Digital Commons Network^™

Genome-Wide Crispr Screens Reveal Zatt As A Synthetic Lethal Target Of Top2-Poison Etoposide That Can Act In A Tdp2-Independent Pathway, Jeong-Min Park, Huimin Zhang, Litong Nie, Chao Wang, Min Huang, Xu Feng, Mengfan Tang, Zhen Chen, Yun Xiong, Namsoo Lee, Siting Li, Ling Yin, Traver Hart, Junjie Chen

Faculty, Staff and Student Publications

Etoposide (ETO) is an anticancer drug that targets topoisomerase II (TOP2). It stabilizes a normally transient TOP2-DNA covalent complex (TOP2cc), thus leading to DNA double-strand breaks (DSBs). Tyrosyl-DNA phosphodiesterases two (TDP2) is directly involved in the repair of TOP2cc by removing phosphotyrosyl peptides from 5'-termini of DSBs. Recent studies suggest that additional factors are required for TOP2cc repair, which include the proteasome and the zinc finger protein associated with TDP2 and TOP2, named ZATT. ZATT may alter the conformation of TOP2cc in a way that renders the accessibility of TDP2 for TOP2cc removal. In this study, our genome-wide clustered regularly …

The Prognostic Value Of Baseline Clinical And Radiologic Imaging Features In Patients With Unresectable Hepatocellular Carcinoma Treated With Atezolizumab Plus Bevacizumab, Mikhail Bogdanov

Faculty, Staff and Student Publications

Membrane asymmetry means that the two sides of membrane are structurally, physically and functionally different. Membrane asymmetry is largely related to the lipid sidedness and particularly to compositional (lipid head and acyl group) and physical (lipid packing order, charge, hydration and H-bonding interactions) differences in the inner and outer leaflets of lipid bilayer. Chemically, structurally and conformationally different non-covalent bound lipid molecules are physically fluid and deformable and enable to interact dynamically to form transient arrangements with asymmetry both perpendicular and parallel to the plane of the lipid bilayer. Although biological membranes are almost universally asymmetric however the asymmetry is …

Environmental Enrichment Devices Are Safe And Effective At Reducing Undesirable Behaviors In California Sea Lions And Northern Elephant Seals During Rehabilitation, Kirsten Donald, Amanda Benedetti, Vinícius Donisete Lima Rodrigues Goulart, Alissa Deming, Hendrik Nollens, Grey Stafford, Sabrina Brando

Faculty, Staff and Student Publications

Environmental enrichment devices (EEDs) have been proven to promote positive wellbeing in zoos and aquariums, and support animals' reintroduction success; however, their use in rehabilitation centers is still limited. This pilot study investigated the safety and efficacy of three EEDs, Artificial Kelp, Horse KONG™ and Wubba Kong™, and their ability to decrease and/or eliminate undesired stereotypic behaviors or looking at staff/staff areas in seven wild California sea lions (CSLs) and eight northern elephant seals (NESs) undergoing rehabilitation in Southern California. Observers conducted instantaneous sampling once a minute during a 30-min baseline, followed by a 30-min EED implementation on one focal …

Renovating A Double Fence With Or Without Notifying The Next Door And Across The Street Neighbors: Why The Biogenic Cytoplasmic Membrane Of Gram-Negative Bacteria Display Asymmetry?, Mikhail Bogdanov

Faculty, Staff and Student Publications

The complex two-membrane organization of the envelope of Gram-negative bacteria imposes an unique biosynthetic and topological constraints that can affect translocation of lipids and proteins synthesized on the cytoplasm facing leaflet of the cytoplasmic (inner) membrane (IM), across the IM and between the IM and outer membrane (OM). Balanced growth of two membranes and continuous loss of phospholipids in the periplasmic leaflet of the IM as metabolic precursors for envelope components and for translocation to the OM requires a constant supply of phospholipids in the IM cytosolic leaflet. At present we have no explanation as to why the biogenic E. …

Visualizing Lipid Membrane Structure With Cryo-Em: Past, Present, And Future, Karan D Sharma, Frederick A Heberle, M Neal Waxham

Faculty, Staff and Student Publications

The development of electron cryomicroscopy (cryo-EM) has evolved immensely in the last several decades and is now well-established in the analysis of protein structure both in isolation and in their cellular context. This review focuses on the history and application of cryo-EM to the analysis of membrane architecture. Parallels between the levels of organization of protein structure are useful in organizing the discussion of the unique parameters that influence the collective behavior that influences membrane structure and function. Importantly, the timescales of lipid motion in bilayers with respect to the timescales of sample vitrification is discussed and reveals what types …

Renovating A Double Fence With Or Without Notifying The Next Door And Across The Street Neighbors: Why The Biogenic Cytoplasmic Membrane Of Gram-Negative Bacteria Display Asymmetry?, Mikhail Bogdanov

Faculty, Staff and Student Publications

The complex two-membrane organization of the envelope of Gram-negative bacteria imposes an unique biosynthetic and topological constraints that can affect translocation of lipids and proteins synthesized on the cytoplasm facing leaflet of the cytoplasmic (inner) membrane (IM), across the IM and between the IM and outer membrane (OM). Balanced growth of two membranes and continuous loss of phospholipids in the periplasmic leaflet of the IM as metabolic precursors for envelope components and for translocation to the OM requires a constant supply of phospholipids in the IM cytosolic leaflet. At present we have no explanation as to why the biogenic E. …

Targeting The Molecular And Immunologic Features Of Leiomyosarcoma, Brandon M Cope, Raymond S Traweek, Rossana Lazcano, Emily Z Keung, Alexander J Lazar, Christina L Roland, Elise F Nassif

Faculty, Staff and Student Publications

Leiomyosarcoma (LMS) is a rare, aggressive mesenchymal tumor with smooth muscle differentiation. LMS is one of the most common histologic subtypes of soft tissue sarcoma; it most frequently occurs in the extremities, retroperitoneum, or uterus. LMS often demonstrates aggressive tumor biology, with a higher risk of developing distant metastatic disease than most sarcoma histologic types. The prognosis is poor, particularly in patients with uterine disease, and there is a need for the development of more effective therapies. Genetically, LMS is karyotypically complex and characterized by a low tumor mutational burden, with frequent alterations in TP53, RB1, PTEN, …

Functional Effects Of Disease-Associated Variants Reveal That The S1-M1 Linker Of The Nmda Receptor Critically Controls Channel Opening, Lingling Xie, Miranda J Mcdaniel, Riley E Perszyk, Sukhan Kim, Gerarda Cappuccio, Kevin A Shapiro, Beatriz Muñoz-Cabello, Pedro A Sanchez-Lara, Katheryn Grand, Jing Zhang, Kelsey A Nocilla, Rehan Sheikh, Lluis Armengol, Roberta Romano, Tyler Mark Pierson, Hongjie Yuan, Scott J Myers, Stephen F Traynelis

Faculty, Staff and Students Publications

The short pre-M1 helix within the S1-M1 linker (also referred to as the pre-M1 linker) between the agonist-binding domain (ABD, S1) and the M1 transmembrane helix of the NMDA receptor (NMDAR) is devoid of missense variants within the healthy population but is a locus for de novo pathogenic variants associated with neurological disorders. Several de novo variants within this helix have been identified in patients presenting early in life with intellectual disability, developmental delay, and/or epilepsy. In this study, we evaluated functional properties for twenty variants within the pre-M1 linker in GRIN1, GRIN2A, and GRIN2B genes, including six novel missense …

The En-Tex Resource Of Multi-Tissue Personal Epigenomes & Variant-Impact Models, Joel Rozowsky, Jiahao Gao, Beatrice Borsari, Yucheng T Yang, Timur Galeev, Gamze Gürsoy, Charles B Epstein, Kun Xiong, Jinrui Xu, Tianxiao Li, Jason Liu, Keyang Yu, Ana Berthel, Zhanlin Chen, Fabio Navarro, Maxwell S Sun, James Wright, Justin Chang, Christopher J F Cameron, Noam Shoresh, Elizabeth Gaskell, Jorg Drenkow, Jessika Adrian, Sergey Aganezov, François Aguet, Gabriela Balderrama-Gutierrez, Samridhi Banskota, Guillermo Barreto Corona, Sora Chee, Surya B Chhetri, Gabriel Conte Cortez Martins, Cassidy Danyko, Carrie A Davis, Daniel Farid, Nina P Farrell, Idan Gabdank, Yoel Gofin, David U Gorkin, Mengting Gu, Vivian Hecht, Benjamin C Hitz, Robbyn Issner, Yunzhe Jiang, Melanie Kirsche, Xiangmeng Kong, Bonita R Lam, Shantao Li, Bian Li, Xiqi Li, Khine Zin Lin, Ruibang Luo, Mark Mackiewicz, Ran Meng, Jill E Moore, Jonathan Mudge, Nicholas Nelson, Chad Nusbaum, Ioann Popov, Henry E Pratt, Yunjiang Qiu, Srividya Ramakrishnan, Joe Raymond, Leonidas Salichos, Alexandra Scavelli, Jacob M Schreiber, Fritz J Sedlazeck, Lei Hoon See, Rachel M Sherman, Xu Shi, Minyi Shi, Cricket Alicia Sloan, J Seth Strattan, Zhen Tan, Forrest Y Tanaka, Anna Vlasova, Jun Wang, Jonathan Werner, Brian Williams, Min Xu, Chengfei Yan, Lu Yu, Christopher Zaleski, Jing Zhang, Kristin Ardlie, J Michael Cherry, Eric M Mendenhall, William S Noble, Zhiping Weng, Morgan E Levine, Alexander Dobin, Barbara Wold, Ali Mortazavi, Bing Ren, Jesse Gillis, Richard M Myers, Michael P Snyder, Jyoti Choudhary, Aleksandar Milosavljevic, Michael C Schatz, Bradley E Bernstein, Roderic Guigó, Thomas R Gingeras, Mark Gerstein

Faculty, Staff and Students Publications

Understanding how genetic variants impact molecular phenotypes is a key goal of functional genomics, currently hindered by reliance on a single haploid reference genome. Here, we present the EN-TEx resource of 1,635 open-access datasets from four donors (∼30 tissues × ∼15 assays). The datasets are mapped to matched, diploid genomes with long-read phasing and structural variants, instantiating a catalog of >1 million allele-specific loci. These loci exhibit coordinated activity along haplotypes and are less conserved than corresponding, non-allele-specific ones. Surprisingly, a deep-learning transformer model can predict the allele-specific activity based only on local nucleotide-sequence context, highlighting the importance of transcription-factor-binding …

Reconstruction Of Critical Sized Maxillofacial Defects Using Composite Allogeneic Tissue Engineering: Systematic Review Of Current Literature, Shaqayeq Ramezanzade, Mahsa Aeinehvand, Heliya Ziaei, Zohaib Khurshid, Seied Omid Keyhan, Hamid R Fallahi, James C Melville, Morvarid Saeinasab, Farshid Sefat

Faculty, Staff and Student Publications

The current review aimed to assess the reliability and efficacy of tissue-engineered composite grafts in the reconstruction of large maxillofacial defects resulting from trauma or a benign pathologic disease. A systematic review of the literature was conducted using PubMed/Medline, Embase, and Scopus up to March 2022. The eligibility criteria included patients who had been treated with composite allogeneic tissue engineering for immediate/delayed reconstruction of large maxillofacial defects with minimum/no bone harvesting site. In the initial search, 2614 papers were obtained, and finally, 13 papers were eligible to be included in the current study. Most included papers were case reports or …

Ultralow-Dose Binary Oncolytic/Helper-Dependent Adenovirus Promotes Antitumor Activity In Preclinical And Clinical Studies, Daniel Wang, Caroline E Porter, Bora Lim, Amanda Rosewell Shaw, Catherine S Robertson, Mae L Woods, Ya Xu, Greyson G W Biegert, Daisuke Morita, Tao Wang, Bambi J Grilley, Helen Heslop, Malcolm K Brenner, Masataka Suzuki

Faculty, Staff and Students Publications

We show that a binary oncolytic/helper-dependent adenovirus (CAdVEC) that both lyses tumor cells and locally expresses the proinflammatory cytokine IL-12 and PD-L1 blocking antibody has potent antitumor activity in humanized mouse models. On the basis of these preclinical studies, we treated four patients with a single intratumoral injection of an ultralow dose of CAdVEC (NCT03740256), representing a dose of oncolytic adenovirus more than 100-fold lower than used in previous trials. While CAdVEC caused no significant toxicities, it repolarized the tumor microenvironment with increased infiltration of CD8 T cells. A single administration of CAdVEC was associated with both locoregional and abscopal …

The Emergence Of A Virus Variant: Dynamics Of A Competition Model With Cross-Immunity Time-Delay Validated By Wastewater Surveillance Data For Covid-19, Bruce Pell, Samantha Brozak, Tin Phan, Fuqing Wu, Yang Kuang

Faculty, Staff and Student Publications

We consider the dynamics of a virus spreading through a population that produces a mutant strain with the ability to infect individuals that were infected with the established strain. Temporary cross-immunity is included using a time delay, but is found to be a harmless delay. We provide some sufficient conditions that guarantee local and global asymptotic stability of the disease-free equilibrium and the two boundary equilibria when the two strains outcompete one another. It is shown that, due to the immune evasion of the emerging strain, the reproduction number of the emerging strain must be significantly lower than that of …

Inferring Gene Regulatory Networks From Rna-Seq Data Using Kernel Classification, Amira Al-Aamri, Andrzej S Kudlicki, Maher Maalouf, Kamal Taha, Dirar Homouz

Faculty, Staff and Student Publications

Gene expression profiling is one of the most recognized techniques for inferring gene regulators and their potential targets in gene regulatory networks (GRN). The purpose of this study is to build a regulatory network for the budding yeast Saccharomyces cerevisiae genome by incorporating the use of RNA-seq and microarray data represented by a wide range of experimental conditions. We introduce a pipeline for data analysis, data preparation, and training models. Several kernel classification models; including one-class, two-class, and rare event classification methods, are used to categorize genes. We test the impact of the normalization techniques on the overall performance of …

Hpv-Related Anal Cancer Is Associated With Changes In The Anorectal Microbiome During Cancer Development, Jacob H Elnaggar, Victoria O Huynh, Daniel Lin, R Tyler Hillman, Chike O Abana, Molly B El Alam, Katarina C Tomasic, Tatiana V Karpinets, Ramez Kouzy, Jae L Phan, Jennifer Wargo, Emma B Holliday, Prajnan Das, Melissa P Mezzari, Nadim J Ajami, Erica J Lynn, Bruce D Minsky, Van K Morris, Andrea Milbourne, Craig A Messick, Ann H Klopp, P Andrew Futreal, Cullen M Taniguchi, Kathleen M Schmeler, Lauren E Colbert

Faculty, Staff and Student Publications

BACKGROUND: Squamous cell carcinoma of the anus (SCCA) is a rare gastrointestinal cancer. Factors associated with progression of HPV infection to anal dysplasia and cancer are unclear and screening guidelines and approaches for anal dysplasia are less clear than for cervical dysplasia. One potential contributing factor is the anorectal microbiome. In this study, we aimed to identify differences in anal microbiome composition in the settings of HPV infection, anal dysplasia, and anal cancer in this rare disease.

METHODS: Patients were enrolled in two prospective studies. Patients with anal dysplasia were part of a cross-sectional cohort that enrolled women with high-grade …

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 …

Language: Its Origin And Ongoing Evolution, Ilia Markov, Kseniia Kharitonova, Elena L Grigorenko

Faculty, Staff and Students Publications

With the present paper, we sought to use research findings to illustrate the following thesis: the evolution of language follows the principles of human evolution. We argued that language does not exist for its own sake, it is one of a multitude of skills that developed to achieve a shared communicative goal, and all its features are reflective of this. Ongoing emerging language adaptations strive to better fit the present state of the human species. Theories of language have evolved from a single-modality to multimodal, from human-specific to usage-based and goal-driven. We proposed that language should be viewed as a …

Hsc-Independent Definitive Hematopoiesis Persists Into Adult Life, Michihiro Kobayashi, Haichao Wei, Takashi Yamanashi, Nathalia Azevedo Portilho, Samuel Cornelius, Noemi Valiente, Chika Nishida, Haizi Cheng, Augusto Latorre, W Jim Zheng, Joonsoo Kang, Jun Seita, David J Shih, Jia Qian Wu, Momoko Yoshimoto

Faculty, Staff and Student Publications

It is widely believed that hematopoiesis after birth is established by hematopoietic stem cells (HSCs) in the bone marrow and that HSC-independent hematopoiesis is limited only to primitive erythro-myeloid cells and tissue-resident innate immune cells arising in the embryo. Here, surprisingly, we find that significant percentages of lymphocytes are not derived from HSCs, even in 1-year-old mice. Instead, multiple waves of hematopoiesis occur from embryonic day 7.5 (E7.5) to E11.5 endothelial cells, which simultaneously produce HSCs and lymphoid progenitors that constitute many layers of adaptive T and B lymphocytes in adult mice. Additionally, HSC lineage tracing reveals that the contribution …

Clinical Outcomes Associated With Npm1 Mutations In Patients With Relapsed Or Refractory Aml, Ghayas C Issa, Aram Bidikian, Sangeetha Venugopal, Marina Konopleva, Courtney D Dinardo, Tapan M Kadia, Gautam Borthakur, Elias Jabbour, Naveen Pemmaraju, Musa Yilmaz, Nicholas J Short, Abhishek Maiti, Koji Sasaki, Lucia Masarova, Sherry Pierce, Koichi Takahashi, Guilin Tang, Sanam Loghavi, Keyur Patel, Michael Andreeff, Kapil Bhalla, Guillermo Garcia-Manero, Farhad Ravandi, Hagop Kantarjian, Naval Daver

Faculty, Staff and Student Publications

Mutations in Nucleophosmin 1 (NPM1) are associated with a favorable prognosis in newly diagnosed acute myeloid leukemia (AML), however, their prognostic impact in relapsed/refractory (R/R) settings are unknown. In a retrospective analysis, we identified 206 patients (12%) with mutated NPM1 (NPM1c) and compared their outcomes to 1516 patients (88%) with NPM1 wild-type (NPM1wt). NPM1c was associated with higher rates of complete remission or complete remission with incomplete count recovery compared with NPM1wt following each line of salvage therapy (first salvage, 56% vs 37%; P < .0001; second salvage, 33% vs 22%; P = .02; third salvage, 24% vs 14%; P = .02). However, NPM1 mutations had no impact on relapse-free survival (RFS) and overall survival (OS) with each salvage therapy with a median OS following salvage 1, 2 or 3 therapies in NPM1c vs NPM1wt of 7.8 vs 6.0; 5.3 vs 4.1; and 3.5 vs 3.6 months, respectively. Notably, the addition of venetoclax to salvage regimens in patients with NPM1c improved RFS and OS (median RFS, 15.8 vs 4.6 months; P = .05; median OS, 14.7 vs 5.9 months; P = .02). In conclusion, NPM1 mutational status has a minimal impact on prognosis in relapsed or refractory AML; therefore, novel treatment strategies are required to improve outcomes in this entity.

Rewired M6a Epitranscriptomic Networks Link Mutant P53 To Neoplastic Transformation, An Xu, Mo Liu, Mo-Fan Huang, Yang Zhang, Ruifeng Hu, Julian A Gingold, Ying Liu, Dandan Zhu, Chian-Shiu Chien, Wei-Chen Wang, Zian Liao, Fei Yuan, Chih-Wei Hsu, Jian Tu, Yao Yu, Taylor Rosen, Feng Xiong, Peilin Jia, Yi-Ping Yang, Danielle A Bazer, Ya-Wen Chen, Wenbo Li, Chad D Huff, Jay-Jiguang Zhu, Francesca Aguilo, Shih-Hwa Chiou, Nathan C Boles, Chien-Chen Lai, Mien-Chie Hung, Zhongming Zhao, Eric L Van Nostrand, Ruiying Zhao, Dung-Fang Lee

Faculty, Staff and Students Publications

N6-methyladenosine (m6A), one of the most prevalent mRNA modifications in eukaryotes, plays a critical role in modulating both biological and pathological processes. However, it is unknown whether mutant p53 neomorphic oncogenic functions exploit dysregulation of m6A epitranscriptomic networks. Here, we investigate Li-Fraumeni syndrome (LFS)-associated neoplastic transformation driven by mutant p53 in iPSC-derived astrocytes, the cell-of-origin of gliomas. We find that mutant p53 but not wild-type (WT) p53 physically interacts with SVIL to recruit the H3K4me3 methyltransferase MLL1 to activate the expression of m6A reader YTHDF2, culminating in an oncogenic phenotype. Aberrant YTHDF2 upregulation markedly hampers expression of multiple m6A-marked tumor-suppressing …

Clinical Features And Shared Mechanisms Of Chronic Gastritis And Osteoporosis, Tao Han, Yili Zhang, Baoyu Qi, Ming Chen, Kai Sun, Xiaokuan Qin, Bowen Yang, He Yin, Aili Xu, Xu Wei, Liguo Zhu

Faculty, Staff and Student Publications

Chronic gastritis (CG) and osteoporosis (OP) are common and occult diseases in the elderly and the relationship of these two diseases have been increasingly exposed. We aimed to explore the clinical characteristics and shared mechanisms of CG patients combined with OP. In the cross-sectional study, all participants were selected from BEYOND study. The CG patients were included and classified into two groups, namely OP group and non-OP group. Univariable and multivariable logistic regression methods were used to evaluate the influencing factors. Furthermore, CG and OP-related genes were obtained from Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified …

Venetoclax For Acute Myeloid Leukemia In Pediatric Patients: A Texas Medical Center Experience, Adriana Trabal, Amber Gibson, Jiasen He, David Mccall, Michael Roth, Cesar Nuñez, Miriam Garcia, Meredith Buzbee, Laurie Toepfer, Aram Bidikian, Naval Daver, Tapan Kadia, Nicholas J Short, Ghayas C Issa, Farhad Ravandi, Courtney D Dinardo, Guillermo Montalban Bravo, Sofia Garces, Andrea Marcogliese, Hana Paek, Zoann Dreyer, Julienne Brackett, Michele Redell, Joanna Yi, Guillermo Garcia-Manero, Marina Konopleva, Alexandra Stevens, Branko Cuglievan

Faculty, Staff and Student Publications

The BCL-2 inhibitor venetoclax improves survival for adult patients with acute myeloid leukemia (AML) in combination with lower-intensity therapies, but its benefit in pediatric patients with AML remains unclear. We retrospectively reviewed two Texas Medical Center institutions' experience with venetoclax in 43 pediatric patients with AML; median age 17 years (range, 0.6-21). This population was highly refractory; 44% of patients (n = 19) had ≥3 prior lines of therapy, 37% (n = 16) had received a prior bone marrow transplant, and 81% (n = 35) had unfavorable genetics KMT2A (n = 17), WT1 (n = 13), FLT3-ITD (n = 10), …

Soybean Gmsaul1, A Bona Fide U-Box E3 Ligase, Negatively Regulates Immunity Likely Through Repressing The Activation Of Gmmpk3, Jun-Mei Li, Mei-Yan Ye, Chaofeng Wang, Xiao-Han Ma, Ni-Ni Wu, Chen-Li Zhong, Yanjun Zhang, Ninghui Cheng, Paul A Nakata, Lirong Zeng, Jian-Zhong Liu

Faculty, Staff and Students Publications

E3 ubiquitin ligases play important roles in plant immunity, but their role in soybean has not been investigated previously. Here, we used Bean pod mottle virus (BPMV)-mediated virus-induced gene silencing (VIGS) to investigate the function of GmSAUL1 (Senescence-Associated E3 Ubiquitin Ligase 1) homologs in soybean. When two closely related SAUL1 homologs were silenced simultaneously, the soybean plants displayed autoimmune phenotypes, which were significantly alleviated by high temperature, suggesting that GmSAUL1a/1b might be guarded by an R protein. Interestingly, silencing GmSAUL1a/1b resulted in the decreased activation of GmMPK6, but increased activation of GmMPK3 in response to flg22, …

Gingival Transcriptomic Patterns Of Macrophage Polarization During Initiation, Progression, And Resolution Of Periodontitis, Octavio A Gonzalez, Sreenatha S Kirakodu, Linh M Nguyen, Jeffrey L Ebersole

Faculty, Staff and Student Publications

Phenotypic and functional heterogeneity of macrophages is clearly a critical component of their effective functions in innate and adaptive immunity. This investigation hypothesized that altered profiles of gene expression in gingival tissues in health, disease, and resolution would reflect changes in macrophage phenotypes occurring in these tissues. The study used a nonhuman primate model to evaluate gene expression profiles as footprints of macrophage variation using a longitudinal experimental model of ligature-induced periodontitis in animals from 3 to 23 years of age to identify aging effects on the gingival environment. Significant differences were observed in distribution of expressed gene levels for …

Defects In Lipid Homeostasis Reflect The Function Of Tango2 In Phospholipid And Neutral Lipid Metabolism, Agustin Leonardo Lujan, Ombretta Foresti, Conor Sugden, Nathalie Brouwers, Alex Mateo Farre, Alessio Vignoli, Mahshid Azamian, Alicia Turner, Jose Wojnacki, Vivek Malhotra

Faculty, Staff and Students Publications

We show that TANGO2 in mammalian cells localizes predominantly to mitochondria and partially at mitochondria sites juxtaposed to lipid droplets (LDs) and the endoplasmic reticulum. HepG2 cells and fibroblasts of patients lacking TANGO2 exhibit enlarged LDs. Quantitative lipidomics revealed a marked increase in lysophosphatidic acid (LPA) and a concomitant decrease in its biosynthetic precursor phosphatidic acid (PA). These changes were exacerbated in nutrient-starved cells. Based on our data, we suggest that TANGO2 function is linked to acyl-CoA metabolism, which is necessary for the acylation of LPA to generate PA. The defect in acyl-CoA availability impacts the metabolism of many other …

Calpain Activity Is Negatively Regulated By A Kctd7-Cullin-3 Complex Via Non-Degradative Ubiquitination, Jaiprakash Sharma, Shalaka Mulherkar, Uan-I Chen, Yan Xiong, Lakshya Bajaj, Byoung-Kyu Cho, Young Ah Goo, Hon-Chiu Eastwood Leung, Kimberley F Tolias, Marco Sardiello

Faculty, Staff and Students Publications

Calpains are a class of non-lysosomal cysteine proteases that exert their regulatory functions via limited proteolysis of their substrates. Similar to the lysosomal and proteasomal systems, calpain dysregulation is implicated in the pathogenesis of neurodegenerative disease and cancer. Despite intensive efforts placed on the identification of mechanisms that regulate calpains, however, calpain protein modifications that regulate calpain activity are incompletely understood. Here we show that calpains are regulated by KCTD7, a cytosolic protein of previously uncharacterized function whose pathogenic mutations result in epilepsy, progressive ataxia, and severe neurocognitive deterioration. We show that KCTD7 works in complex with Cullin-3 and Rbx1 …

A Randomized Phase I/Ii Safety And Immunogenicity Study Of The Montanide-Adjuvanted Sars-Cov-2 Spike Protein-Rbd-Fc Vaccine, Aks-452, Eline A Feitsma, Yester F Janssen, Hendrikus H Boersma, Yannick Van Sleen, Debbie Van Baarle, David G Alleva, Thomas M Lancaster, Thillainaygam Sathiyaseelan, Sylaja Murikipudi, Andrea R Delpero, Melanie M Scully, Ramya Ragupathy, Sravya Kotha, Jeffrey R Haworth, Nishit J Shah, Vidhya Rao, Shashikant Nagre, Shannon E Ronca, Freedom M Green, Ari Aminetzah, Frans Sollie, Schelto Kruijff, Maarten Brom, Gooitzen M Van Dam, Todd C Zion

Faculty, Staff and Students Publications

BACKGROUND: Previous interim data from a phase I study of AKS-452, a subunit vaccine comprising an Fc fusion of the respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein receptor binding domain (SP/RBD) emulsified in the water-in-oil adjuvant, Montanide™ ISA 720, suggested a good safety and immunogenicity profile in healthy adults. This phase I study was completed and two dosing regimens were further evaluated in this phase II study.

METHODS: This phase II randomized, open-labelled, parallel group study was conducted at a single site in The Netherlands with 52 healthy adults (18 - 72 years) receiving AKS-452 subcutaneously at one 90 µg …

Convergent Deployment Of Ancestral Functions During The Evolution Of Mammalian Flight Membranes, Charles Y Feigin, Jorge A Moreno, Raul Ramos, Sarah A Mereby, Ares Alivisatos, Wei Wang, Renée Van Amerongen, Jasmin Camacho, John J Rasweiler, Richard R Behringer, Bruce Ostrow, Maksim V Plikus, Ricardo Mallarino

Faculty, Staff and Student Publications

Lateral flight membranes, or patagia, have evolved repeatedly in diverse mammalian lineages. While little is known about patagium development, its recurrent evolution may suggest a shared molecular basis. By combining transcriptomics, developmental experiments, and mouse transgenics, we demonstrate that lateral Wnt5a expression in the marsupial sugar glider (Petaurus breviceps) promotes the differentiation of its patagium primordium. We further show that this function of Wnt5a reprises ancestral roles in skin morphogenesis predating mammalian flight and has been convergently used during patagium evolution in eutherian bats. Moreover, we find that many genes involved in limb development have been redeployed during …

Aberrant Function Of Pathogenic Stat3 Mutant Proteins Is Linked To Altered Stability Of Monomers And Homodimers, Moses M Kasembeli, Efiyenia Kaparos, Uddalak Bharadwaj, Ahmad Allaw, Alain Khouri, Bianca Acot, David J Tweardy

Faculty, Staff and Student Publications

STAT3 mutations, predominantly in the DNA-binding domain (DBD) and Src-homology 2 domain (SH2D), cause rare cases of immunodeficiency, malignancy, and autoimmunity. The exact mechanisms by which these mutations abrogate or enhance STAT3 function are not completely understood. Here, we examined how loss-of-function (LOF) and gain-of-function (GOF) STAT3 mutations within the DBD and SH2D affect monomer and homodimer protein stability as well as their effect on key STAT3 activation events, including recruitment to phosphotyrosine (pY) sites within peptide hormone receptors, tyrosine phosphorylation at Y705, dimerization, nuclear translocation, and DNA binding. The DBD LOF mutants showed reduced DNA binding when homodimerized, whereas …

A Phase 2 Study Of Interleukin-22 And Systemic Corticosteroids As Initial Treatment For Acute Gvhd Of The Lower Gi Tract, Doris M Ponce, Amin M Alousi, Ryotaro Nakamura, John Slingerland, Marco Calafiore, Karamjeet S Sandhu, Juliet N Barker, Sean Devlin, Jinru Shia, Sergio Giralt, Miguel-Angel Perales, Gillian Moore, Samira Fatmi, Cristina Soto, Antonio Gomes, Paul Giardina, Leeann Marcello, Xiaoqiang Yan, Tom Tang, Kevin Dreyer, Jianmin Chen, William L Daley, Jonathan U Peled, Marcel R M Van Den Brink, Alan M Hanash

Faculty, Staff and Student Publications

Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality following allogeneic hematopoietic transplantation. In experimental models, interleukin-22 promotes epithelial regeneration and induces innate antimicrobial molecules. We conducted a multicenter single-arm phase 2 study evaluating the safety and efficacy of a novel recombinant human interleukin-22 dimer, F-652, used in combination with systemic corticosteroids for treatment of newly diagnosed lower gastrointestinal acute GVHD. The most common adverse events were cytopenias and electrolyte abnormalities, and there were no dose-limiting toxicities. Out of 27 patients, 19 (70%; 80% confidence interval, 56%-79%) achieved a day-28 treatment response, meeting the prespecified primary endpoint. Responders …

Cc16 Augmentation Reduces Exaggerated Copd-Like Disease In Cc16-Deficient Mice, Joselyn Rojas-Quintero, Maria Eugenia Laucho-Contreras, Xiaoyun Wang, Quynh-Anh Fucci, Patrick R Burkett, Se-Jin Kim, Duo Zhang, Yohannes Tesfaigzi, Yuhong Li, Abhiram R Bhashyam, Zhang Li, Haider Khamas, Bartolome Celli, Aprile L Pilon, Francesca Polverino, Caroline A Owen

Faculty, Staff and Students Publications

Low Club Cell 16 kDa protein (CC16) plasma levels are linked to accelerated lung function decline in patients with chronic obstructive pulmonary disease (COPD). Cigarette smoke-exposed (CS-exposed) Cc16-/- mice have exaggerated COPD-like disease associated with increased NF-κB activation in their lungs. It is unclear whether CC16 augmentation can reverse exaggerated COPD in CS-exposed Cc16-/- mice and whether increased NF-κB activation contributes to the exaggerated COPD in CS-exposed Cc16-/- lungs. CS-exposed WT and Cc16-/- mice were treated with recombinant human CC16 (rhCC16) or an NF-κB inhibitor versus vehicle beginning at the midpoint of the exposures. COPD-like disease and NF-κB activation were …