Digital Commons Network^™

Minifast: A Sensitive And Fast Miniaturized Microscope For In Vivo Neural Recording, Jill Juneau, Guillaume Duret, Joshua P Chu, Blake Madruga, Conor C Dorian, Alexander V Rodriguez, Savva Morozov, Daniel Aharoni, Jacob T Robinson, François St-Pierre, Peyman Golshani, Caleb Kemere

Faculty, Staff and Students Publications

Significance: Observing the activity of large populations of neurons in vivo is critical for understanding brain function and dysfunction. The use of fluorescent genetically encoded calcium indicators (GECIs) in conjunction with miniaturized microscopes is an exciting emerging toolset for recording neural activity in unrestrained animals. Despite their potential, current miniaturized microscope designs are limited using image sensors with low frame rates, sensitivity, and resolution. Beyond GECIs, there are many neuroscience applications that would benefit from the use of other emerging neural indicators, such as fluorescent genetically encoded voltage indicators (GEVIs) that have faster temporal resolution to match neuron spiking, yet …

The Hidden Link Between Endometriosis And Obesity: A State-Of-The-Art Review, Shefali N Desai, Christina C Reed, Yamely Mendez, Qiannan Yang, Xiaoming Guan

Faculty, Staff and Students Publications

Endometriosis remains an under-researched disease with a wide range of symptoms. Endometriosis reduces a woman's quality of life and professional productivity, yet its exact causes, risk factors, and treatment have yet to be elucidated. Body mass index and endometriosis have been observed to be inversely related; however, this relationship may only be a correlation rather than a causation. Obesity may play a role in the inflammation and cell proliferation associated with endometriosis through the complex signaling pathways of adipokines. A literature review was done on endometriosis and obesity to gain insight and synthesize knowledge about opportunities to improve endometriosis care, …

Nasal Microbiome And Phageome Profiles Are Associated With Prospective Respiratory Viral Infection Risk In School-Age Children, Michael S Kelly, Ching-Ying Huang, Minsik Kim, Dastan Haghnazari, Aribah Baig, Ye Sun, Bryan R Lenneman, Michael J Tisza, Amparito Cunningham, Diane Gold, Wanda Phipatanakul, Peggy S Lai

Faculty, Staff and Students Publications

Background: Respiratory viral infections are common and can trigger asthma exacerbations in children. The roles of the nasal microbiome and phageome (viruses that infect microbes) are not well understood.

Objective: We sought to characterize the epidemiology of respiratory viral infections and the interplay between the nasal microbiome, phageome, and viral infections in school-age children with asthma.

Methods: We performed metagenomic sequencing and quantitative RT-PCR detection of respiratory viruses on 375 nasal samples from 227 school-age children with asthma collected routinely 3 times over a year. Surveys on parent-reported cold and asthma symptoms were administered routinely every 2 months. We evaluated …

Cressent: A Bioinformatics Toolkit To Explore And Improve Ssdna Virus Annotation, Ricardo R Pavan, Matthew B Sullivan, Michael J Tisza

Faculty, Staff and Students Publications

ssDNA viruses are important components of diverse ecosystems; however, it remains challenging to systematically identify and classify them. This is partly due to their broad host range and resulting genomic diversity, structure and rapid evolutionary rates. In addition, distinguishing genuine ssDNA genomes from contaminating sequences in metagenomic datasets (e.g. from commercial kits) has been an unresolved issue for years. Here, we present CRESSENT (CRESS-DNA Extended aNnotation Toolkit), a comprehensive and modular bioinformatic pipeline focused on ssDNA virus 'genome-to-analysis' and annotation. The pipeline integrates multiple functionalities organized into several modules: sequence dereplication, decontamination, phylogenetic analysis, …

Unusual Endoscopic Remission In An Anti-Tumor Necrosis Factor Refractory Case Of Severe Ulcerative Colitis During Upadacitinib Therapy, Carine A Halaby, Charlotte F Kim, Richard Kellermayer

Faculty, Staff and Students Publications

No abstract provided.

Maternal Myo-Inositol Intake And Congenital Heart Defects In Offspring: A Population-Based Case-Control Study, Ruiqi Cen, L Joseph Su, Jun Ying, Mohammed S Orloff, Elijah H Bolin, Xiangyang Lou, Lynn M Almli, Lorenzo D Botto, Marilyn L Browne, Richard H Finnell, Mary M Jenkins, Eirini Nestoridi, Andrew F Olshan, Paul A Romitti, Gary M Shaw, Wendy N Nembhard

Faculty, Staff and Students Publications

Objective: To investigate associations between maternal periconceptional (three months prior through the third pregnancy month) myo-inositol intake and the odds of selected congenital heart defects in offspring.

Design: A population-based case-control study using the National Birth Defects Prevention Study (NBDPS) database.

Setting: United States.

Population or sample: Women with singleton live births without major birth defects (controls) and women with singleton live births, stillbirths, or terminations with selected nonsyndromic congenital heart defects (CHD; cases).

Methods: Descriptive analyses, logistic regression models, ascertainment of myo-inositol intake from supplements and food using a shortened food frequency questionnaire and survey.

Main outcome measures: Odds …

A Scalable Organoid Model Of Urothelial Aging For Metabolic Interrogation, Infection Modeling, And Reversal Of Age-Associated Changes, Adwaita R Parab, Arnold M Salazar, Steven J Bark, Margarita Divenko, Vasanta Putluri, D'Feau J Lieu, Aadya S Singh, Nagireddy Putluri, Indira U Mysorekar

Faculty, Staff and Students Publications

Aging leads to a progressive decline in overall bladder function resulting in lower urinary tract symptoms and increased susceptibility to infections. However, tissue-specific mechanisms of aging, specifically the contributions of the urothelium, remain elusive. Here, we introduce mouse bladder epithelium-derived organoids (mBEDOs) as a scalable platform to model urothelial aging. mBEDOs from aged mice recapitulate key features of age-associated cellular reprogramming, including oxidative stress, senescence, and DNA damage. We demonstrate the utility of mBEDOs for modeling Uropathogenic Escherichia coli (UPEC) infection, generating assembloids between mBEDOs and macrophages to model epithelial-immune interactions, and genetic perturbation. Using the mBEDO platform, we also …

Deep Brain Stimulation Response Circuits In Obsessive-Compulsive Disorder, Andreas Horn, Ningfei Li, Garance M Meyer, Ron Gadot, Nicole R Provenza, Sameer A Sheth

Faculty, Staff and Students Publications

In the field of deep brain stimulation (DBS), two major themes are currently making significant progress. First, the framework of connectomic DBS, in which circuits that are associated with improvements of specific symptoms are described and targeted to improve and potentially personalize treatment. Second, the concept of brain sensing and adaptive DBS, which aims at identifying neural biomarkers that may guide stimulation in a closed-loop fashion.

In DBS for Obsessive Compulsive Disorder (OCD), substantial progress has been made on both ends, over the last five years. Together, results begin to draw a picture of exactly which circuit is …

Integrated Transcriptomic Landscape Of Medulloblastoma And Ependymoma Reveals Novel Tumor Subtype-Specific Biology, Sonali Arora, Nicholas Nuechterlein, Matt Jensen, Gregory Glatzer, Philipp Sievers, Srinidhi Varadharajan, Andrey Korshunov, Felix Sahm, Stephen C Mack, Michael D Taylor, Taranjit S Gujral, Eric C Holland

Faculty, Staff and Students Publications

Background: Medulloblastoma and ependymoma are common pediatric central nervous system tumors with significant molecular and clinical heterogeneity. While molecular subgrouping has enabled classification into molecular subtypes, the extent of heterogeneity within these subgroups remains poorly defined.

Methods: We collected bulk RNA sequencing data from 888 medulloblastoma and 370 ependymoma tumors to establish a comprehensive reference landscape. After rigorous batch effect correction, normalization, and dimensionality reduction, we generated a unified landscape to explore gene expression, signaling pathways, RNA fusions, and copy number variations.

Results: Our transcriptional analysis revealed distinct clustering patterns, including two primary ependymoma compartments, EPN-E1 and EPN-E2, each with …

Cyclic Amp-Dependent Regulation Of Ryanodine Receptors In Healthy And Diseased Hearts, Mohit M Hulsurkar, Isabelle Ong, Joshua A Keefe, Issam H Abu-Taha, Dobromir Dobrev, Xander H T Wehrens

Faculty, Staff and Students Publications

Cyclic adenosine monophosphate (cAMP) is a critical second messenger in cardiomyocytes, regulating essential cellular functions. Upon G-protein-coupled receptor stimulation, adenylyl cyclase (AC) synthesizes cAMP, which phosphodiesterase (PDE) enzymes subsequently degrade. Recent studies challenge the traditional view of uniform cAMP signaling, revealing nanodomain-specific regulation within cardiomyocytes. This localized cAMP signaling modulates key Ca2+-handling proteins, including ryanodine receptor type-2 (RyR2), through channel-bound protein kinases and PDEs. Additionally, nucleoside-diphosphate kinases (NDPKs), particularly NDPK-C, contribute to cAMP synthesis and RyR2 regulation. Elevated NDPK-C levels in failing hearts correlate with increased cAMP levels, enhanced sarcoplasmic reticulum Ca2+ release, and cardiac arrhythmias. Furthermore, cAMP influences the …

Global Dose Prescription Variances Exemplified Through Oropharynx Cancer: When Is 70 Gray 70 Gray?, Christian Rønn Hansen, Tony Tadic, Manju Sharma, Gareth Price, Jens Petersen, Mohamed A Naser, Ying Xiao, Nataliya Kovalchuk, Pernille Lassen, Jens Overgaard, Lachlan Mcdowell, Prabhakar Ramachandran, Jun Won Kim, Clifton David Fuller, David J Thomson, Jørgen Johansen, Jeppe Friborg, Sue S Yom, Andrew Hope

Faculty, Staff and Student Publications

Purpose/objectives: Radiation therapy treatment planning hinges on a critical factor: the prescribed dose. Surprisingly, there is no consistent, standardized global approach to evaluating the dosimetry of this prescription across different centers treating head and neck cancer (HNC). This study aimed to quantify global dose variations for identical prescriptions across international centers treating oropharyngeal cancer, to establish the foundation for future outcome-based studies and improve consistency of interpretation worldwide.

Materials and methods: The study included patients with oropharyngeal cancer who were consecutively treated from 2017 onward with intensity-modulated radiation therapy or volumetric modulated arc therapy at 8 globally recognized radiation therapy …

Preoperative Malnutrition Is Associated With Increased Postoperative Complications Following Lumbar Fusion: A Propensity-Matched Analysis, Ali Mehaidli, Muaaz Wajahath, Jad Lawand, Omar Abdalla, Lorenzo Deveza, Noah Hodson, Ryan J Berger, Kevin Taliaferro

Faculty, Staff and Students Publications

Background: Lumbar fusion (LF) is a common surgical intervention for degenerative spinal conditions but carries significant short- and long-term risks. Preoperative malnutrition, characterized by low serum albumin or leukocyte counts, impairs wound healing and increases susceptibility to infection, yet its influence on LF outcomes remains underexplored. This study evaluates the association between preoperative malnutrition and long-term postoperative outcomes following LF.

Methods: Adult patients undergoing LF between 2003 and 2023 were identified in the TriNetX US Collaborative Network. Malnutrition was defined as serum albumin < 3.5 g/dL or leukocyte count < 1,500/mm3 within 1 year preoperatively. A 1:1 propensity score match was performed for demographics, comorbidities, surgical approach, and body mass index (BMI), yielding two cohorts (n=20,693 each). Ninety-day and 5‑year postoperative outcomes were compared using hazard ratios (HRs) with 95% confidence intervals (CIs).

Results: Malnourished patients experienced significantly higher 90‑day rates of transfusion (8.4% vs. 4.5%; HR 1.87, 95% CI: …

Beyond Bile Acids Synthesis: Metabolomics Profiling Highlights Extensive Metabolic Dysregulation And Treatment Response In Ctx, Monte A Del Monte, Jennifer Hanson, Penelope E Bonnen

Faculty, Staff and Students Publications

Background: Cerebrotendinous xanthomatosis (CTX) is an inherited metabolic disorder caused by variants in CYP27A1 leading to loss of sterol-27-hydroxylase activity. Sterol-27-hydroxylase generates two classes of bioactive signaling molecules: bile acids and oxysterols. The broader metabolic consequences resulting from perturbations in bile acid and oxysterol signaling and their reversibility with FDA-approved treatment chenodeoxycholic acid (CDCA), are not fully described.

Methods: To establish a comprehensive map of metabolic consequences of CTX, we performed large-scale, untargeted plasma metabolomics in a single subject with CTX, both before and after 6 months of CDCA therapy, and compared results with a reference cohort of over 1100 …

Functional Genomic Analysis Of Non-Canonical Dna Regulatory Elements Of The Aryl Hydrocarbon Receptor, Shayan Shahriar, Tajhal D Patel, Manjula Nakka, Sandra L Grimm, Cristian Coarfa, Daniel A Gorelick

Faculty, Staff and Students Publications

The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor activated by environmental toxicants like halogenated and polycyclic aromatic hydrocarbons, which then binds to DNA and regulates gene expression. AHR is implicated in numerous physiological processes, including liver and immune function, cell cycle control, oncogenesis, and metabolism. Traditionally, AHR binds a consensus DNA sequence (GCGTG), the xenobiotic response element (XRE), recruits coregulators, and modulates gene expression. Yet, recent evidence suggests AHR can also regulate gene expression via a non-consensus sequence (GGGA), termed the non-consensus XRE (NC-XRE). The prevalence and functional significance of NC-XRE motifs in the genome have remained unclear. …

An Application-Based Ontological Knowledge Base Of Medications To Support Health Literacy And Adherence For The Consumer Population: An Aging Population Use Case, Clifford Chen, Muhammad Amith, Kirk Roberts, Rebecca Mauldin, Renata Komalasari, Cui Tao

Faculty, Staff and Student Publications

No abstract provided.

Translating Cardiovascular Ion Channel And Ca2+ Signalling Mechanisms Into Therapeutic Insights, Silvia Marchianò, Miguel Martín-Aragón Baudel, Charlotte E R Smith, Gonzalo Hernandez Hernandez, Donald M Bers, Patrick M Boyle, Dobromir Dobrev, Shanna Hamilton, Osama F Harraz, Na Li, Thomas A Longden, William E Louch, Madeline Nieves-Cintron, Matthew A Nystoriak, Walter Lee Murfee, Przemysław B Radwański, Swapnil K Sonkusare, Manuel F Navedo, Eleonora Grandi

Faculty, Staff and Students Publications

Cardiovascular diseases remain the leading cause of mortality worldwide, driven by complex, multi-scale mechanisms that span molecular, cellular, and organ-level dysfunction. Effective therapeutic strategies therefore require integrative approaches that link fundamental biology to translational applications. The 8th UC Davis CardioVascular Symposium gathered experts in ion channel biophysics, Ca2+ signaling, arrhythmia mechanisms, and cardiovascular physiology to discuss recent advances and define emerging priorities. This white paper synthesizes the key themes and consensus points that emerged, highlighting progress in two core domains: (1) advances in cardiovascular electrophysiology and arrhythmia mechanisms, and (2) spatiotemporal dynamics of Ca2+ signaling in cardiac and vascular function …

Kdm4a Promotes Nepc Progression Through Regulation Of Myc Expression, Celia Sze Ling Mak, Ming Zhu, Jie Fu, Xin Liang, Xiaoxuan Wang, Fei Yuan, Feng Wang, Anh G Hoang, Xingzhi Song, Peter Shepherd, Derek Liang, Jessica Suh, Jordan Contreras, Thisawin Dang, Cindy Yan, Brandon Figueroa, Mathias Mazzocco, Athena Luo, Bijeta Pradhan, Jiwon Park, Mirrah Bashir, Miao Zhang, Eric Metzger, Roland Schüle, Abhinav K Jain, Ellen Karasik, Daniel Frigo, Barbara A Foster, Min Gyu Lee, Paul Corn, Christopher J Logothetis, Ana Aparicio, Nora Navone, Patricia Troncoso, Zhi Tan, Jianhua Zhang, Sue-Hwa Lin, Guocan Wang

Faculty, Staff and Students Publications

Neuroendocrine prostate cancer (NEPC) is a highly aggressive and lethal subtype of prostate cancer (PCa) that often emerges in response to androgen receptor pathway inhibitors (ARPIs), which are widely used in treating metastatic castration-resistant and hormone-sensitive prostate cancer. The incidence of NEPC is increasing, yet effective therapeutic strategies remain limited due to an incomplete understanding of its molecular drivers. Through transcriptomic analyses of human prostate tumor samples, we identified the histone lysine demethylase KDM4A as uniquely overexpressed in human and mouse NEPC compared to prostate adenocarcinoma. Functional validation demonstrated that KDM4A is a key regulator of NEPC progression and a …

Beyond Neurons: Impact Of Cannabidiol On Glial Cells In Ischemic Stroke, Victória Linden De Rezende, Khiany Mathias, Cinara Ludvig Gonçalves, Rafael Mariano De Bitencourt, Tatiana Barichello, Fabricia Petronilho

Faculty, Staff and Student Publications

Ischemic stroke triggers a complex cascade of events involving inflammation, oxidative stress, and glial cell dysfunction, all of which contribute to neuronal damage and impaired recovery. Glial cells (e.g., astrocytes, microglia, and oligodendrocytes) play key roles in neuroinflammatory responses, making them attractive targets for therapeutic modulation. Cannabidiol, a non-psychoactive phytocannabinoid from Cannabis sativa, exhibits anti-inflammatory, antioxidant, and neuroprotective properties. Preclinical evidence indicates that cannabidiol attenuates glial reactivity, reduces pro-inflammatory signaling, mitigates oxidative stress, and preserves blood-brain and intestinal barrier integrity in stroke models. Moreover, cannabidiol modulates key molecular pathways (e.g., nuclear factor-κB, tumor necrosis factor, and calcium-related signaling), contributing to …

Differentiation In The Human Urothelia Is Defined By Distinct Alternative Polyadenylation, Ninh B Le, Surbhi Sona, Briana Santo, Yi Zhang, Rosie Ou, R Allen Schweickart, Veena Kochat, William I Padron, Kunal Rai, Shih-Han Lee, Joo Mi Yi, Oliver Wessely, Byron H Lee, Angela H Ting

Faculty, Staff and Student Publications

Distinct epithelial cell states arise during differentiation, but mechanisms generating transcriptomic diversity among them remain poorly defined. The human ureter urothelium contains basal progenitor, intermediate cells, and terminally differentiated umbrella cells. Prior single-cell RNA sequencing revealed similar global gene expression profiles across these states, raising the question of how distinct identities emerge. Here, we show that alternative cleavage and polyadenylation (APA) introduces a major layer of transcriptomic diversity during urothelial differentiation, largely independent of changes in mRNA levels. Analysis of 13,544 urothelial cells identified hundreds of differentiation-associated APA events. Single-cell imaging revealed spatially specific APA patterns, and reporter assays demonstrated …

Differentiation In The Human Urothelia Is Defined By Distinct Alternative Polyadenylation, Ninh B Le, Surbhi Sona, Briana Santo, Yi Zhang, Rosie Ou, R Allen Schweickart, Veena Kochat, William I Padron, Kunal Rai, Shih-Han Lee, Joo Mi Yi, Oliver Wessely, Byron H Lee, Angela H Ting

Faculty, Staff and Student Publications

Distinct epithelial cell states arise during differentiation, but mechanisms generating transcriptomic diversity among them remain poorly defined. The human ureter urothelium contains basal progenitor, intermediate cells, and terminally differentiated umbrella cells. Prior single-cell RNA sequencing revealed similar global gene expression profiles across these states, raising the question of how distinct identities emerge. Here, we show that alternative cleavage and polyadenylation (APA) introduces a major layer of transcriptomic diversity during urothelial differentiation, largely independent of changes in mRNA levels. Analysis of 13,544 urothelial cells identified hundreds of differentiation-associated APA events. Single-cell imaging revealed spatially specific APA patterns, and reporter assays demonstrated …

Mechanistic Insights Into The Antimicrobial Effect Of Benzodioxane-Benzamides Against Escherichia Coli, Lorenzo Suigo, Alessia Lanzini, Valentina Straniero, William Margolin

Faculty, Staff and Student Publications

Background/Objectives: The bacterial cell division machinery is emerging as an attractive target for antimicrobial compounds. FtsZ, a highly conserved essential division protein, is the target for a number of small molecules such as benzamides. Recent studies show that benzodioxane-benzamides (BDOBs) are among the most potent inhibitors of FtsZ function in Gram-positive bacteria, although their ability to inhibit Gram-negative FtsZ, in particular Escherichia coli FtsZ, has been more controversial.

Methods: Here, we use genetic and cytological methods to demonstrate that FtsZ of efflux pump-disabled E. coli can be efficiently targeted by BDOBs.

Results: We show that engineered mutants …

Payload Diversification Overcomes Resistance And Guides Sequential Antibody-Drug Conjugate Therapy In Breast Cancer, Dileep Reddy Rampa, Minji Seo, Nanae Ogata, Zhaoxuan Yang, Nithya Sridhar, Fujii Takeo, Chalothorn Wannaphut, Jennifer A Maynard, Kyoji Tsuchikama, George W Sledge, Naoto T Ueno, Jangsoon Lee

Faculty, Staff and Student Publications

Purpose: Antibody-drug conjugates (ADCs) have transformed the treatment of breast cancer. FDA-approved ADCs such as trastuzumab deruxtecan (T-DXd), sacituzumab govitecan (SG), and datopotamab deruxtecan (Dato-DXd) have demonstrated clinical benefit; however, drug resistance will almost inevitably emerge in the metastatic setting, and there is no established strategy for selecting subsequent ADCs after disease progression to the first exposure to the ADC. This study aimed to define mechanisms of acquired resistance and evaluate rational sequencing approaches.

Experimental design: We generated breast cancer cell lines resistant to T-DXd (TDXd-R) and SG (SG-R). We assessed antigen expression, internalization, and resistance pathways, including efflux transporter …

Expression Spectrum Of Te-Driven Transcripts In Human Adult Tissues, Benpeng Miao, Xinlong Luo, Amina Ademovic, Yushan Yang, Tao P Wu, Bo A Zhang

Faculty, Staff and Students Publications

Background

Transposable elements (TEs) are vital components of eukaryotic genomes and have played a critical role in genome evolution. Although most TEs are silenced in the mammalian genome, increasing evidence suggests that certain TEs are actively involved in gene regulation during early developmental stages. However, the extent to which human TEs drive gene transcription in adult tissues remains largely unexplored.

Results

In this study, we systematically analyze 17,329 human transcriptomes to investigate how TEs influence gene transcription across 47 adult tissues. Our findings reveal that TE-driven transcripts are broadly expressed in human tissues, contributing to both housekeeping functions and tissue-specific …

Changing Bodies And The History Of Anthropometrics, Moramay López-Alonso

History of Medicine Seminar

No abstract provided.

Tead-Independent Mechanisms Of Yap Function In Cardiomyocyte Cell Cycle Reentry, Bing Xie, Jeffrey Steimle, Vaibhav Deshmukh, Lin Liu, Chang-Ru Tsai, Todd R Heallen, Wyatt Paltzer, Yuka Morikawa, Fansen Meng, Jun Wang, James F Martin

Faculty, Staff and Students Publications

Adult mammalian hearts exhibit limited regenerative capacity because of the restricted renewal of cardiomyocytes. Recent studies reveal that mammalian hearts exhibit transient regenerative potential within a short time frame after birth, suggesting a regulatory mechanism that prevents adult hearts from initiating a regenerative response to cardiac injury. Here, we discovered that an active form of YAP, named YAP6SA, which is not inhibited by the Hippo signaling pathway and does not interact with TEADs, induces cardiomyocyte cell cycle reentry. In addition, YAP6SA interacts with scaffold protein MPDZ to regulate Rho GTPases and promote cell cycle progression in cardiomyocytes (CMs). Importantly, YAP6SA …

De Novo Variants In The Splicing Factor Gene Sf3b1 Are Associated With Neurodevelopmental Disorders, Kevin Uguen, Tiffany Bergot, Marie-Pier Scott-Boyer, Solène Chapalain, Camille Desdouets, Séverine Commet, Changlian Zhu, Yiran Xu, Yangong Wang, Tony Roscioli, Frederic Tran-Mau-Them, Laurence Faivre, Julien Maraval, Julian Delanne, Anne-Sophie Denommé-Pichon, Antonio Vitobello, Céline Jost, Marc Planes, Susan Hiatt, Patricia Wheeler, Claudia Gonzaga-Jauregui, Heng Wang, Baozhong Xin, Valerie Sency, Michael C Kruer, Somayeh Bakhtiari, Patrick Sulem, Cynthia Curry, Trine Prescott, Gertrud Strobl-Wildemann, Theresa Brunet, Martine Doco Fenzy, Thomas Courtin, Céline Poirsier, Trine Bjørg Hammer, Christina D Fenger, Melissa Macpherson, Kosuke Izumi, Jacqueline Leonard, Dong Li, Elaine H Zackai, Ian A Glass, Scott Ward, Philippe M Campeau, Maria Carla Hermida Borroto, Laurence Le Moigno, Hilde Van Esch, Liesbeth De Waele, Daniel G Calame, James R Lupski, Giulia Barcia, Cristina Peduto, Pauline Planté-Bordeneuve, Lucie Dupuis, Roberto Mendoza-Londono, Dimitri J Stavropoulos, Jennifer Gillibert-Duplantier, Thomas Besnard, Laura Do Souto Ferreira, Benjamin Cogné, Stéphane Bézieau, Arnaud Droit, Laurent Corcos, Eric Lippert, Claude Férec, Sebastien Küry, Delphine G Bernard

Faculty, Staff and Students Publications

SF3B1 is an essential and ubiquitous splicing factor that plays a pivotal role in the early steps of pre-mRNA splicing. Recurrent somatic missense mutations in SF3B1 are frequent in cancers, but no constitutional variant has been reported so far. We describe here a cohort of 26 individuals with neurodevelopmental disorders, harbouring SF3B1 constitutional heterozygous variants that appeared mostly de novo. Patients present with a global developmental delay, associated with variable neurological and facial dysmorphic traits. A dichotomy may emerge between patients harbouring predicted loss of function (n = 9) and missense variants (n = 17), the latter being associated with …

Intestinal Epithelial Tlr5 Signaling Promotes Barrier-Supportive Macrophages, Ming-Ting Tsai, Ryann Callaghan, Charles Ng, Lisette Peres-Tintin, Dean B Matthews, Nikketa Stanford, Karuna Ganesh, Mary K Estes, Gretchen E Diehl

Faculty, Staff and Students Publications

Intestinal macrophages are essential for epithelial barrier repair. In homeostasis, macrophages are continuously replenished by recruitment of circulating CCR2+ monocytes into the intestinal lamina propria. This requires the commensal microbiota, however, the specific microbial factors and downstream host pathways that coordinate macrophage replenishment are inadequately understood. Here, we show that colonization with an E. coli isolate increased CCR2+ macrophages in the intestine and ameliorated pathology in a colitis model. Using human colonic organoids, we showed E. coli colonization induced CCL2 secretion by intestinal epithelial stem cells which promoted monocyte migration. In vivo, protection was abolished in the absence of epithelial …

The Gene Encoding Ornithine Decarboxylase For Putrescine Biosynthesis Is Essential For The Viability Of Fusobacterium Nucleatum, Shiqi Xu, Bibek G C, Alex Phan, Chenggang Wu

Faculty, Staff and Student Publications

Fusobacterium nucleatum is a Gram-negative anaerobe associated with periodontitis and colorectal cancer. It secretes putrescine, a polyamine that promotes biofilm formation by oral co-colonizers and enhances the proliferation of cancer cells. However, the physiological importance of putrescine for F. nucleatum itself remains unexplored. Here, we show that putrescine biosynthesis, mediated by the ornithine decarboxylase gene oda, is essential for F. nucleatum viability. Deletion of oda was only possible when a functional copy was provided in trans, and CRISPR interference of oda expression resulted in complete growth defects. The essentiality of oda was conserved across multiple subspecies. Supplementation with …

Qsox1: A Mysterious Golgi-Localized Disulfide Bond Catalyst And An Emerging Cancer Regulator, Shike Wang, Guan-Yu Xiao, Xiaochao Tan

Faculty, Staff and Student Publications

Quiescin sulfhydryl oxidase 1 (QSOX1) is a disulfide bond-forming enzyme with both disulfide isomerase and oxidoreductase activities. It plays an important role in protein folding, stability, and secretion. Growing evidence demonstrates that QSOX1 is upregulated in multiple cancer types and influences key behaviors of cancer cells, including proliferation, migration, invasion, and metastasis. Elevated QSOX1 expression is also associated with tumor malignancy and disease relapse. However, the molecular mechanisms by which QSOX1 drives cancer progression remain incompletely understood. In this review, we summarize current knowledge of QSOX1 expression and regulation in cancer, discuss its functional roles, and highlight key unanswered questions …

Simulated Complex Cells Contribute To Object Recognition Through Representational Untangling, Mitchell B Slapik, Harel Z Shouval

Faculty, Staff and Student Publications

The visual system performs a remarkable feat: it takes complex retinal activation patterns and decodes them for object recognition. This operation, termed "representational untangling," organizes neural representations by clustering similar objects together while separating different categories of objects. While representational untangling is usually associated with higher-order visual areas like the inferior temporal cortex, it remains unclear how the early visual system contributes to this process-whether through highly selective neurons or high-dimensional population codes. This article investigates how a computational model of early vision contributes to representational untangling. Using a computational visual hierarchy and two different data sets consisting of numerals …