Digital Commons Network^™

High Molecular Diagnostic Yields And Novel Phenotypic Expansions Involving Syndromic Anorectal Malformations, Raymond Belanger Deloge, Xiaonan Zhao, Pamela N Luna, Chad A Shaw, Jill A Rosenfeld, Daryl A Scott

Faculty, Staff and Students Publications

Evidence suggests that genetic factors contribute to the development of anorectal malformations (ARMs). However, the etiology of the majority of ARMs cases remains unclear. Exome sequencing (ES) may be underutilized in the diagnostic workup of ARMs due to uncertainty regarding its diagnostic yield. In a clinical database of ~17,000 individuals referred for ES, we identified 130 individuals with syndromic ARMs. A definitive or probable diagnosis was made in 45 of these individuals for a diagnostic yield of 34.6% (45/130). The molecular diagnostic yield of individuals who initially met criteria for VACTERL association was lower than those who did not (26.8% …

Profiling Disease-Selective Drug Targets: From Proteomics To Ligandomics, Prabuddha Waduge, Hong Tian, Keith A Webster, Wei Li

Faculty, Staff and Students Publications

Despite advancements in omics technologies, including proteomics and transcriptomics, identification of therapeutic targets remains challenging. Ligandomics recently emerged as a unique technology of functional proteomics for global profiling of cell-binding protein ligands. When applied to diseased versus healthy vasculatures, comparative ligandomics systematically maps novel disease-restricted ligands that allow selective targeting of pathological but not physiological pathways, providing high efficacy with intrinsic safety. In this review, we discuss the potential of cellular ligands as therapeutic targets and summarize the development of ligandomics. We further compare the advantages and limitations of different omics technologies for drug target discovery and discuss target selection …

Failure Of Nasal Defect Closures Following The Use Of Continuous Positive Airway Pressure, Yelena Dokic, Emily Powell, John Kohorst, Ikue Shimizu

Faculty, Staff and Students Publications

In this paper, we report a case series of three patients who developed nasal tip necrosis following Mohs micrographic surgery (MMS), complicated by the concomitant use of a continuous positive airway pressure (CPAP) machine for sleep apnea.

Prevalence And Predictors Of Using Antibiotics Without A Prescription In A Pediatric Population In The United States, Kiara Olmeda, Barbara W Trautner, Lindsey Laytner, Juanita Salinas, Stephanie Marton, Larissa Grigoryan

Faculty, Staff and Students Publications

Non-prescription antibiotic use (using antibiotics without clinical guidance) increases the risk of the development of antibiotic resistance, adverse drug reactions, and other potential patient harm. Few studies have explored non-prescription use in children in the U.S. From January 2021 to April 2022, a diverse sample of caregivers of children under 18 years were surveyed in English and Spanish at two safety net clinics in Texas. We assessed the prevalence of antibiotic use in children in the previous 12 months, storage of antimicrobials, and intended use of non-prescription antibiotics (professed intention for future non-prescription antibiotic use). We also measured sociodemographic factors, …

2022 American College Of Rheumatology Guideline For Vaccinations In Patients With Rheumatic And Musculoskeletal Diseases, Anne R Bass, Eliza Chakravarty, Elie A Akl, Clifton O Bingham, Leonard Calabrese, Laura C Cappelli, Sindhu R Johnson, Lisa F Imundo, Kevin L Winthrop, Reuben J Arasaratnam, Lindsey R Baden, Roberta Berard, S Louis Bridges, Jonathan T L Cheah, Jeffrey R Curtis, Polly J Ferguson, Ida Hakkarinen, Karen B Onel, Grayson Schultz, Vidya Sivaraman, Benjamin J Smith, Jeffrey A Sparks, Tiphanie P Vogel, Eleanor Anderson Williams, Cassandra Calabrese, Joanne S Cunha, Joann Fontanarosa, Miriah C Gillispie-Taylor, Elena Gkrouzman, Priyanka Iyer, Kimberly S Lakin, Alexandra Legge, Mindy S Lo, Megan M Lockwood, Rebecca E Sadun, Namrata Singh, Nancy Sullivan, Herman Tam, Marat Turgunbaev, Amy S Turner, James Reston

Faculty, Staff and Students Publications

OBJECTIVE: To provide evidence-based recommendations on the use of vaccinations in children and adults with rheumatic and musculoskeletal diseases (RMDs).

METHODS: This guideline follows American College of Rheumatology (ACR) policy guiding management of conflicts of interest and disclosures and the ACR guideline development process, which includes the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. It also adheres to the Appraisal of Guidelines for Research and Evaluation (AGREE) criteria. A core leadership team consisting of adult and pediatric rheumatologists and a guideline methodologist drafted clinical population, intervention, comparator, outcomes (PICO) questions. A review team performed a systematic literature review …

Robust Deep Learning Object Recognition Models Rely On Low Frequency Information In Natural Images, Zhe Li, Josue Ortega Caro, Evgenia Rusak, Wieland Brendel, Matthias Bethge, Fabio Anselmi, Ankit B Patel, Andreas S Tolias, Xaq Pitkow

Faculty, Staff and Students Publications

Machine learning models have difficulty generalizing to data outside of the distribution they were trained on. In particular, vision models are usually vulnerable to adversarial attacks or common corruptions, to which the human visual system is robust. Recent studies have found that regularizing machine learning models to favor brain-like representations can improve model robustness, but it is unclear why. We hypothesize that the increased model robustness is partly due to the low spatial frequency preference inherited from the neural representation. We tested this simple hypothesis with several frequency-oriented analyses, including the design and use of hybrid images to probe model …

Ectopic Lymphoid Structures In The Aged Lacrimal Glands, Jeremias G Galletti, Kaitlin K Scholand, Claudia M Trujillo-Vargas, Zhiyuan Yu, Olivier Mauduit, Vanessa Delcroix, Helen P Makarenkova, Cintia S De Paiva

Faculty, Staff and Students Publications

Aging is a complex biological process in which many organs are pathologically affected. We previously reported that aged C57BL/6J had increased lacrimal gland (LG) lymphoid infiltrates that suggest ectopic lymphoid structures. However, these ectopic lymphoid structures have not been fully investigated. Using C57BL/6J mice of different ages, we analyzed the transcriptome of aged murine LGs and characterized the B and T cell populations. Age-related changes in the LG include increased differentially expressed genes associated with B and T cell activation, germinal center formation, and infiltration by marginal zone-like B cells. We also identified an age-related increase in B1

Thoracolumbar Scoliosis In Pediatric Patients With Loeys-Dietz Syndrome: A Case Series, Melissa A Lopresti, Prazwal Athukuri, A Basit Khan, Marc Prablek, Rajan Patel, Rory Mayer, David F Bauer, Frank T Gerow, Shaine A Morris, Sandi Lam, Vijay Ravindra

Faculty, Staff and Students Publications

Background Loeys-Dietz syndrome (LDS) is a genetic connective tissue disorder that predominantly affects cardiovascular, skeletal, and craniofacial structures. Associated thoracolumbar scoliosis in LDS can be challenging to manage, though other etiologies of pediatric scoliosis have better-defined management guidelines. We examined our institutional experience regarding the treatment of pediatric patients with LDS and scoliosis. Methodology In this retrospective study, all patients seen at our pediatric tertiary care center from 2004 through 2018 with a diagnosis of LDS were reviewed, and those with radiographic diagnoses of scoliosis (full-length scoliosis X-rays) were included. Demographic, clinical, and radiographic parameters were collected, and management strategies …

Phase Separation In Biology And Disease; Current Perspectives And Open Questions, Steven Boeynaems, Shasha Chong, Jörg Gsponer, Liam Holt, Dragomir Milovanovic, Diana M Mitrea, Oliver Mueller-Cajar, Bede Portz, John F Reilly, Christopher D Reinkemeier, Benjamin R Sabari, Serena Sanulli, James Shorter, Emily Sontag, Lucia Strader, Jeanne Stachowiak, Stephanie C Weber, Michael White, Huaiying Zhang, Markus Zweckstetter, Shana Elbaum-Garfinkle, Richard Kriwacki

Faculty, Staff and Students Publications

In the past almost 15 years, we witnessed the birth of a new scientific field focused on the existence, formation, biological functions, and disease associations of membraneless bodies in cells, now referred to as biomolecular condensates. Pioneering studies from several laboratories [reviewed in [1–3]] supported a model wherein biomolecular condensates associated with diverse biological processes form through the process of phase separation. These and other findings that followed have revolutionized our understanding of how biomolecules are organized in space and time within cells to perform myriad biological functions, including cell fate determination, signal transduction, endocytosis, regulation …

In Vivo White Matter Microstructure In Adolescents With Early-Onset Psychosis: A Multi-Site Mega-Analysis, Claudia Barth, Sinead Kelly, Stener Nerland, Neda Jahanshad, Clara Alloza, Sonia Ambrogi, Ole A Andreassen, Dimitrios Andreou, Celso Arango, Inmaculada Baeza, Nerisa Banaj, Carrie E Bearden, Michael Berk, Hannes Bohman, Josefina Castro-Fornieles, Yann Chye, Benedicto Crespo-Facorro, Elena De La Serna, Covadonga M Díaz-Caneja, Tiril P Gurholt, Catherine E Hegarty, Anthony James, Joost Janssen, Cecilie Johannessen, Erik G Jönsson, Katherine H Karlsgodt, Peter Kochunov, Noemi G Lois, Mathias Lundberg, Anne M Myhre, Saül Pascual-Diaz, Fabrizio Piras, Runar E Smelror, Gianfranco Spalletta, Therese S Stokkan, Gisela Sugranyes, Chao Suo, Sophia I Thomopoulos, Diana Tordesillas-Gutiérrez, Daniela Vecchio, Kirsten Wedervang-Resell, Laura A Wortinger, Paul M Thompson, Ingrid Agartz

Faculty, Staff and Students Publications

Emerging evidence suggests brain white matter alterations in adolescents with early-onset psychosis (EOP; age of onset <18 >years). However, as neuroimaging methods vary and sample sizes are modest, results remain inconclusive. Using harmonized data processing protocols and a mega-analytic approach, we compared white matter microstructure in EOP and healthy controls using diffusion tensor imaging (DTI). Our sample included 321 adolescents with EOP (median age = 16.6 years, interquartile range (IQR) = 2.14, 46.4% females) and 265 adolescent healthy controls (median age = 16.2 years, IQR = 2.43, 57.7% females) pooled from nine sites. All sites extracted mean fractional anisotropy (FA), mean …

Brain Ageing In Schizophrenia: Evidence From 26 International Cohorts Via The Enigma Schizophrenia Consortium, Constantinos Constantinides, Laura K M Han, Clara Alloza, Linda Antonella Antonucci, Celso Arango, Rosa Ayesa-Arriola, Nerisa Banaj, Alessandro Bertolino, Stefan Borgwardt, Jason Bruggemann, Juan Bustillo, Oleg Bykhovski, Vince Calhoun, Vaughan Carr, Stanley Catts, Young-Chul Chung, Benedicto Crespo-Facorro, Covadonga M Díaz-Caneja, Gary Donohoe, Stefan Du Plessis, Jesse Edmond, Stefan Ehrlich, Robin Emsley, Lisa T Eyler, Paola Fuentes-Claramonte, Foivos Georgiadis, Melissa Green, Amalia Guerrero-Pedraza, Minji Ha, Tim Hahn, Frans A Henskens, Laurena Holleran, Stephanie Homan, Philipp Homan, Neda Jahanshad, Joost Janssen, Ellen Ji, Stefan Kaiser, Vasily Kaleda, Minah Kim, Woo-Sung Kim, Matthias Kirschner, Peter Kochunov, Yoo Bin Kwak, Jun Soo Kwon, Irina Lebedeva, Jingyu Liu, Patricia Mitchie, Stijn Michielse, David Mothersill, Bryan Mowry, Víctor Ortiz-García De La Foz, Christos Pantelis, Giulio Pergola, Fabrizio Piras, Edith Pomarol-Clotet, Adrian Preda, Yann Quidé, Paul E Rasser, Kelly Rootes-Murdy, Raymond Salvador, Marina Sangiuliano, Salvador Sarró, Ulrich Schall, André Schmidt, Rodney J Scott, Pierluigi Selvaggi, Kang Sim, Antonin Skoch, Gianfranco Spalletta, Filip Spaniel, Sophia I Thomopoulos, David Tomecek, Alexander S Tomyshev, Diana Tordesillas-Gutiérrez, Therese Van Amelsvoort, Javier Vázquez-Bourgon, Daniela Vecchio, Aristotle Voineskos, Cynthia S Weickert, Thomas Weickert, Paul M Thompson, Lianne Schmaal, Theo G M Van Erp, Jessica Turner, James H Cole, Enigma Schizophrenia Consortium, Danai Dima, Esther Walton

Faculty, Staff and Students Publications

Schizophrenia (SZ) is associated with an increased risk of life-long cognitive impairments, age-related chronic disease, and premature mortality. We investigated evidence for advanced brain ageing in adult SZ patients, and whether this was associated with clinical characteristics in a prospective meta-analytic study conducted by the ENIGMA Schizophrenia Working Group. The study included data from 26 cohorts worldwide, with a total of 2803 SZ patients (mean age 34.2 years; range 18–72 years; 67% male) and 2598 healthy controls (mean age 33.8 years, range 18–73 years, 55% male). Brain-predicted age was individually estimated using a model trained on independent data based on …

Determinants And Mechanisms Of The Low Fusogenicity And High Dependence On Endosomal Entry Of Omicron Subvariants, Panke Qu, John P Evans, Chaitanya Kurhade, Cong Zeng, Yi-Min Zheng, Kai Xu, Pei-Yong Shi, Xuping Xie, Shan-Lu Liu

Faculty, Staff and Student Publications

The rapid spread and strong immune evasion of the SARS-CoV-2 Omicron subvariants has raised serious concerns for the global COVID-19 pandemic. These new variants exhibit generally reduced fusogenicity and increased endosomal entry pathway utilization compared to the ancestral D614G variant, the underlying mechanisms of which remain elusive. Here, we show that the C-terminal S1 mutations of the BA.1.1 subvariant, H655Y and T547K, critically govern the low fusogenicity of Omicron. Notably, H655Y also dictates the enhanced endosome entry pathway utilization. Mechanistically, T547K and H655Y likely stabilize the spike trimer conformation as suggested by increased molecular interactions in structural modeling and enhanced …

Allosteric Autoregulation Of Dna Binding Via A Dna-Mimicking Protein Domain: A Biophysical Study Of Znf410-Dna Interaction Using Small Angle X-Ray Scattering, Gundeep Kaur, Ren Ren, Michal Hammel, John R Horton, Jie Yang, Yu Cao, Chenxi He, Fei Lan, Xianjiang Lan, Gerd A Blobel, Robert M Blumenthal, Xing Zhang, Xiaodong Cheng

Faculty, Staff and Student Publications

ZNF410 is a highly-conserved transcription factor, remarkable in that it recognizes a 15-base pair DNA element but has just a single responsive target gene in mammalian erythroid cells. ZNF410 includes a tandem array of five zinc-fingers (ZFs), surrounded by uncharacterized N- and C-terminal regions. Unexpectedly, full-length ZNF410 has reduced DNA binding affinity, compared to that of the isolated DNA binding ZF array, both in vitro and in cells. AlphaFold predicts a partially-folded N-terminal subdomain that includes a 30-residue long helix, preceded by a hairpin loop rich in acidic (aspartate/glutamate) and serine/threonine residues. This hairpin loop is predicted by AlphaFold to …

Jaml Immunotherapy Targets Recently Activated Tumor-Infiltrating Cd8+ T Cells, Simon Eschweiler, Alice Wang, Ciro Ramírez-Suástegui, Adrian Von Witzleben, Yingcong Li, Serena J Chee, Hayley Simon, Monalisa Mondal, Matthew Ellis, Gareth J Thomas, Vivek Chandra, Christian H Ottensmeier, Pandurangan Vijayanand

Faculty, Staff and Student Publications

Junctional adhesion molecule-like protein (JAML) serves as a co-stimulatory molecule in γδ T cells. While it has recently been described as a cancer immunotherapy target in mice, its potential to cause toxicity, specific mode of action with regard to its cellular targets, and whether it can be targeted in humans remain unknown. Here, we show that JAML is induced by T cell receptor engagement, reveal that this induction is linked to cis-regulatory interactions between the CD3D and JAML gene loci. When compared with other immunotherapy targets plagued by low target specificity and end-organ toxicity, we find JAML to be mostly …

Narrative Review Of Single Ventricle: Where Are We After 40 Years?, Antonio F Corno, Tina O Findley, Jorge D Salazar

Faculty, Staff and Student Publications

Background and objective: Key medical and surgical advances have been made in the longitudinal management of patients with "functionally" single ventricle physiology, with the principles of Fontan circulation applied to other complex congenital heart defects. The purpose of this article is to review all of the innovations, starting from fetal life, that led to a change of strategy for single ventricle.

Methods: Our literature review included all full articles published in English language on the Cochrane, MedLine, and Embase with references to "single ventricle" and "univentricular hearts", including the initial history of the treatments for this congenital heart defects as …

Narrative Review Of Single Ventricle: Where Are We After 40 Years?, Antonio F Corno, Tina O Findley, Jorge D Salazar

Faculty, Staff and Student Publications

BACKGROUND AND OBJECTIVE: Key medical and surgical advances have been made in the longitudinal management of patients with "functionally" single ventricle physiology, with the principles of Fontan circulation applied to other complex congenital heart defects. The purpose of this article is to review all of the innovations, starting from fetal life, that led to a change of strategy for single ventricle.

METHODS: Our literature review included all full articles published in English language on the Cochrane, MedLine, and Embase with references to "single ventricle" and "univentricular hearts", including the initial history of the treatments for this congenital heart defects as …

Prognostic Significance Of Acellular Mucin In Patients Undergoing Cytoreductive Surgery And Hyperthermic Intraperitoneal Chemotherapy (Crs/Hipec) For Appendiceal Neoplasms, Derek J Erstad, Kristen A Robinson, Karen Beaty, Safia Rafeeq, Yi-Ju Chiang, Kanwal Raghav, John P Shen, Michael J Overman, Wai Chin Foo, Melissa W Taggart, Paul F Mansfield, Richard E Royal, Keith F Fournier, Christopher P Scally

Faculty, Staff and Student Publications

Introduction: Appendiceal neoplasms have a propensity for peritoneal dissemination. The standard of care for select individuals is CRS/HIPEC. In the current 8th AJCC Staging system, a finding of only intraperitoneal acellular mucin (M1a) is classified as Stage IVa. There is concern that the current AJCC system may over-stage patients.

Methods: This was a single-institution retrospective review of 164 cases of mucinous appendiceal neoplasm. Patients undergoing CRS/HIPEC with M1a disease were compared to patients with peritoneal deposits containing tumor cells (well-differentiated adenocarcinoma; low-grade mucinous carcinoma peritonei-M1b,G1). Overall and recurrence-free survival were assessed.

Results: Median age was 51 years, 70% were female, …

Cedar: Incorporating Cell Type Hierarchy Improves Cell Type-Specific Differential Analyses In Bulk Omics Data, Luxiao Chen, Ziyi Li, Hao Wu

Faculty, Staff and Student Publications

Bulk high-throughput omics data contain signals from a mixture of cell types. Recent developments of deconvolution methods facilitate cell type-specific inferences from bulk data. Our real data exploration suggests that differential expression or methylation status is often correlated among cell types. Based on this observation, we develop a novel statistical method named CeDAR to incorporate the cell type hierarchy in cell type-specific differential analyses of bulk data. Extensive simulation and real data analyses demonstrate that this approach significantly improves the accuracy and power in detecting cell type-specific differential signals compared with existing methods, especially in low-abundance cell types.

Recovering False Negatives In Crispr Fitness Screens With Jloe, Merve Dede, Traver Hart

Faculty, Staff and Student Publications

It is widely accepted that pooled library CRISPR knockout screens offer greater sensitivity and specificity than prior technologies in detecting genes whose disruption leads to fitness defects, a critical step in identifying candidate cancer targets. However, the assumption that CRISPR screens are saturating has been largely untested. Through integrated analysis of screen data in cancer cell lines generated by the Cancer Dependency Map, we show that a typical CRISPR screen has a ∼20% false negative rate, in addition to library-specific false negatives. Replicability falls sharply as gene expression decreases, while cancer subtype-specific genes within a tissue show distinct profiles compared …

Excess Folic Acid Intake Increases Dna De Novo Point Mutations, Xuanye Cao, Jianfeng Xu, Ying L Lin, Robert M Cabrera, Qiuying Chen, Chaofan Zhang, John W Steele, Xiao Han, Steven S Gross, Bogdan J Wlodarczyk, James R Lupski, Wei Li, Hongyan Wang, Richard H Finnell, Yunping Lei

Faculty, Staff and Students Publications

No abstract provided.

Does The Potocki-Lupski Syndrome Convey The Autism Spectrum Disorder Phenotype? Case Report And Scoping Review, Oksana I Talantseva, Galina V Portnova, Raisa S Romanova, Daria A Martynova, Olga V Sysoeva, Elena L Grigorenko

Faculty, Staff and Students Publications

Potocki-Lupski Syndrome (PTLS) is a rare condition associated with a duplication of 17p11.2 that may underlie a wide range of congenital abnormalities and heterogeneous behavioral phenotypes. Along with developmental delay and intellectual disability, autism-specific traits are often reported to be the most common among patients with PTLS. To contribute to the discussion of the role of autism spectrum disorder (ASD) in the PTLS phenotype, we present a case of a female adolescent with a de novo dup(17) (p11.2p11.2) without ASD features, focusing on in-depth clinical, behavioral, and electrophysiological (EEG) evaluations. Among EEG features, we found the atypical peak-slow wave patterns …

Clic And Membrane Wound Repair Pathways Enable Pandemic Norovirus Entry And Infection, B Vijayalakshmi Ayyar, Khalil Ettayebi, Wilhelm Salmen, Umesh C Karandikar, Frederick H Neill, Victoria R Tenge, Sue E Crawford, Erhard Bieberich, B V Venkataram Prasad, Robert L Atmar, Mary K Estes

Faculty, Staff and Students Publications

Globally, most cases of gastroenteritis are caused by pandemic GII.4 human norovirus (HuNoV) strains with no approved therapies or vaccines available. The cellular pathways that these strains exploit for cell entry and internalization are unknown. Here, using nontransformed human jejunal enteroids (HIEs) that recapitulate the physiology of the gastrointestinal tract, we show that infectious GII.4 virions and virus-like particles are endocytosed using a unique combination of endosomal acidification-dependent clathrin-independent carriers (CLIC), acid sphingomyelinase (ASM)-mediated lysosomal exocytosis, and membrane wound repair pathways. We found that besides the known interaction of the viral capsid Protruding (P) domain with host glycans, the Shell …

Analysis Of Acquired Resistance Mechanisms To Osimertinib In Patients With Egfr-Mutated Advanced Non-Small Cell Lung Cancer From The Aura3 Trial, Juliann Chmielecki, Tony Mok, Yi-Long Wu, Ji-Youn Han, Myung-Ju Ahn, Suresh S Ramalingam, Thomas John, Isamu Okamoto, James Chih-Hsin Yang, Frances A Shepherd, Krishna C Bulusu, Gianluca Laus, Barbara Collins, J Carl Barrett, Ryan J Hartmaier, Vassiliki Papadimitrakopoulou

Faculty, Staff and Student Publications

Osimertinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), potently and selectively inhibits EGFR-TKI-sensitizing and EGFR T790M resistance mutations. This analysis evaluates acquired resistance mechanisms to second-line osimertinib (n = 78) in patients with EGFR T790M advanced non-small cell lung cancer (NSCLC) from AURA3 (NCT02151981), a randomized phase 3 study comparing osimertinib with chemotherapy. Plasma samples collected at baseline and disease progression/treatment discontinuation are analyzed using next-generation sequencing. Half (50%) of patients have undetectable plasma EGFR T790M at disease progression and/or treatment discontinuation. Fifteen patients (19%) have >1 resistance-related genomic alteration; MET amplification (14/78, 18%) and EGFR C797X mutation …

The Tfiis N-Terminal Domain (Tnd): A Transcription Assembly Module At The Interface Of Order And Disorder, Katerina Cermakova, Vaclav Veverka, H Courtney Hodges

Faculty, Staff and Students Publications

Interaction scaffolds that selectively recognize disordered protein strongly shape protein interactomes. An important scaffold of this type that contributes to transcription is the TFIIS N-terminal domain (TND). The TND is a five-helical bundle that has no known enzymatic activity, but instead selectively reads intrinsically disordered sequences of other proteins. Here, we review the structural and functional properties of TNDs and their cognate disordered ligands known as TND-interacting motifs (TIMs). TNDs or TIMs are found in prominent members of the transcription machinery, including TFIIS, super elongation complex, SWI/SNF, Mediator, IWS1, SPT6, PP1-PNUTS phosphatase, elongin, H3K36me3 readers, the transcription factor MYC, and …

Mecp2 Regulates Gdf11, A Dosage-Sensitive Gene Critical For Neurological Function, Sameer S Bajikar, Ashley G Anderson, Jian Zhou, Mark A Durham, Alexander J Trostle, Ying-Wooi Wan, Zhandong Liu, Huda Y Zoghbi

Faculty, Staff and Students Publications

Loss- and gain-of-function of MeCP2 causes Rett syndrome (RTT) and MECP2 duplication syndrome (MDS), respectively. MeCP2 binds methyl-cytosines to finely tune gene expression in the brain, but identifying genes robustly regulated by MeCP2 has been difficult. By integrating multiple transcriptomics datasets, we revealed that MeCP2 finely regulates growth differentiation factor 11 (Gdf11). Gdf11 is down-regulated in RTT mouse models and, conversely, up-regulated in MDS mouse models. Strikingly, genetically normalizing Gdf11 dosage levels improved several behavioral deficits in a mouse model of MDS. Next, we discovered that losing one copy of Gdf11 alone was sufficient to cause multiple neurobehavioral …

Uncovering Novel Regulators Of Memory Using C Elegans Genetic And Genomic Analysis, Katie L Brandel-Ankrapp, Rachel N Arey

Faculty, Staff and Students Publications

How organisms learn and encode memory is an outstanding question in neuroscience research. Specifically, how memories are acquired and consolidated at the level of molecular and gene pathways remains unclear. In addition, memory is disrupted in a wide variety of neurological disorders; therefore, discovering molecular regulators of memory may reveal therapeutic targets for these disorders. C. elegans are an excellent model to uncover molecular and genetic regulators of memory. Indeed, the nematode's invariant neuronal lineage, fully mapped genome, and conserved associative behaviors have allowed the development of a breadth of genetic and genomic tools to examine learning and memory. In …

Kras-Mutant Lung Cancer: Targeting Molecular And Immunologic Pathways, Therapeutic Advantages And Restrictions, Nastaran Karimi, Seyed Javad Moghaddam

Faculty, Staff and Student Publications

RAS mutations are among the most common oncogenic mutations in human cancers. Among RAS mutations, KRAS has the highest frequency and is present in almost 30% of non-small-cell lung cancer (NSCLC) patients. Lung cancer is the number one cause of mortality among cancers as a consequence of outrageous aggressiveness and late diagnosis. High mortality rates have been the reason behind numerous investigations and clinical trials to discover proper therapeutic agents targeting KRAS. These approaches include the following: direct KRAS targeting; synthetic lethality partner inhibitors; targeting of KRAS membrane association and associated metabolic rewiring; autophagy inhibitors; downstream inhibitors; and immunotherapies and …

Monitoring Resistance And Biochemical Studies Of Three Egyptian Field Strains Of Spodoptera Littoralis (Lepidoptera: Noctuidae) To Six Insecticides, Moataz A M Moustafa, Rasha I A Moteleb, Yehia F Ghoneim, Sameh Sh Hafez, Reham E Ali, Essam E A Eweis, Nancy N Hassan

Faculty, Staff and Student Publications

BACKGROUND:

METHODS: Laboratory bioassays were carried out using the leaf-dipping method to examine the susceptibility of the laboratory and field strains to the tested insecticides. Activities of detoxification enzymes were determined in an attempt to identify resistance mechanisms.

RESULTS: The results showed that LC

CONCLUSION: Our findings, along with other tactics, are expected to help with the resistance management of

Microrna Profiles In Intestinal Epithelial Cells In A Mouse Model Of Sepsis, Siqingaowa Caidengbate, Yuichi Akama, Anik Banerjee, Khwanchanok Mokmued, Eiji Kawamoto, Arong Gaowa, Louise D Mccullough, Motomu Shimaoka, Juneyoung Lee, Eun Jeong Park

Faculty, Staff and Student Publications

Sepsis is a systemic inflammatory disorder that leads to the dysfunction of multiple organs. In the intestine, the deregulation of the epithelial barrier contributes to the development of sepsis by triggering continuous exposure to harmful factors. However, sepsis-induced epigenetic changes in gene-regulation networks within intestinal epithelial cells (IECs) remain unexplored. In this study, we analyzed the expression profile of microRNAs (miRNAs) in IECs isolated from a mouse model of sepsis generated via cecal slurry injection. Among 239 miRNAs, 14 miRNAs were upregulated, and 9 miRNAs were downregulated in the IECs by sepsis. Upregulated miRNAs in IECs from septic mice, particularly …

Feasibility Of [18f]Fspg Pet For Early Response Assessment To Combined Blockade Of Egfr And Glutamine Metabolism In Wild-Type Kras Colorectal Cancer, Seong-Woo Bae, Jianbo Wang, Dimitra K Georgiou, Xiaoxia Wen, Allison S Cohen, Ling Geng, Mohammed Noor Tantawy, H Charles Manning

Faculty, Staff and Student Publications

Early response assessment is critical for personalizing cancer therapy. Emerging therapeutic regimens with encouraging results in the wild-type (WT) KRAS colorectal cancer (CRC) setting include inhibitors of epidermal growth factor receptor (EGFR) and glutaminolysis. Towards predicting clinical outcome, this preclinical study evaluated non-invasive positron emission tomography (PET) with (4S)-4-(3-[18F]fluoropropyl)-L-glutamic acid ([18F]FSPG) in treatment-sensitive and treatment-resistant WT KRAS CRC patient-derived xenografts (PDXs). Tumor-bearing mice were imaged with [18F]FSPG PET before and one week following the initiation of treatment with either EGFR-targeted monoclonal antibody (mAb) therapy, glutaminase inhibitor therapy, or the combination. Imaging was correlated with tumor volume and histology. In PDX …