang, Yuxing Liao, Caleb M Lindgren, Weiping Ma, Lei Ma, Michael J Maccoss, Fernanda Martins Rodrigues, Wilson Mckerrow, Ngoc Nguyen, Robert Oldroyd, Alexander Pilozzi, Pietro Pugliese, Boris Reva, Paul Rudnick, Kelly V Ruggles, Dmitry Rykunov, Sara R Savage, Michael Schnaubelt, Tobias Schraink, Zhiao Shi, Deepak Singhal, Xiaoyu Song, Erik Storrs, Nadezhda V Terekhanova, Ratna R Thangudu, Mathangi Thiagarajan, Liang-Bo Wang, Joshua M Wang, Ying Wang, Bo Wen, Yige Wu, Matthew A Wyczalkowski, Yi Xin, Lijun Yao, Xinpei Yi, Hui Zhang, Qing Zhang, Maya Zuhl, Gad Getz, Li Ding, Alexey I Nesvizhskii, Pei Wang, Ana I Robles, Bing Zhang, Samuel H Payne

Faculty, Staff and Students Publications

The National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium (CPTAC) investigates tumors from a proteogenomic perspective, creating rich multi-omics datasets connecting genomic aberrations to cancer phenotypes. To facilitate pan-cancer investigations, we have generated harmonized genomic, transcriptomic, proteomic, and clinical data for >1000 tumors in 10 cohorts to create a cohesive and powerful dataset for scientific discovery. We outline efforts by the CPTAC pan-cancer working group in data harmonization, data dissemination, and computational resources for aiding biological discoveries. We also discuss challenges for multi-omics data integration and analysis, specifically the unique challenges of working with both nucleotide sequencing and mass spectrometry …

A Multicenter, Controlled Human Infection Study Of Influenza A(H1n1)Pdm09 In Healthy Adults, Justin R Ortiz, David I Bernstein, Daniel F Hoft, Christopher W Woods, Micah T Mcclain, Sharon E Frey, Rebecca C Brady, Christopher Bryant, Ashley Wegel, Robert W Frenck, Emmanuel B Walter, Getahun Abate, Sarah R Williams, Robert L Atmar, Wendy A Keitel, Nadine Rouphael, Mathew J Memoli, Mamodikoe K Makhene, Paul C Roberts, Kathleen M Neuzil

Faculty, Staff and Students Publications

BACKGROUND: We evaluated the associations between baseline influenza virus-specific hemagglutination inhibition (HAI) and microneutralization (MN) titers and subsequent symptomatic influenza virus infection in a controlled human infection study.

METHODS: We inoculated unvaccinated healthy adults aged 18-49 years with an influenza A/California/04/2009/H1N1pdm-like virus (NCT04044352). We collected serial safety labs, serum for HAI and MN, and nasopharyngeal swabs for reverse-transcription polymerase chain reaction (RT-PCR) testing. Analyses used the putative seroprotective titer of ≥40 for HAI and MN. The primary clinical outcome was mild-to-moderate influenza disease (MMID), defined as ≥1 postchallenge positive qualitative RT-PCR test with a qualifying symptom/clinical finding.

RESULTS: Of 76 …

Our Search Of Immune Invaders In The Aged Lacrimal Gland, Claudia M Trujillo-Vargas, Cintia S De Paiva

Faculty, Staff and Students Publications

No abstract provided.

Characterization Of Vascular Morphology Of Neovascular Age-Related Macular Degeneration By Indocyanine Green Angiography, Anish Attarde, Thomas S Riad, Zhao Zhang, Manisha Ahir, Yingbin Fu

Faculty, Staff and Students Publications

Age-related macular degeneration (AMD) is a leading cause of blindness among older individuals, and its prevalence is rapidly increasing due to the aging population. Choroidal neovascularization (CNV) or wet AMD, which accounts for 10%-20% of all AMD cases, is responsible for an alarming 80%-90% of AMD-related blindness. Current anti-VEGF therapies show suboptimal responses in approximately 50% of patients. Resistance to anti-VEGF treatment in CNV patients is often associated with arteriolar CNV, while responders tend to have capillary CNV. While fluorescein angiography (FA) is commonly used to assess leakage patterns in wet AMD patients and animal models, it does not provide …

Structural Underpinnings Of Mutation Rate Variations In The Human Genome, Zian Liu, Md Abul Hassan Samee

Faculty, Staff and Students Publications

Single nucleotide mutation rates have critical implications for human evolution and genetic diseases. Importantly, the rates vary substantially across the genome and the principles underlying such variations remain poorly understood. A recent model explained much of this variation by considering higher-order nucleotide interactions in the 7-mer sequence context around mutated nucleotides. This model's success implicates a connection between DNA shape and mutation rates. DNA shape, i.e. structural properties like helical twist and tilt, is known to capture interactions between nucleotides within a local context. Thus, we hypothesized that changes in DNA shape features at and around mutated positions can explain …

Author Correction: Membrane Translocation Process Revealed By In Situ Structures Of Type Ii Secretion System Secretins, Zhili Yu, Yaoming Wu, Muyuan Chen, Tong Huo, Wei Zheng, Steven J Ludtke, Xiaodong Shi, Zhao Wang

Faculty, Staff and Students Publications

No abstract provided.

Strategies For The Genomic Analysis Of Admixed Populations, Taotao Tan, Elizabeth G Atkinson

Faculty, Staff and Students Publications

Admixed populations constitute a large portion of global human genetic diversity, yet they are often left out of genomics analyses. This exclusion is problematic, as it leads to disparities in the understanding of the genetic structure and history of diverse cohorts and the performance of genomic medicine across populations. Admixed populations have particular statistical challenges, as they inherit genomic segments from multiple source populations-the primary reason they have historically been excluded from genetic studies. In recent years, however, an increasing number of statistical methods and software tools have been developed to account for and leverage admixture in the context of …

Generation Of A Novel Stra8-Driven Cre Recombinase Strain For Use In Pre-Meiotic Germ Cells In Mice†, Avery A Ahmed, Ernesto Salas, Denise G Lanza, Jason D Heaney, Stephanie A Pangas

Faculty, Staff and Students Publications

The development of oocytes occurs over a broad time frame, starting at the earliest stages of embryogenesis and continuing into adulthood. Conditional knockout technologies such as the Cre/loxP recombination system are useful for analyzing oocyte development at specific stages, but not every time frame has appropriate Cre drivers, for instance, during oocyte meiotic initiation through early prophase I in the embryo. Here, we generated a novel knockin mouse line that produces a bicistronic transcript from the endogenous Stra8 locus that includes a "self-cleaving" 2A peptide upstream of cre. This allows for high efficiency cleavage and production of both proteins individually …

Somatic Cell Structural Variant Mutagenesis And Neurologic Disease, James R Lupski

Faculty, Staff and Students Publications

Detection of organismal mosaic states for variant alleles faces technical and analytical challenges, as does the association of such variant alleles with susceptibility to neurologic disease. In this issue of Cell Genomics, Maury et al.¹ reanalyze genotyping arrays of a schizophrenia cohort providing evidence for the contribution of somatic structural variant mutagenesis and rare variant alleles.

A Dimensional Approach To Discrepancy In Parenting Styles In Russian Families, Marina A Zhukova, Nan Li, Vitalii Zhukov, Elena L Grigorenko

Faculty, Staff and Students Publications

We investigated the magnitude and direction of differences in parenting styles as they relate to children's mental health problems, as assessed using the CBCL. The sample consisted of 306 families residing in a large industrial city in Russia. We aimed to expand the cross-cultural literature on parenting styles by assessing a sample of Russian families and analyzing how agreement versus disagreement between self-reported and partner-reported parenting styles related to children's mental health problems. The findings suggested that both congruence and incongruence between parenting styles could be associated with children's mental health problems. When parents agreed about high warmth and matched …

Comparison Of Near-Infrared Spectroscopy-Based Cerebral Autoregulatory Indices In Extremely Low Birth Weight Infants, Howard Chao, Sebastian Acosta, Craig Rusin, Christopher Rhee

Faculty, Staff and Students Publications

BACKGROUND: Premature infants are born with immature cerebral autoregulation function and are vulnerable to pressure passive cerebral circulation and subsequent brain injury. Measurements derived from near-infrared spectroscopy (NIRS) have enabled continuous assessment of cerebral vasoreactivity. Although NIRS has enabled a growing field of research, the lack of clear standardization in the field remains problematic. A major limitation of current literature is the absence of a comparative analysis of the different methodologies.

OBJECTIVES: To determine the relationship between NIRS-derived continuous indices of cerebral autoregulation in a cohort of extremely low birth weight (ELBW) infants.

METHODS: Premature infants of birth weight 401-1000 …

A De Novo Missense Variant In Ezh1 Associated With Developmental Delay Exhibits Functional Deficits In Drosophila Melanogaster, Sharayu V Jangam, Lauren C Briere, Kristy L Jay, Jonathan C Andrews, Melissa A Walker, Lance H Rodan, Frances A High, Undiagnosed Diseases Network, Shinya Yamamoto, David A Sweetser, Michael F Wangler

Faculty, Staff and Students Publications

EZH1, a polycomb repressive complex-2 component, is involved in a myriad of cellular processes. EZH1 represses transcription of downstream target genes through histone 3 lysine27 (H3K27) trimethylation (H3K27me3). Genetic variants in histone modifiers have been associated with developmental disorders, while EZH1 has not yet been linked to any human disease. However, the paralog EZH2 is associated with Weaver syndrome. Here we report a previously undiagnosed individual with a novel neurodevelopmental phenotype identified to have a de novo missense variant in EZH1 through exome sequencing. The individual presented in infancy with neurodevelopmental delay and hypotonia and was later noted to have …

Dimethyl Sulfoxide Inhibits Bile Acid Synthesis In Healthy Mice But Does Not Protect Mice From Bile-Acid-Induced Liver Damage, Xi Chen, Huiqiao Li, Yu'e Liu, Jing Qi, Bingning Dong, Shixia Huang, Shangang Zhao, Yi Zhu

Faculty, Staff and Students Publications

Bile acids serve a vital function in lipid digestion and absorption; however, their accumulation can precipitate liver damage. In our study, we probed the effects of dimethyl sulfoxide (DMSO) on bile acid synthesis and the ensuing liver damage in mice induced by bile acids. Our findings indicate that DMSO efficaciously curbs bile acid synthesis by inhibiting key enzymes involved in the biosynthetic pathway, both in cultured primary hepatocytes and in vivo. Contrarily, we observed that DMSO treatment did not confer protection against bile-acid-induced liver damage in two distinct mouse models: one induced by a 0.1% DDC diet, leading to bile …

Loss Of Microrna-30a And Sex-Specific Effects On The Neonatal Hyperoxic Lung Injury, Sandra L Grimm, Samuel Reddick, Xiaoyu Dong, Connor Leek, Amy Xiao Wang, Manuel Cantu Gutierrez, Sean M Hartig, Bhagavatula Moorthy, Cristian Coarfa, Krithika Lingappan

Faculty, Staff and Students Publications

BACKGROUND: Bronchopulmonary dysplasia (BPD) is characterized by an arrest in lung development and is a leading cause of morbidity in premature neonates. It has been well documented that BPD disproportionally affects males compared to females, but the molecular mechanisms behind this sex-dependent bias remain unclear. Female mice show greater preservation of alveolarization and angiogenesis when exposed to hyperoxia, accompanied by increased miR-30a expression. In this investigation, we tested the hypothesis that loss of miR-30a would result in male and female mice experiencing similar impairments in alveolarization and angiogenesis under hyperoxic conditions.

METHODS: Wild-type and miR-30a−/− neonatal mice were exposed …

Dna-Encoded Chemical Libraries Yield Non-Covalent And Non-Peptidic Sars-Cov-2 Main Protease Inhibitors, Ravikumar Jimmidi, Srinivas Chamakuri, Shuo Lu, Melek Nihan Ucisik, Peng-Jen Chen, Kurt M Bohren, Seyed Arad Moghadasi, Leroy Versteeg, Christina Nnabuife, Jian-Yuan Li, Xuan Qin, Ying-Chu Chen, John C Faver, Pranavanand Nyshadham, Kiran L Sharma, Banumathi Sankaran, Allison Judge, Zhifeng Yu, Feng Li, Jeroen Pollet, Reuben S Harris, Martin M Matzuk, Timothy Palzkill, Damian W Young

Faculty, Staff and Students Publications

The development of SARS-CoV-2 main protease (Mpro) inhibitors for the treatment of COVID-19 has mostly benefitted from X-ray structures and preexisting knowledge of inhibitors; however, an efficient method to generate Mpro inhibitors, which circumvents such information would be advantageous. As an alternative approach, we show here that DNA-encoded chemistry technology (DEC-Tec) can be used to discover inhibitors of Mpro. An affinity selection of a 4-billion-membered DNA-encoded chemical library (DECL) using Mpro as bait produces novel non-covalent and non-peptide-based small molecule inhibitors of Mpro with low nanomolar Ki values. Furthermore, these compounds demonstrate efficacy against mutant forms of Mpro that …

Reduced Racial Disparity As A Result Of Survival Improvement In Prostate Cancer, Baoyi Zhang, Jianrong Li, Mabel Tang, Chao Cheng

Faculty, Staff and Students Publications

Prostate cancer is a cancer type associated with a high level of racial and socioeconomic disparities as reported by many previous studies. However, the changes in these disparities in the past two decades have not been systematically studied. In this study, we investigated the Surveillance Epidemiology End Results (SEER) data for prostate cancer patients diagnosed during 2004-2018. African Americans and Asians showed significantly better and worse cancer-specific survival (CSS), respectively, compared to non-Hispanic white individuals after adjusting for confounding factors such as age and cancer stage. Importantly, the data indicated that racial disparities fluctuated and reached the highest level during …

Skp2-Mediated Mlkl Degradation Confers Cisplatin-Resistant In Non-Small Cell Lung Cancer Cells, Huiling Zhou, Li Zhou, Qing Guan, Xuyang Hou, Cong Wang, Lijun Liu, Jian Wang, Xinfang Yu, Wei Li, Haidan Liu

Faculty, Staff and Students Publications

Non-small cell lung cancer (NSCLC) is the most prevalent type of cancer and the leading cause of cancer-related death. Chemotherapeutic resistance is a major obstacle in treating NSCLC patients. Here, we discovered that the E3 ligase Skp2 is overexpressed, accompanied by the downregulation of necroptosis-related regulator MLKL in human NSCLC tissues and cell lines. Knockdown of Skp2 inhibited viability, anchorage-independent growth, and in vivo tumor development of NSCLC cells. We also found that the Skp2 protein is negatively correlated with MLKL in NSCLC tissues. Moreover, Skp2 is increased and accompanied by an upregulation of MLKL ubiquitination and degradation in cisplatin-resistant …

Chromatin Architectural Factor Ctcf Is Essential For Progesterone-Dependent Uterine Maturation, Sylvia C Hewitt, Artiom Gruzdev, Cynthia J Willson, San-Pin Wu, John P Lydon, Niels Galjart, Francesco J Demayo

Faculty, Staff and Students Publications

Receptors for estrogen and progesterone frequently interact, via Cohesin/CTCF loop extrusion, at enhancers distal from regulated genes. Loss-of-function CTCF mutation in >20% of human endometrial tumors indicates its importance in uterine homeostasis. To better understand how CTCF-mediated enhancer-gene interactions impact endometrial development and function, the Ctcf gene was selectively deleted in female reproductive tissues of mice. Prepubertal Ctcf

Delayed Skeletal Development And Igf-1 Deficiency In A Mouse Model Of Lysinuric Protein Intolerance, Bridget M Stroup, Xiaohui Li, Sara Ho, Haonan Zhouyao, Yuqing Chen, Safa Ani, Brian Dawson, Zixue Jin, Ronit Marom, Ming-Ming Jiang, Isabel Lorenzo, Daniel Rosen, Denise Lanza, Nathalie Aceves, Sara Koh, John R Seavitt, Jason D Heaney, Brendan Lee, Lindsay C Burrage

Faculty, Staff and Students Publications

SLC7A7 deficiency, or lysinuric protein intolerance (LPI), causes loss of function of the y+LAT1 transporter critical for efflux of arginine, lysine and ornithine in certain cells. LPI is characterized by urea cycle dysfunction, renal disease, immune dysregulation, growth failure, delayed bone age and osteoporosis. We previously reported that Slc7a7 knockout mice (C57BL/6×129/SvEv F2) recapitulate LPI phenotypes, including growth failure. Our main objective in this study was to characterize the skeletal phenotype in these mice. Compared to wild-type littermates, juvenile Slc7a7 knockout mice demonstrated 70% lower body weights, 87% lower plasma IGF-1 concentrations and delayed skeletal development. Because poor survival prevents …

Disparities In Antifibrotic Medication Utilization Among Veterans With Idiopathic Pulmonary Fibrosis, Bhavika Kaul, Joyce S Lee, Laura A Petersen, Charles Mcculloch, Ivan O Rosas, Venkata D Bandi, Ning Zhang, Alison M Dedent, Harold R Collard, Mary A Whooley

Faculty, Staff and Students Publications

BACKGROUND: Two antifibrotic medications, pirfenidone and nintedanib, are approved for the treatment of idiopathic pulmonary fibrosis (IPF). Little is known about their real-world adoption.

RESEARCH QUESTION: What are the real-world antifibrotic utilization rates and factors associated with uptake among a national cohort of veterans with IPF?

STUDY DESIGN AND METHODS: This study identified veterans with IPF who received care either provided by the Veterans Affairs (VA) Healthcare System or non-VA care paid for by the VA. Patients who had filled at least one antifibrotic prescription through the VA pharmacy or Medicare Part D between October 15, 2014, and December 31, …

Nonalcoholic Steatohepatitis-Related Hepatocellular Carcinoma: Pathogenesis And Treatment, Josep M Llovet, Catherine E Willoughby, Amit G Singal, Tim F Greten, Mathias Heikenwälder, Hashem B El-Serag, Richard S Finn, Scott L Friedman

Faculty, Staff and Students Publications

Nonalcoholic fatty liver disease (NAFLD), including its more severe manifestation, nonalcoholic steatohepatitis (NASH), has a global prevalence of 20-25% and is a major public health problem. Its incidence is increasing in parallel to the rise in obesity, diabetes and metabolic syndrome. Progression from NASH to NASH-related hepatocellular carcinoma (HCC) (~2% of cases per year) is influenced by many factors, including the tissue and immune microenvironment, germline mutations in PNPLA3, and the microbiome. NASH-HCC has unique molecular and immune traits compared with other aetiologies of HCC and is equally prevalent in men and women. Comorbidities associated with NASH, such as obesity …

Heterogeneity Of The Group B Streptococcal Type Vii Secretion System And Influence On Colonization Of The Female Genital Tract, Brady L Spencer, Alyx M Job, Clare M Robertson, Zainab A Hameed, Camille Serchejian, Caitlin S Wiafe-Kwakye, Jéssica C Mendonça, Morgan A Apolonio, Prescilla E Nagao, Melody N Neely, Natalia Korotkova, Konstantin V Korotkov, Kathryn A Patras, Kelly S Doran

Faculty, Staff and Students Publications

Type VIIb secretion systems (T7SSb) in Gram-positive bacteria facilitate physiology, interbacterial competition, and/or virulence via EssC ATPase-driven secretion of small ɑ-helical proteins and toxins. Recently, we characterized T7SSb in group B Streptococcus (GBS), a leading cause of infection in newborns and immunocompromised adults. GBS T7SS comprises four subtypes based on variation in the C-terminus of EssC and the repertoire of downstream effectors; however, the intraspecies diversity of GBS T7SS and impact on GBS-host interactions remains unknown. Bioinformatic analysis indicates that GBS T7SS loci encode subtype-specific putative effectors, which have low interspecies and inter-subtype homology but contain similar domains/motifs and therefore …

Deconvolution Of Cancer Cell States By The Xdec-Sm Method, Oscar D Murillo, Varduhi Petrosyan, Emily L Laplante, Lacey E Dobrolecki, Michael T Lewis, Aleksandar Milosavljevic

Faculty, Staff and Students Publications

Proper characterization of cancer cell states within the tumor microenvironment is a key to accurately identifying matching experimental models and the development of precision therapies. To reconstruct this information from bulk RNA-seq profiles, we developed the XDec Simplex Mapping (XDec-SM) reference-optional deconvolution method that maps tumors and the states of constituent cells onto a biologically interpretable low-dimensional space. The method identifies gene sets informative for deconvolution from relevant single-cell profiling data when such profiles are available. When applied to breast tumors in The Cancer Genome Atlas (TCGA), XDec-SM infers the identity of constituent cell types and their proportions. XDec-SM also …

Spatial Mapping Of The Dna Adducts In Cancer, Kimiko L Krieger, Elise K Mann, Kevin J Lee, Elyse Bolterstein, Deborah Jebakumar, Michael M Ittmann, Valeria L Dal Zotto, Mohamed Shaban, Arun Sreekumar, Natalie R Gassman

Faculty, Staff and Students Publications

DNA adducts and strand breaks are induced by various exogenous and endogenous agents. Accumulation of DNA damage is implicated in many disease processes, including cancer, aging, and neurodegeneration. The continuous acquisition of DNA damage from exogenous and endogenous stressors coupled with defects in DNA repair pathways contribute to the accumulation of DNA damage within the genome and genomic instability. While mutational burden offers some insight into the level of DNA damage a cell may have experienced and subsequently repaired, it does not quantify DNA adducts and strand breaks. Mutational burden also infers the identity of the DNA damage. With advances …

Cation Leak Through The Atp1a3 Pump Causes Spasticity And Intellectual Disability, Daniel G Calame, Cristina Moreno Vadillo, Seth Berger, Timothy Lotze, Marwan Shinawi, Javaher Poupak, Corina Heller, Julie Cohen, Richard Person, Aida Telegrafi, Chalongchai Phitsanuwong, Kaylene Fiala, Isabelle Thiffault, Florencia Del Viso, Dihong Zhou, Emily A Fleming, Tomi Pastinen, Ali Fatemi, Sruthi Thomas, Samuel I Pascual, Rosa J Torres, Carmen Prior, Clara Gómez-González, Saskia Biskup, James R Lupski, Dragan Maric, Miguel Holmgren, Debra Regier, Sho T Yano

Faculty, Staff and Students Publications

ATP1A3 encodes the α3 subunit of the sodium-potassium ATPase, one of two isoforms responsible for powering electrochemical gradients in neurons. Heterozygous pathogenic ATP1A3 variants produce several distinct neurological syndromes, yet the molecular basis for phenotypic variability is unclear.

We report a novel recurrent variant, ATP1A3(NM_152296.5):c.2324C>T; p.(Pro775Leu), in nine individuals associated with the primary clinical features of progressive or non-progressive spasticity and developmental delay/intellectual disability. No patients fulfil diagnostic criteria for ATP1A3-associated syndromes, including alternating hemiplegia of childhood, rapid-onset dystonia-parkinsonism or cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss (CAPOS), and none were suspected of having an ATP1A3 …

Multiscale Analysis Of Pangenomes Enables Improved Representation Of Genomic Diversity For Repetitive And Clinically Relevant Genes, Chen-Shan Chin, Sairam Behera, Asif Khalak, Fritz J Sedlazeck, Peter H Sudmant, Justin Wagner, Justin M Zook

Faculty, Staff and Students Publications

Advancements in sequencing technologies and assembly methods enable the regular production of high-quality genome assemblies characterizing complex regions. However, challenges remain in efficiently interpreting variation at various scales, from smaller tandem repeats to megabase rearrangements, across many human genomes. We present a PanGenome Research Tool Kit (PGR-TK) enabling analyses of complex pangenome structural and haplotype variation at multiple scales. We apply the graph decomposition methods in PGR-TK to the class II major histocompatibility complex demonstrating the importance of the human pangenome for analyzing complicated regions. Moreover, we investigate the Y-chromosome genes, DAZ1/DAZ2/DAZ3/DAZ4, of which structural variants have been linked to …

Proteomics Of Adjacent-To-Tumor Samples Uncovers Clinically Relevant Biological Events In Hepatocellular Carcinoma, Hongwen Zhu, Youpei Lin, Dayun Lu, Shisheng Wang, Yuejia Liu, Liangqing Dong, Qian Meng, Jing Gao, Yuqiu Wang, Nixue Song, Yuying Suo, Li Ding, Pei Wang, Bing Zhang, Daming Gao, Jia Fan, Qiang Gao, Hu Zhou

Faculty, Staff and Students Publications

Normal adjacent tissues (NATs) of hepatocellular carcinoma (HCC) differ from healthy liver tissues and their heterogeneity may contain biological information associated with disease occurrence and clinical outcome that has yet to be fully evaluated at the proteomic level. This study provides a detailed description of the heterogeneity of NATs and the differences between NATs and healthy livers and revealed that molecular features of tumor subgroups in HCC were partially reflected in their respective NATs. Proteomic data classified HCC NATs into two subtypes (Subtypes 1 and 2), and Subtype 2 was associated with poor prognosis and high-risk recurrence. The pathway and …