Digital Commons Network^™

Crem Is A Regulatory Checkpoint Of Car And Il-15 Signalling In Nk Cells, Hind Rafei, Rafet Basar, Sunil Acharya, Yu-Sung Hsu, Pinghua Liu, Deqiang Zhang, Toszka Bohn, Qingnan Liang, Vakul Mohanty, Ranjan Upadhyay, Ping Li, Pravin Phadatare, Merve Dede, Donghai Xiong, Huihui Fan, Corry Mathew Jones, Sebastian Kunz, May Daher, Ana Karen Nunez Cortes, Mayra Shanley, Bin Liu, Sadie Mae Moseley, Chenyu Zhang, Dexing Fang, Pinaki Banerjee, Nadima Uprety, Ye Li, Rejeena Shrestha, Xinhai Wan, Hong Shen, Vernikka Woods, April Lamour Gilbert, Seema Rawal, Jinzhuang Dou, Yukun Tan, Jeong-Min Park, Francia Reyes Silva, Alexander Biederstädt, Mecit Kaplan, Xin Ru Jiang, Inci Biederstädt, Bijender Kumar, Silvia Tiberti, Madison Moore, Jingling Jin, Ryan Z Yang, Luis Muniz-Feliciano, Samuel Rosemore, Paul Lin, Gary M Deyter, Natalie Wall Fowlkes, Abhinav K Jain, David Marin, Anirban Maitra, Ken Chen, Tobias Bopp, Elizabeth J Shpall, Katayoun Rezvani

Faculty, Staff and Student Publications

Chimeric antigen receptor (CAR) natural killer (NK) cell immunotherapy offers a promising approach against cancer1-3. However, the molecular mechanisms that regulate CAR-NK cell activity remain unclear. Here we identify the transcription factor cyclic AMP response element modulator (CREM) as a crucial regulator of NK cell function. Transcriptomic analysis revealed a significant induction of CREM in CAR-NK cells during the peak of effector function after adoptive transfer in a tumour mouse model, and this peak coincided with signatures of both activation and dysfunction. We demonstrate that both CAR activation and interleukin-15 signalling rapidly induce CREM upregulation in NK cells. Functionally, CREM …

Protocol To Detect M22g Modification On Single Trna Iso-Decoders By Immuno-Northern Blotting, Sseu-Pei Hwang, Katherine Barondeau, Catherine Denicourt

Faculty, Staff and Student Publications

tRNA modifications are highly dynamic and play crucial roles in regulating gene expression. Here, we present an assay for analyzing N2, N2-dimethylguanosine (m22G) modifications on tRNAs using an antibody-based detection approach. We describe steps for isolating tRNAs from human cells via ion-exchange chromatography, capturing specific tRNA iso-decoders on streptavidin magnetic beads, and detecting modifications through immuno-northern blotting. This approach enables researchers to investigate other tRNA modifications using specific antibodies or downstream approaches such as mass spectrometry.

Amyloid Accumulation, Brain Atrophy, And Cognitive Decline In Emergent Alzheimer's Disease, Ying Xia, Pierrick Bourgeat, Vincent Doré, Jurgen Fripp, Yen Ying Lim, Simon M. Laws, Christopher Fowler, Christopher C. Rowe, Colin L. Masters, Elizabeth J. Coulson, Paul Maruff

Research outputs 2022 to 2026

Introduction : Emergent Alzheimer's disease (AD) represents a transitional stage where cognitively unimpaired (CU) individuals exhibit subthreshold but increasing amyloid-β (Aβ) levels. The impact of Aβ accumulation on brain volume loss and cognition during this early stage remains unclear. Methods: This retrospective cohort study analyzed data from 408 CU participants who were initially Aβ− (< 15 Centiloids) and followed for up to 15 years. Changes in basal forebrain and hippocampal volume, along with domain-specific cognitive performance, were compared between those who progressed to Aβ+ (≥20 Centiloids) and those who remained Aβ−. Results: Sixty-five CU participants progressed to Aβ+, indicating emergent AD, and showed faster Aβ accumulation and subtle memory decline. However, no significant differences in rate of BF and hippocampal atrophy were observed between groups. Discussion: The results suggest that during this emergent phase of AD, Aβ accumulation is associated with episodic memory loss, in the absence of detectable accelerated brain atrophy. Highlights: Identified cognitively unimpaired individuals in the emergent stage of Alzheimer's disease (AD). Emergent AD exhibits a greater rate of amyloid-β (Aβ) accumulation. No accelerated volume loss detected in the basal forebrain or hippocampus. Emergent AD is also associated with a subtle decline in memory. Early Aβ accumulation may impair cognitive function before structural atrophy.

Emergence Of Cellular Nematic Order Is A Conserved Feature Of Gastrulation In Animal Embryos, Xin Li, Robert J Huebner, Margot L K Williams, Jessica Sawyer, Mark Peifer, John B Wallingford, D Thirumalai

Faculty, Staff and Students Publications

Cells undergo dramatic morphological changes during embryogenesis, yet how these changes affect the formation of ordered tissues remains elusive. Here, we show that a phase transition leading to the formation of a nematic liquid crystal state during gastrulation in the development of embryos of fish, frogs, and fruit flies occurs by a common mechanism despite substantial differences between these evolutionarily distant animals. Importantly, nematic order forms early before any discernible changes in the shapes of cells. All three species exhibit similar propagation of the nematic phase, reminiscent of nucleation and growth mechanisms. The spatial correlations in the nematic phase in …

Fetal Body Composition And Organ Volume Trajectories In Association With Maternal Perceived Stress Or Depressive Symptoms In The Fetal 3d Study, Alexandra Jean-Louis, Jessica L Gleason, Zhen Chen, Kathryn A Wagner, William A Grobman, Roger B Newman, Wesley Lee, Robert Gore-Langton, Seth Sherman, John Owen, Deborah A Wing, Daniel W Skupski, Jagteshwar Grewal, Katherine L Grantz

Faculty, Staff and Students Publications

Objectives: Evaluate associations between maternal perceived stress and depressive symptoms, and fetal body composition and organ volumes.

Methods: In the NICHD Fetal 3D Study (2015-2019; n = 2457), stress and depressive symptoms were assessed at enrollment (10-13 weeks). High stress was defined as a Perceived Stress Scale (PSS) score ≥15 and high depressive symptoms, defined as an Edinburgh Postnatal Depression Scale (EPDS) score ≥10. Fetal body composition and organ volumes (cerebellar, lung, liver, and kidney) were measured up to five times between 15 and 40 weeks using three-dimensional (3D) ultrasound technology. Trajectories of body composition and organ volumes across pregnancy …

Metabolomic Data May Support The Development Of Personalized Nutrition Approaches To Type 2 Diabetes Management, Danielle J Lee, Shragvi Balaji, Jerome I Rotter, Alexis C Wood

Faculty, Staff and Students Publications

Diet is a major modifiable risk factor for type 2 diabetes (T2D), and suboptimal diets continue to contribute substantially to the population burden of T2D. Personalized nutrition proponents argue that specializing recommendations to interindividual differences in diet-health relationships will yield reductions in disease risk. However, how to personalize diet, and to whom, to reduce T2D risk remains unclear. Metabolites offer promise in this respect, as they capture (in part) dietary intake after the processes of digestion, processing, and absorption. The incorporation of metabolite data into diet-health studies therefore offers the opportunity to examine how the effects of food on the …

Fgf21 Promotes Longevity In Diet-Induced Obesity Through Metabolic Benefits Independent Of Growth Suppression, Christy M Gliniak, Ruth Gordillo, Yun-Hee Youm, Qian Lin, Clair Crewe, Zhuzhen Zhang, Bianca C Field, Teppei Fujikawa, Megan Virostek, Shangang Zhao, Yi Zhu, Clifford J Rosen, Tamas L Horvath, Vishwa Deep Dixit, Philipp E Scherer

Faculty, Staff and Students Publications

Approximately 35% of US adults over 65 are obese, highlighting the need for therapies targeting age-related metabolic issues. Fibroblast growth factor 21 (FGF21), a hormone mainly produced by the liver, improves metabolism and extends lifespan. To explore its effects without developmental confounders, we generated mice with adipocyte-specific FGF21 overexpression beginning in adulthood. When fed a high-fat diet, these mice lived up to 3.3 years, resisted weight gain, improved insulin sensitivity, and showed reduced liver steatosis. Aged transgenic mice also displayed lower levels of inflammatory immune cells and lipotoxic ceramides in visceral adipose tissue, benefits that occurred even in the absence …

Role Of Kctd13 In Modulating Ar And Sox9 Expression In Different Penile Cell Populations, Carolina J Jorgez, Ahmed Chahdi, Hunter Flores, Marisol O'Neill, Abhishek Seth

Faculty, Staff and Students Publications

Objective: Micropenis is a condition with significant physical and psychological implications caused mainly by decreased androgen action in penile development. Kctd13-knockout (Kctd13-KO) mice have micropenis, cryptorchidism, and fertility defects because of reduced levels of androgen receptor (AR) and SOX9. We hypothesized that normalizing the levels of AR and SOX9 in the Kctd13-KO penis could help us to understand the mechanism of action of these signaling pathways on penile development.

Methods: We generated transgenic mice lacking Kctd13 and conditionally expressing AR in the urethral mesenchyme after Cre activation with Twist2cre (Kctd13-KO; AR-CMV; Twist2cre; herein called AR+), and Sox9 in the urethral …

Identification Of Distinct Biological Groups Of Patients With Cryptogenic Norse Via Inflammatory Profiling, Martin Guillemaud, Mario Chavez, Firas Kobeissy, Annamaria Vezzani, Anthony D Jimenez, Maysaa Merhi Basha, Ayush Batra, Sophie Demeret, Onome Eka, Krista Eschbach, Brandon Foreman, Nicolas Gaspard, Elizabeth E Gerard, Teneille Emma Gofton, Hiba A Haider, Stephen T Hantus, Charles L Howe, Amy Jongeling, Mariel Kalkach-Aparicio, Padmaja Kandula, Karnig Kazazian, Minjee Kim, Yi-Chen Lai, Clémence Marois, Andrew Mellor, Wazim Mohamed, Mikaela Morales, Cederic M Pimentel, Alexandra M Ramirez, Claude Steriade, Aaron F Struck, Olga Taraschenko, Nathan Torcida Sedano, Mark S Wainwright, Ji Yeoun Yoo, Kevin K W Wang, Vincent Navarro, Lawrence J Hirsch, Aurélie Hanin

Faculty, Staff and Students Publications

Background and objectives: Emerging evidence suggests that immune dysregulation plays a pivotal role in triggering cryptogenic new-onset refractory status epilepticus (c-NORSE), prompting a consensus on early initiation of immunotherapy. However, despite similar timing of administration, responses to immunotherapies have been varied and unpredictable, suggesting the presence of heterogeneous underlying mechanisms. The aim of this study was to identify distinct inflammatory response subtypes in patients with c-NORSE by analyzing their cytokine profiles. Insights into underlying mechanisms were sought to understand the pathophysiology and guide personalized therapies to improve patient outcomes.

Methods: Sixty-two patients with c-NORSE were included. A comprehensive panel …

Functional Regulation Of Macrophages By Ces1d-Mediated Lipid Signaling In Immunometabolism, Long J Shao, Fathima Elizondo, Feng Gao, Rabie Habib, Xin Li, Katherine Pham, Jazmin Ysaguirre, Maryam Elizondo, Shirindokht Shirazi, Kristin L Eckel-Mahan, Sean Hartig, Huaizhu Wu, Kai Sun

Faculty, Staff and Student Publications

Objective: Macrophage accumulation in metabolically active tissues during obesity is common in both animals and humans, but the lipid signaling mechanisms that trigger macrophage inflammation remain unclear. This study investigates the role of Ces1d, an unconventional lipase, in regulating macrophage inflammation under nutritional stress.

Methods: A myeloid-specific Ces1d knockout (LysM-Cre-Ces1d floxed/floxed, KO) mouse model was used for the studies. For in vitro tests, bone marrow-derived macrophages (BMDMs) from control (Ces1d floxed/floxed, WT) and KO mice were assessed for migration, polarization, and activation. For in vivo experiments, WT and KO mice were induced to obesity via a high-fat diet (HFD) and …

Muscle Rev-Erb Controls Time-Dependent Adaptations To Chronic Exercise In Mice, Jidong Liu, Fang Xiao, Abhinav Choubey, Udhaya Kumar S, Yanxiang Wang, Sungguan Hong, Tingting Yang, Husniye Gul Otlu, Ege Sanem Oturmaz, Emanuele Loro, Yuxiang Sun, Pradip Saha, Tejvir S Khurana, Li Chen, Xinguo Hou, Zheng Sun

Center on Aging Staff Publications

The best time of the day for chronic exercise training and the mechanism underlying the timing effects is unclear. Here, we show that low-intensity, low-volume treadmill training in mice before sleep yields greater benefits than after waking for muscle contractile performance and systemic glucose tolerance. Baseline muscle performance also exhibits diurnal variations, with higher strength but lower endurance before sleep than after waking. Muscle-specific knockout of circadian clock genes Rev-erbα/β (Rev-MKO) in male mice eradicates the diurnal variations in both training and baseline conditions without affecting muscle mass, mitochondrial content, food intake, or spontaneous activities. Multi-omics and metabolic measurements reveal …

Mental Health, Racism, And Contemporary Challenges Of Being Black In America, Michael Mcclam

Staff and Researcher Publications

No abstract provided.

Coordinated Regulation By Lncrnas Results In Tight Lncrna-Target Couplings, Hua-Sheng Chiu, Sonal Somvanshi, Chung-Te Chang, Eric James De Bony De Lavergne, Zhaowen Wei, Chih-Hung Hsieh, Wim Trypsteen, Kathleen A Scorsone, Ektaben Patel, Tien T Tang, David B Flint, Mohammad Javad Najaf Panah, Hyunjae Ryan Kim, Purva Rathi, Yan-Hwa Wu Lee, Sarah E Woodfield, Sanjeev A Vasudevan, Andras Attila Heczey, M Waleed Gaber, Gabriel O Sawakuchi, Ting-Wen Chen, Pieter Mestdagh, Xuerui Yang, Pavel Sumazin

Faculty, Staff and Student Publications

The determination of long non-coding RNA (lncRNA) function is a major challenge in RNA biology with applications to basic, translational, and medical research. We developed BigHorn to computationally infer lncRNA-DNA interactions that mediate transcription and chromatin-remodeling factor activity. Its accurate inference enabled the identification of lncRNAs that coordinately regulate both the transcriptional and post-transcriptional processing of their targets. These lncRNAs may act as molecular chaperones, regulating the stability and translation of mRNAs they helped transcribe, leading to tightly coupled expression profiles. Our analysis suggests that lncRNAs regulate cancer genes across tumor contexts, thus propagating the effects of non-coding alterations to …

The Long-Term Effects Of Chemotherapy On Normal Blood Cells, Emily Mitchell, My H Pham, Anna Clay, Rashesh Sanghvi, Nicholas Williams, Sandra Pietsch, Joanne I Hsu, Nina Friesgaard Øbro, Hyunchul Jung, Aditi Vedi, Sarah Moody, Jingwei Wang, Daniel Leonganmornlert, Michael Spencer Chapman, Ellie Dunstone, Anna Santarsieri, Alex Cagan, Heather E Machado, E Joanna Baxter, George Follows, Daniel J Hodson, Ultan Mcdermott, Gary J Doherty, Inigo Martincorena, Laura Humphreys, Krishnaa Mahbubani, Kourosh Saeb Parsy, Koichi Takahashi, Margaret A Goodell, David Kent, Elisa Laurenti, Peter J Campbell, Raheleh Rahbari, Jyoti Nangalia, Michael R Stratton

Faculty, Staff and Student Publications

Several chemotherapeutic agents act by increasing DNA damage in cancer cells, triggering cell death. However, there is limited understanding of the extent and long-term consequences of collateral DNA damage in normal tissues. To investigate the impact of chemotherapy on mutation burdens and the cell population structure of normal tissue, we sequenced blood cell genomes from 23 individuals aged 3-80 years who were treated with a range of chemotherapy regimens. Substantial additional somatic mutation loads with characteristic mutational signatures were imposed by some chemotherapeutic agents, but the effects were dependent on the drug and blood cell types. Chemotherapy induced premature changes …

Distinguishing Pex2 And Pex16 Gene Variant Severity For Mild, Severe And Atypical Peroxisome Biogenesis Disorders, Vanessa A Gomez, Oguz Kanca, Sharayu V Jangam, Saurabh Srivastav, Jonathan C Andrews, Michael F Wangler

Duncan NRI Faculty and Staff Publications

Peroxisomal biogenesis disorders (PBD) are autosomal recessive diseases caused by mutations in specific PEX genes that impair peroxisome formation, leading to multi-systemic failure. Symptoms vary, even in patients with variants in the same PEX gene. Our goal is to select PEX mutations and use Drosophila to model a severity spectrum based on genotype-phenotype correlations. Utilizing KozakGAL4 (KZ) cassettes, we replaced the coding sequence of Pex with a GAL4 driver, ideal for making 'humanized' flies in which human PEX can replace the fly loss. We generated Pex2KZ and Pex16KZ lines and assessed them in various behavior assays, confirming their severe phenotypes. …

Sequencing-Based Detection Of Measles In Wastewater: Texas, January 2025, Sara Javornik Cregeen, Michael J Tisza, Blake Hanson, Marissa Cook, Anil Surathu, Rebecca Schneider, Jingjing Wu, Kirstin Short, Kaavya Domakonda, Loren Hopkins, Matthew C Ross, Joseph F Petrosino, Jennifer Deegan, Lauren B Stadler, Eric Boerwinkle, Anthony Maresso

Center for Medical Ethics and Health Policy Staff Publications

Measles is a potentially deadly viral infection spread via respiratory droplets from infected individuals. Outbreaks occur when vaccine coverage drops below the threshold of herd, or community, immunity. Using a sequencing-based approach, we report the prospective (January 7, 2025) detection of measles in nucleic acid extracts from 2 wastewater treatment plants in Houston, Texas, with a population of more than 218 000 residents. The sequencing data from 2 samples contained 53 unique reads mapping to 11 different regions of the measles virus genome with a 99.4% match to genotype B3. Importantly, no detections were observed from 821 previous samples from …

Against The Phrase "Aggressive Care", Trevor M Bibler

Center for Medical Ethics and Health Policy Staff Publications

Language is the primary technology clinical ethicists use as they offer guidance about norms. Like any other piece of technology, to use the technology well requires attention, intention, skill, and knowledge. Word choice becomes a matter of professional practice. The Brief Report offers clinical ethicists several reasons for rejecting the phrase "aggressive care." Instead, ethicists should consider replacing "aggressive care" with the adjacent concept of a "recovery-focused path." The virtues of this neologism include: the opportunity to set aside the emotion of "aggression," the phrase's accuracy when capturing the intention of the patient or their representative, and an unappreciated rhetorical …

Gut Virome Profile In New Onset Treatment Naïve Saudi Children With Ulcerative Colitis, Mohammad El Mouzan, Tor C Savidge, Ahmed Al Sarkhy, Shyam Badu, Badr Alsaleem, Mohammad Al Mofarreh, Abdullah Almasood, Asaad Assiri

Faculty, Staff and Students Publications

Background: Gut microbiome imbalance is well established in ulcerative colitis (UC) in Western populations. Significantly less is known about the gut virome and whether geography impacts the UC-associated microbiome. The aim of this study was to characterize gut bacteriophage changes, as well as to identify phage-bacterial associations that can serve as potential biomarkers of UC.

Methods: Twenty children with UC and 20 healthy controls were enrolled in the study. Inclusion criteria included newly diagnosed treatment-naïve children with UC with no antibiotic exposure for at least six months prior to sample collection. Deoxyribonucleic acid (DNA) was extracted from stool and rectal …

Short-Term Neurologic Outcomes In Pediatric Extracorporeal Membrane Oxygenation Are Proportional To Bleeding Severity Graded By A Novel Bleeding Scale, Katherine Doane, Danielle Guffey, Laura L Loftis, Trung C Nguyen, Matthew A Musick, Amanda Ruth, Ryan D Coleman, Jun Teruya, Christine Allen, Melania M Bembea, Brian Boville, Jamie Furlong-Dillard, Santosh Kaipa, Mara Leimanis, Matthew P Malone, Lindsey K Rasmussen, Ahmed Said, Marie E Steiner, Deanna T Tzanetos, Heather Viamonte, Linda Wallenkamp, Arun Saini

Faculty, Staff and Students Publications

Patients admitted to a pediatric intensive care unit (PICU) need individualized nutrition support that is tailored to their particular disease severity, nutritional status, and therapeutic interventions. We aim to evaluate how calories and proteins are provided during the first seven days of hospitalization for children in critical condition with organ dysfunction (OD). A single-center retrospective cohort study of children aged 2–18 years, mechanically ventilated > 48 h, and admitted > 7 days to a PICU from 2016 to 2017 was carried out. Nutrition support included enteral and parenteral nutrition. We calculated scores for the Pediatric Sequential Organ Failure Assessment (pSOFA) on days …

A Lysosomal Surveillance Response To Stress Extends Healthspan, Terytty Yang Li, Arwen W Gao, Rendan Yang, Yu Sun, Yuxuan Lei, Xiaoxu Li, Lin Chen, Yasmine J Liu, Rachel N Arey, Kimberly Morales, Raya B Liu, Wenzheng Wang, Ang Zhou, Tong-Jin Zhao, Weisha Li, Amélia Lalou, Qi Wang, Tanes Lima, Riekelt H Houtkooper, Johan Auwerx

Faculty, Staff and Students Publications

Lysosomes are cytoplasmic organelles central for the degradation of macromolecules to maintain cellular homoeostasis and health. However, how lysosomal activity can be boosted to counteract ageing and ageing-related diseases remains elusive. Here we reveal that silencing specific vacuolar H+-ATPase subunits (for example, vha-6), which are essential for intestinal lumen acidification in Caenorhabditis elegans, extends lifespan by ~60%. This longevity phenotype can be explained by an adaptive transcriptional response typified by induction of a set of transcripts involved in lysosomal function and proteolysis, which we termed the lysosomal surveillance response (LySR). LySR activation is characterized by boosted lysosomal activity …

Unfolding The Mystery Of Autoimmunity: The Environmental Determinants Of Diabetes In The Young (Teddy) Study, Marian Rewers, Daniel Agardh, Suzanne Bennett Johnson, Ezio Bonifacio, Helena Elding Larsson, Patricia Gesualdo, William Hagopian, Michael J Haller, Heikki Hyöty, Randi Johnson, Richard Mcindoe, Eoin Mckinney, Jessica Melin, Åke Lernmark, Richard E Lloyd, Kristian F Lynch, Jill M Norris, Stephen S Rich, Roswith Roth, Desmond Schatz, Jorma Toppari, Eric Triplett, Kendra Vehik, Suvi M Virtanen, Anette-G Ziegler, Beena Akolkar, Jeffrey P Krischer, Teddy Study Group

Faculty, Staff and Students Publications

In 2025, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at the National Institutes of Health celebrates 75 years of leadership in diabetes research. The NIDDK serves people of the U.S. affected by or at risk for many chronic diseases, including diabetes and other endocrine, metabolic, and digestive disorders, by funding innovative research to develop better treatment and prevention and a cure for these conditions. Autoimmunity that leads to type 1 diabetes or celiac disease or thyroid autoimmunity affects 1 in 20 children and adolescents in the U.S. While treatments are available, prevention of these common autoimmune …

A Hypomorphic Model Of Cps1 Deficiency For Investigating The Effects Of Hyperammonemia On The Developing Nervous System, Stuti Bakshi, Taryn Diep, Brandon J Willis, Rachel Reyes, Grace F Wu, Georgios Makris, Martin Poms, Isabel Day, Qin Sun, Irina Zhuravka, Lindsay Lueptow, Michelle Tang, Gareth A Cromie, Aimée M Dudley, Johannes Häberle, Gerald S Lipshutz

Faculty, Staff and Students Publications

Carbamoyl phosphate synthetase 1 (CPS1) deficiency is a rare metabolic disorder that, in neonatal onset, is typically characterized by severe life-threatening and neurologically injuring hyperammonemic episodes with high unmet patient need. Patients that retain limited enzyme activity may present later in life with less severe hyperammonemia. CPS1 drives the first step in the urea cycle, the pathway terrestrial mammals utilize to metabolize nitrogen. In order to probe the effect of hyperammonemia on the developing nervous system and explore new therapies, a murine Cps1 exon 3-4 mutant was previously generated. However, these mice die within 24 h of birth, limiting study …

Cardiovascular-Kidney-Metabolic Effects: Steroidal And Nonsteroidal Mineralocorticoid Receptor Antagonists, Biykem Bozkurt, James L Januzzi, Shweta Bansal

Faculty, Staff and Students Publications

Cardiovascular (CV)-kidney-metabolic (CKM) syndrome is a complex disorder characterized by the co-occurrence of CV risk factors, including chronic kidney disease (CKD), hypertension, and metabolic dysfunction, which creates a vicious cycle where one factor negatively impacts the others, ultimately leading to poor overall CV and kidney outcomes. Overactivation of the mineralocorticoid receptor, through binding with aldosterone and ligand-independent mechanisms, is implicated in the pathogenesis of CKM; mineralocorticoid receptor antagonists (MRAs) can block this interaction. Steroidal MRAs are currently recommended for people with heart failure (HF) with reduced ejection fraction and hypertension; however, the role of nonsteroidal MRAs in CKM is evolving. …

Glioblastoma-Instructed Astrocytes Suppress Tumour-Specific T Cell Immunity, Camilo Faust Akl, Brian M Andersen, Zhaorong Li, Federico Giovannoni, Martin Diebold, Liliana M Sanmarco, Michael Kilian, Luca Fehrenbacher, Florian Pernin, Joseph M Rone, Hong-Gyun Lee, Gavin Piester, Jessica E Kenison, Joon-Hyuk Lee, Tomer Illouz, Carolina M Polonio, Léna Srun, Jazmin Martinez, Elizabeth N Chung, Anton Schüle, Agustin Plasencia, Lucinda Li, Kylynne Ferrara, Mercedes Lewandrowski, Craig A Strathdee, Lorena Lerner, Christophe Quéva, Iain C Clark, Benjamin Deneen, Judy Lieberman, David H Sherr, Jack P Antel, Michael A Wheeler, Keith L Ligon, E Antonio Chiocca, Marco Prinz, David A Reardon, Francisco J Quintana

Faculty, Staff and Students Publications

Glioblastoma is the most common and aggressive primary brain cancer and shows minimal response to therapies. The immunosuppressive tumour microenvironment in glioblastoma contributes to the limited therapeutic response. Astrocytes are abundant in the central nervous system and have important immunoregulatory roles. However, little is known about their role in the immune response to glioblastoma1. Here we used single-cell and bulk RNA sequencing of clinical glioblastoma samples and samples from preclinical models, multiplexed immunofluorescence, in vivo CRISPR-based cell-specific genetic perturbations and in vitro mouse and human experimental systems to address this gap in knowledge. We identified an astrocyte subset …

Endothelium- And Fibroblast-Derived C-Type Natriuretic Peptide Prevents The Development And Progression Of Aortic Aneurysm, Aisah A Aubdool, Amie J Moyes, Cristina Perez-Ternero, Reshma S Baliga, Jaspinder Singh Sanghera, M Taaha Syed, Kareemah Jaigirdar, Anmolpreet K Panesar, Janice C Tsui, Yanming Li, Hernan G Vasquez, Ying H Shen, Scott A Lemaire, Juliette Raffort, Ziad Mallat, Hong S Lu, Alan Daugherty, Adrian J Hobbs

Faculty, Staff and Students Publications

Background: Thoracic (TAA) and abdominal (AAA) aortic aneurysm are life-threatening diseases characterized by dilation, inflammation, and structural weakness; development of pharmacological therapies is desperately needed. CNP (C-type natriuretic peptide) plays a key role in vascular homeostasis, mediating vasodilator, anti-inflammatory, and antiatherogenic actions. Since such processes drive AA, we determined the role of endogenous CNP in offsetting pathogenesis.

Methods: Tissue from patients with AA was analyzed to determine the consequences on CNP signaling. Ascending and suprarenal aortic diameters were assessed at baseline and following Ang II (angiotensin II; 1.44 mg/kg per day) infusion in wild-type, endothelium-restricted (ecCNP-/-), fibroblast-restricted (fbCNP-/-), global CNP …

Cryoem Structure Of The Slfn14 Endoribonuclease Reveals Insight Into Rna Binding And Cleavage, Justin Van Riper, Arleth O Martinez-Claros, Lie Wang, Hannah E Schneiderman, Sweta Maheshwari, Monica C Pillon

Faculty, Staff and Students Publications

The SLFN14 endoribonuclease is a post-transcriptional regulator that targets the ribosome and its associated RNA substrates for codon-bias translational repression. SLFN14 nuclease activity is linked to antiviral defense and platelet function. Despite its prominent role in gene regulation, the molecular signals regulating SLFN14 substrate recognition and catalytic activation remain unclear. SLFN14 dysregulation is linked to human diseases, including ribosomopathies and inherited thrombocytopenia, thus underscoring the importance of establishing the signals coordinating its RNA processing activity. Here, we reconstitute active full-length human SLFN14 and report a high-resolution cryoEM reconstruction of the SLFN14•RNA complex. The structure reveals a medallion-like architecture that shares …

Inhibition Of Srebp-1c Rescues Hepatic Cyp7b1 Expression And Bile Acid Synthesis In Malnourished Mice, Xiaoyang Wan, Krishnakant G Soni, Jong Min Choi, Sun Yun Jung, Margaret E Conner, Geoffrey A Preidis

Faculty, Staff and Students Publications

Malnutrition decreases intestinal bile acids, resulting in inefficient nutrient absorption and impaired catch-up growth. Mechanisms by which bile acid depletion occurs in malnutrition are unknown. Using a mouse model of early-life malnutrition, we explored bile acid homeostasis, focusing on transcriptional repression of CYP7B1, a rate-limiting enzyme in the alternative pathway of bile acid biosynthesis, by SREBP-1c, a master regulator of lipid metabolism. Mice were maintained on a low-protein low-fat or isocaloric control chow until eight weeks of age when livers were harvested for proteome profiling, western blot, RT-qPCR, and chromatin immunoprecipitation. Cultured hepatocytes and mice were treated with the SREBP-1c …

Mass Spectrometry Imaging Reveals Alterations In Protein And N-Glycan Molecular Signatures In Endometriosis Tissues, Monica Lin, Erin H Seeley, Suzanne Ledet, Christina Salazar, Michael T Breen, Livia S Eberlin

Faculty, Staff and Students Publications

Endometriosis is a gynecological condition characterized by the uncontrolled growth of endometrial-like tissue outside the uterine cavity. Although highly prevalent, the biological mechanisms of endometriosis are poorly understood, and the disease is often misdiagnosed due to the unavailability of pre-operative diagnostic methods. Thus, better characterization of molecular markers of endometriosis are critical to improve our understanding of the disease and management of patients. Here, we used matrix-assisted laser desorption ionization mass spectrometry (MALDI MS) imaging to investigate protein and N-glycan molecular signatures in eutopic endometrium and endometriosis lesions from tissues prospectively collected from patients. MALDI MS imaging of intact proteins …

Ad-Sge-Dkk3 Gene Therapy Overcomes Resistance To Immune Checkpoint Blockade In Pleural Mesothelioma, Hee-Jin Jang, Meera Patel, Daniel Y Wang, Sung Wook Kang, Jong Min Choi, Claire Lee, Monica Vilchis, Ji Seon Shim, Sonali Mitra, Priyanka Ranchod, Allen Kuncheria, William Hudson, Peter Jindra, Veronica Lenge De Rosen, Maheshwari Ramineni, Ernest Ramsay Camp, Farrah Kheradmand, R Taylor Ripley, Shawn S Groth, Hyun-Sung Lee, Bryan M Burt

Faculty, Staff and Students Publications

Purpose: Immune checkpoint inhibitors (ICI) have limited efficacy in pleural mesothelioma. We investigated the role of Dickkopf WNT signaling pathway inhibitor 3 (DKK3) in overcoming treatment resistance.

Patients and methods: We performed preclinical studies to elucidate DKK3's role in ICI-resistant mouse mesothelioma. Based on these findings, we conducted a single-arm, phase II clinical trial of a combination of Ad-SGE-DKK3 and nivolumab for chemotherapy-refractory epithelioid pleural mesothelioma, with the objective response rate as the primary outcome.

Results: DKK3 was significantly reduced in human epithelioid mesothelioma. Overexpression of DKK3 in cancer cells activated the p53 pathway, enhanced glycolysis, increased surface PD-L1, and …

Automated Assignment Grading With Large Language Models: Insights From A Bioinformatics Course, Pavlin G Poličar, Martin Špendl, Tomaž Curk, Blaž Zupan

Faculty, Staff and Students Publications

Motivation: Providing students with individualized feedback through assignments is a cornerstone of education that supports their learning and development. Studies have shown that timely, high-quality feedback plays a critical role in improving learning outcomes. However, providing personalized feedback on a large scale in classes with large numbers of students is often impractical due to the significant time and effort required. Recent advances in natural language processing and large language models (LLMs) offer a promising solution by enabling the efficient delivery of personalized feedback. These technologies can reduce the workload of course staff while improving student satisfaction and learning outcomes. Their …