Digital Commons Network^™

Mecp2 Interacts With The Super Elongation Complex To Regulate Transcription, Jun Young Sonn, Wonho Kim, Marta Iwanaszko, Yuki Aoi, Yan Li, Guantong Qi, Luke Parkitny, Janice L Brissette, Lorin Weiner, Juan Botas, Ismael Al-Ramahi, Ali Shilatifard, Huda Y Zoghbi

Faculty, Staff and Students Publications

Loss-of-function mutations in methyl-CpG binding protein 2 (MECP2) cause Rett syndrome. While we know that MeCP2 binds to methylated cytosines on DNA, the full breadth of the molecular mechanisms by which MeCP2 regulates gene expression remains incompletely understood. Here, using a genetic modifier screen, we identify the super elongation complex, a P-TEFb–containing elongation factor that releases promoter-proximally paused RNA polymerase II, as a genetic interactor of MECP2. MeCP2 physically interacts with SEC subunits and directly binds AFF4, the scaffold of the SEC, via the transcriptional repression domain. Furthermore, MeCP2 facilitates the binding of AFF4 on a subset …

Microbial Associations And Viruses On The Risk Of Celiac Disease (Mavric): A Longitudinal Post-Hoc Case-Cohort Study, Kristian F Lynch, Eric W Triplett, Heikki Hyöty, Angelica P Ahrens, Jutta E Laiho, Joseph F Petrosino, Richard E Lloyd, Daniel Agardh

Faculty, Staff and Students Publications

Celiac disease etiopathogenesis requires genetic predisposition and exposure to gluten, yet these factors alone are not sufficient. Larger longitudinal studies are needed to determine the role of time-varying infections and gut microorganisms. The aim was to design a celiac disease case-cohort longitudinal study using The Environmental Determinants of Diabetes in the Young (TEDDY) study. By age 3-years, persistent tissue transglutaminase autoantibodies (tTGA), i.e., celiac disease autoimmunity (CDA), was confirmed in 704 of the 6132 genetically at-risk TEDDY children. Celiac disease onset (CD-onset) was defined as the age CDA developed when followed by a biopsy-proven diagnosis. A competing risk analysis on …

Participatory Implementation Science To Enhance Knowledge And Build The Capacity To Increase The Uptake And Sustainability Of Hpv Vaccination Among Girls In Nigeria, Peter Kalulu, Olufunto A Olusanya, Nkiruka Obodoechina, Maria A Afadapa, Temitope Ojo, Priscilla A Kabutey, Caven N Ngoe, Ashley Bardon, Juliet Iwelunmor, Et Al.

2020-Current year OA Pubs

BACKGROUND: Human papillomavirus (HPV) vaccination can prevent cancer in low- and middle-income countries (LMICs), but its uptake remains low, especially in Nigeria. Understanding participatory approaches can help identify local strategies to increase, build capacity for, and sustain vaccine uptake. This study evaluated the effectiveness of an innovation bootcamp in enhancing the knowledge and skills of youth implementers about HPV and cervical cancer as a strategy to increase vaccine uptake among Nigerian girls aged 9-14 years. An innovation bootcamp is an intensive training program that engages end users to build capacity and skills.

METHODS: This was a five-week hybrid bootcamp guided …

Structure Of An Lgr Dimer, An Evolutionary Predecessor Of Glycoprotein Hormone Receptors, Zhen Gong, Shuobing Chen, Ziao Fu, Brian Kloss, Chi Wang, Jonathan Kim, Oliver B Clarke, Qing R Fan, Wayne A Hendrickson

2020-Current year OA Pubs

Glycoprotein hormones (GpHs) produced in the human pituitary act through receptors (GpHRs) in the gonads to support reproduction and in the thyroid for metabolism. GpHs are heterodimeric cystine-knot proteins; their receptors bind cognate hormones at an extracellular domain and signal through a transmembrane domain to heterotrimeric G proteins. GpHs and GpHRs have co-evolved from invertebrate counterparts. Structures of the human receptors as isolated for cryogenic electron microscopy (cryo-EM) are all monomeric despite compelling evidence for their functioning as dimers. Here we characterize the homologous receptor from Caenorhabditis elegans. Its biochemical properties are notably similar to those of the thyroid stimulating …

“I Missed My Other Oncologist”: Established Relationships As Barriers And Facilitators To Accessing Car-T And Autologous Transplantation, Zachary A. K. Frosch, Clark Meshack, Caitlin Meeker, Asya Varshavsky-Yanovsky, Rashmi Khanal, Michael Bromberg, Ashwin Chandar, Emmanuel Quien, Jordan Carter, Shazia K. Nakhoda, Marcus Messmer, Charissa Montgomery, Jason A. Incorvati, Nadia D. Ali, Michael J. Styler, Carolyn Y. Fang

Division of Gastroenterology and Hepatology Faculty Papers

BACKGROUND: Autologous stem cell transplantation (ASCT) and chimeric antigen receptor T-cell therapy (CAR-T) can provide significant clinical benefit, but are not equally available to all patients. Oncologist continuity and trust are important to patients, and may act as barriers to receipt of therapy. However, detailed data are lacking on the mechanism by which these might affect receipt of therapy, or how this barrier may be overcome.

METHODS: We conducted a qualitative interview study with patients with non-Hodgkin lymphoma (NHL), classic Hodgkin lymphoma (cHL) or multiple myeloma (MM) eligible for or treated with ASCT/CAR-T. Participants were recruited from a multi-site academic …

The Mechanism Of Action Of Remote Electrical Neuromodulation (Ren) In Treating Migraine And Potentially Other Idiopathic Pain Conditions, Marius Birlea, Christopher L. Robinson, Eden Mama, Alit Stark-Inbar, Alon Ironi, Daniel Atashsokhan, Thomas Berk

College of Nursing Faculty Papers & Presentations

Purpose of Review

This review provides evidence for the mechanism of action (MOA) of Remote Electrical Neuromodulation (REN), a non-pharmacological therapeutic technology for treating migraine and other symptoms manifested by certain idiopathic pain diseases. It discusses the main physiological and anatomical aspects associated with conditioned pain modulation (CPM), and how REN is applied for the treatment of migraine pain and other symptoms.

Recent Findings

The REN wearable device (Nerivio®) is FDA cleared for acute and preventive treatment of migraine in patients aged 8 years and above, and CE marked in patients aged 12 and above. In brief, the REN MOA …

Feasibility And Acceptability Of An Implementation Strategy To Enhance Use Of Classroom-Based Physical Activity Approaches In Elementary Schools: A Mixed Methods Study, Timothy J Walker, Derek W Craig, Christopher D Pfledderer, Matthew Lee, Kempson Onadeko, Emma E Saving, John B Bartholomew, Maria E Fernández

Faculty, Staff and Student Publications

Background: Classroom-based approaches are an evidence-based way to improve children's physical activity; however, they are inconsistently implemented in schools. We developed MAGIC (Movement for Academic Growth In Classrooms), a multifaceted implementation strategy that consists of leadership training, teacher training, and a monthly newsletter to improve use of classroom-based physical activity approaches. The purpose of this study is to examine the feasibility and acceptability of MAGIC among elementary school teachers and leaders.

Methods: We used an embedded, convergent mixed methods design. We provided the MAGIC implementation strategy to a partner elementary school. We then administered surveys to teachers to quantitatively examine …

Developing Ehealth Interventions To Improve Diabetes Management In Emerging Adulthood: Qualitative Formative Study, April Idalski Carcone, Deepika Baskar, Aishah Mahmood, Karen Macdonell, Susan Eggly, Samiran Ghosh, Colleen Buggs-Saxton, Steven J Ondersma, Deborah A Ellis

Faculty, Staff and Student Publications

Background: Emerging adulthood is a high-risk period during which many with type 1 diabetes demonstrate suboptimal diabetes management and glycemic control. There is a need for effective, scalable interventions designed specifically for this population. Technology-based approaches are readily accessible to this age group. Furthermore, interventions consistent with self-determination theory-which posits that the fulfillment of psychological needs for autonomy, self-efficacy, and relatedness promotes intrinsic motivation for change-may resonate well with emerging adults' developmental needs for establishing independence and autonomy, and growing their social network.

Objective: This study aimed to enhance the potential relevance, sustainability, and efficacy of 3 self-determination theory-informed mobile …

Brain Power Comparison Between Microgravity And Head-Down Tilt Bed Rest: An Electroencephalography Approach, María Sevilla-García, Adrián Quivira-Lopesino, Pablo Cuesta, Sandra Pusil, Ricardo Bruña, Patrique Fiedler, Fernando Maestu, Ana Maria Cebolla, Guy Cheron, Katharina Brauns, Alexander C Stahn, Michael E Funke

Faculty, Staff and Student Publications

This study examines neurophysiological changes in microgravity by comparing EEG data from two ground analog 60-day head-down tilt bed rest (HDBR) experiments (ESA/DLR “Cocktail” and “RSL”) and the NEUROSPAT experiment in space. The primary objective was to determine whether HDBR could effectively model spaceflight’s impact on the human brain’s EEG signal. In the HDBR dataset, increases in relative delta (2–4 Hz) (p <  0.01) and theta (4–8 Hz) (p <  0.001) power bands were observed during a two-month HDBR experiment, predominantly in the left temporal and parieto-occipital regions. Conversely, the NEUROSPAT dataset showed a significant increase in beta (12–30 Hz) (p <  0.05) power in the left somatosensory cortex during in-flight conditions, suggesting a potential adaptation to disrupted proprioceptive input and motor control in microgravity. The contrasting findings between the two datasets indicate that while HDBR can simulate some aspects of microgravity, it may not serve as a model for all central nervous system changes, especially those related to proprioception and motor functions. This highlights the need for further research, including larger sample sizes, consistent EEG recording conditions, and integration of additional physiological and cognitive markers to fully understand the effects of prolonged microgravity.

Accelerating Digital Mental Health: The Society Of Digital Psychiatry's Three-Pronged Road Map For Education, Digital Navigators, And Ai, John Torous, Kathryn Taylor Ledley, Carla Gorban, Gillian Strudwick, Julian Schwarz, Soumya Choudhary, Margaret Emerson, Michelle Patriquin, Allison Dempsey, Jason Bantjes, Laura Ospina-Pinillos, Jennie Hornick, Shruti Kochhar

Faculty, Staff and Student Publications

Digital mental health tools such as apps, virtual reality, and artificial intelligence (AI) hold great promise but continue to face barriers to widespread clinical adoption. The Society of Digital Psychiatry, in partnership with JMIR Mental Health, presents a 3-pronged road map to accelerate their safe, effective, and equitable implementation. First, education: integrate digital psychiatry into core training and professional development through a global webinar series, annual symposium, newsletter, and an updated open-access curriculum addressing AI and the evolving digital navigator role. Second, AI standards: develop transparent, actionable benchmarks and consensus guidance through initiatives like MindBench.ai to assess reasoning, safety, and …

Crispr Disruption Of Scarna1 Reduces Pseudouridylation In Spliceosomal Rna U2 At U89 And Perturbs The Transcriptome In Hek293t Cells., Amanda Gardner-Kay, Lynndy Le, Michael Filla, Nataliya Kibiryeva, James O'Brien, Douglas C. Bittel

Manuscripts, Articles, Book Chapters and Other Papers

Small Cajal body-associated RNAs (scaRNAs) are essential for biochemical modification of spliceosomal RNAs and spliceosome function. Changes in scaRNA expression level have been associated with developmental issues, including cancer and congenital heart defects (CHDs), although the mechanism remains unclear. Small Cajal body-associated RNA 1 (scaRNA1) guides pseudouridylation at uridine 89 (Ψ89) of the spliceosomal RNA U2, a highly conserved modification that may be critical for spliceosome function. To investigate the role of scaRNA1 in splicing regulation, CRISPR-Cas9 genome editing was used to introduce targeted deletions in the scaRNA1 locus in HEK293T cells. Edited clones were identified by T7 endonuclease I …

A Phase 1/2 Study Of Ds-1594 Menin Inhibitor In Relapsed/Refractory Acute Leukemias, Jayastu Senapati, Marina Konopleva, Ghayas C Issa, Elias Jabbour, Tapan Kadia, Courtney Dinardo, Gautam Borthakur, Naveen Pemmaraju, Nicholas J Short, Musa Yilmaz, Indraneel Deshmukh, Joie Alvarez, Sanam Loghavi, Guilin Tang, Hussein A Abbas, Michael Andreeff, Kapil Bhalla, Narasimha M Midde, Nabil Said, Amy Noyalis, Derek E Mires, Jing Ning, Lianchun Xiao, Farhad Ravandi, Guillermo Garcia-Manero, Hagop M Kantarjian, Naval G Daver

Faculty, Staff and Student Publications

Several menin inhibitors are in development targeting menin dependent leukemias, however available preclinical results show variable level of activity. We report the phase 1 portion (to establish a recommended phase 2 dose [RP2D]) and pharmacokinetic analysis of a phase 1/2 first-in-human clinical trial of DS-1594b menin inhibitor. Eligible patients included adults (≥ 18 years of age) with relapsed/refractory (R/R) acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) including but not restricted to those with KMT2A-rearrangement (r) or NPM1 mutation. Seventeen patients at a median of age 56 years (range, 19-82 years) were treated, 15 (88%) had R/R AML, and …

Human Plasma Proteomic Profile Of Clonal Hematopoiesis, Zhi Yu, Amélie Vromman, Ngoc Quynh H Nguyen, Art Schuermans, Linke Li, Thiago Rentz, Tetsushi Nakao, Shamsudheen K Vellarikkal, Md Mesbah Uddin, Abhishek Niroula, Gabriel Griffin, Michael C Honigberg, Amy E Lin, Christopher J Gibson, Daniel H Katz, Usman A Tahir, Shi Fang, Jacqueline S Dron, Michael Pan, Sara Haidermota, Shriienidhie Ganesh, Tajmara Antoine, Joshua Weinstock, Thomas R Austin, Ramachandran S Vasan, Gina M Peloso, Whitney Hornsby, Peter Ganz, Joann E Manson, Bernhard Haring, Charles Kooperberg, Alexander P Reiner, Joshua C Bis, Bruce M Psaty, Yuan-I Min, Adolfo Correa, Leslie A Lange, Wendy S Post, Jerome I Rotter, Stephen S Rich, James G Wilson, Benjamin L Ebert, Bing Yu, Christie M Ballantyne, Josef Coresh, Vijay G Sankaran, Alexander G Bick, Siddhartha Jaiswal, Robert E Gerszten, Nhlbi Trans-Omics For Precision Medicine, Peter Libby, Rajat M Gupta, Pradeep Natarajan

Faculty, Staff and Student Publications

Plasma proteomic profiles associated with subclinical somatic mutations in blood cells may offer insights into downstream clinical consequences. Here we explore these patterns in clonal hematopoiesis of indeterminate potential (CHIP), which is linked to several cancer and non-cancer outcomes, including coronary artery disease (CAD). Among 61,833 participants (3881 with CHIP) from TOPMed and UK Biobank (UKB) with blood-based DNA sequencing and proteomic measurements (1,148 proteins by SomaScan in TOPMed and 2917 proteins by Olink in UKB), we identify 32 and 345 proteins from TOPMed and UKB, respectively, associated with CHIP and most prevalent driver genes (DNMT3A, TET2, and ASXL1). These …

Non-Invasive Ultrasonic Neuromodulation Of The Human Nucleus Accumbens Impacts Reward Sensitivity, Siti N Yaakub, John Eraifej, Nadège Bault, Mathilde Lojkiewiez, Elouan Bellec, Jamie Roberts, Noah S Philip, Amir Puyan Divanbeighi Zand, Alexander L Green, Matthew F S Rushworth, Elsa F Fouragnan

School of Psychology

Precisely neuromodulating deep brain regions could bring transformative advancements in both neuroscience and treatment. We demonstrate that non-invasive transcranial ultrasound stimulation (TUS) can selectively modulate deep brain activity and affect learning and decision making, comparable to deep brain stimulation (DBS). We tested whether TUS could causally influence neural and behavioural responses by targeting the nucleus accumbens (NAcc) using a reinforcement learning task. Twenty-six healthy adults completed a within-subject TUS-fMRI experiment with three conditions: TUS to the NAcc, dorsal anterior cingulate cortex (dACC), or Sham. After TUS, participants performed a probabilistic learning task during fMRI. TUS-NAcc altered BOLD responses to reward …

Dna Extrusion Size Determines Pathway Choice During Cag Repeat Expansion, Mayuri Bhatia, Ashutosh S. Phadte, Anna Lakhina, Anthony R. Monte Carloi Iii, Sarah Barndt, Anna Pluciennik

Department of Biochemistry and Molecular Biology Faculty Papers

DNA triplet repeat expansion causes several primarly neurological disorders like Huntington's disease, myotonic dystrophy type 1, and fragile-X related disorders. There is general consensus that recognition of extrahelical extrusions or hairpin-loop structures (formed by strand slippage) by the DNA mismatch repair protein MutSβ leads to repeat expansion by a mutagenic process. By contrast, the FAN1 nuclease attenuates triplet repeat expansion, the molecular basis of which was explained by our recent finding that FAN1 nuclease cleaves and initiates removal of extrahelical extrusions. Here we show that extrusions containing two or more triplet repeats are subject to recognition and processing by either …

Predicting The Response Of Triple Negative Breast Cancer To Neoadjuvant Systemic Therapy Via Biology-Based Modeling And Habitat Analysis, Casey E Stowers, Chengyue Wu, Clinton Yam, Jingfei Ma, Gaiane M Rauch, Thomas E Yankeelov

Faculty, Staff and Student Publications

Despite being the standard-of-care treatment, neoadjuvant therapy (NAT) attains a complete response only in approximately half of the patients with triple negative breast cancer. Thus, methods to predict and optimize patient response to NAT are needed. Previously, we employed patient-specific MRI data to calibrate a biology-based mathematical model that describes cell movement, proliferation, and death due to drug at the tumor level and cell proliferation at an image voxel level. We now extend our approach by using MRI data to group voxels into "habitats" whereby tumor cells of a habitat share the same proliferation. With this approach, we now calibrate …

Loss Of Idh1 And Idh2 Mutations During The Evolution Of Metastatic Chondrosarcoma, William Cross, Iben Lyskjær, Christopher Davies, Abigail Bunkum, Ana Maia Rocha, Tom Lesluyes, Fernanda Amary, Roberto Tirabosco, Cristina Naceur-Lombardelli, Mariam Jamal-Hanjani, Charles Swanton, Nischalan Pillay, Simone Zaccaria, Adrienne M Flanagan, Peter Van Loo

Faculty, Staff and Student Publications

Driver mutations in IDH1 and IDH2 are initiating events in the evolution of chondrosarcoma and several other cancer types. Here, we present evidence that mutant IDH1 is recurrently lost in metastatic central chondrosarcoma. This may reflect either relaxed positive selection for the mutant IDH1 locus, or negative selection for the hypermethylation phenotype later in tumor evolution. This finding highlights the challenge for therapeutic intervention by mutant IDH1 inhibitors in chondrosarcoma.

Successful Implementation Of Stroke Risk Screening For Sickle Cell Anemia In The Displace Study: Results Of A Cluster Randomized Trial, Alyssa M Schlenz, Monica L Hulbert, Et Al.

2020-Current year OA Pubs

BACKGROUND: Stroke risk screening using transcranial Doppler (TCD) is a critical evidence-based tool for children with sickle cell anemia (SCA) that has been poorly implemented in the United States. The Dissemination and Implementation of Stroke Prevention Looking at the Care Environment (DISPLACE) study was designed to improve rates of stroke risk screening for SCA using interventions informed by an extensive multi-level barriers and facilitators assessment. This report describes the final outcomes of a large, randomized implementation trial comparing two intervention arms: 1) an application designed to track TCD implementation, ProviderMinder™, versus 2) ProviderMinder™ plus a single coordinator intervention. All sites …

Strengthening Implementation Science Research To Improve Adolescent And Young Adult Hiv-Prevention And Care In Sub-Saharan Africa: Patc3h-In, Geri R Donenberg, Ucheoma Nwaozuru, Sylvia Adebajo, Joseph D Tucker, Juliet Iwelunmor, Lisa M Kuhns, Brenda Gati Mirembe, Lisa Hightow-Weidman, Brian Zanoni, Tapiwa A Tembo, Maria Felix Lupogo, Franklin Yates

2020-Current year OA Pubs

BACKGROUND: Despite significant progress in HIV prevention and treatment, uptake of evidence-based interventions among adolescents and young adults (AYA), particularly in low- and middle-income countries (LMICs), remains low. Implementation research can optimize strategies to enhance reach, uptake, and equitable access to these innovations. The Prevention and Treatment through a Comprehensive Care Continuum for HIV-affected Adolescents in Resource-Constrained Settings Implementation Science Network (PATC

METHODS: The PATC

RESULTS: The PATC

CONCLUSIONS: The PATC

CLINICAL TRIAL NUMBER: Not Applicable.

Waiting Room And Hallway Care For Older Adults: A Qualitative Study With Emergency Nurses And Technicians, Sarah J Nessen, Ari B Friedman, Annika R Bhananker, K Jane Muir, Anita N Chary

Faculty, Staff and Students Publications

Background: Emergency Department (ED) crowding places older ED patients at risk for adverse outcomes. Crowding often necessitates ED waiting room and hallway care, but there has been limited research on approaches to care for older adults in these settings. Frontline clinician insights can inform best practices for older adults in the context of the ongoing ED crowding crisis. Our objective was to describe the experiences of emergency nurses and technicians in providing waiting room and hallway care for older adults.

Methods: This qualitative study used individual, semi-structured interviews with a purposive sample of 20 ED nurses and technicians at a …

Investigating The Neuronal Role Of The Proteasomal Atpase Subunit Gene Psmc5 In Neurodevelopmental Proteasomopathies, Sébastien Küry, Janelle E Stanton, Geeske M Van Woerden, Amélie Bosc-Rosati, Tzung-Chien Hsieh, Lise Bray, Marielle Oloudé, Cory Rosenfelt, Marie Pier Scott-Boyer, Victoria Most, Tianyun Wang, Jonas J Papendorf, Charlotte De Konink, Wallid Deb, Virginie Vignard, Maja Studencka-Turski, Thomas Besnard, Anna M Hajdukowicz, Franziska G Thiel, Sophie Wolfgramm, Laëtitia Florenceau, Silvestre Cuinat, Sylvain Marsac, Yann Verrès, Audrey Dangoumau, Léa Poirier, Ingrid M Wentzensen, Annabelle Tuttle, Cara Forster, Johanna Striesow, Richard Golnik, Damara Ortiz, Laura Jenkins, Jill A Rosenfeld, Alban Ziegler, Clara Houdayer, Dominique Bonneau, Erin Torti, Amber Begtrup, Kristin G Monaghan, Sureni V Mullegama, Catharina M L Nienke Volker-Touw, Koen L I Van Gassen, Renske Oegema, Mirjam S De Pagter, Katharina Steindl, Anita Rauch, Ivan Ivanovski, Kimberly Mcdonald, Emily Boothe, Andrew Dauber, Janice Baker, Noelle Andrea V Fabie, Raphael A Bernier, Tychele N Turner, Siddharth Srivastava, Kira A Dies, Lindsay C Swanson, Carrie Costin, Alali Abdulrazak, Rebekah K Jobling, John Pappas, Rachel Rabin, Dmitriy Niyazov, Anne Chun-Hui Tsai, Karen Kovak, David B Beck, May Christine V Malicdan, David R Adams, Lynne Wolfe, Rebecca D Ganetzky, Colleen C Muraresku, Davit Babikyan, Zdeněk Sedláček, Miroslava Hančárová, Andrew T Timberlake, Hind Al Saif, Berkley Nestler, Kayla King, M J Hajianpour, Gregory Costain, D'Arcy Prendergast, Chumei Li, David Geneviève, Antonio Vitobello, Arthur Sorlin, Christophe Philippe, Tamar Harel, Ori Toker, Ataf Sabir, Derek Lim, Mark J Hamilton, Lisa J Bryson, Elaine Cleary, Sacha Weber, Trevor L Hoffman, Anna M Cueto-González, Eduardo F Tizzano, David Gómez-Andrés, Marta Codina-Solà, Athina Ververi, Efterpi Pavlidou, Alexandros Lambropoulos, Kyriakos Garganis, Marlène Rio, Jonathan Levy, Sarah J Langas, Anne M Mcrae, Mathieu K Lessard, Maria Daniela D'Agostino, Isabelle De Bie, Meret Wegler, Rami Abou Jamra, Susanne B Kamphausen, Viktoria Bothe, Lorraine Potocki, Eric Olinger, Yves Sznajer, Elsa Wiame, Michelle L Thompson, Molly C Schroeder, Catherine Gooch, Raphael A Smith, Arti Pandya, Larissa M Busch, Uwe Völker, Elke Hammer, Kristian Wende, Benjamin Cogné, Bertrand Isidor, Jens Meiler, Clémentine Ripoll, Stéphanie Bigou, Frédéric Laumonnier, Peter W Hildebrand, Evan E Eichler, Kirsty Mcwalter, Peter M Krawitz, Florence Roux-Dalvai, Ype Elgersma, Julien Marcoux, Marie-Pierre Bousquet, Arnaud Droit, Jeremie Poschmann, Andreas M Grabrucker, Francois V Bolduc, Stéphane Bézieau, Frédéric Ebstein, Elke Krüger

Faculty, Staff and Students Publications

Neurodevelopmental proteasomopathies are a group of disorders caused by variants in proteasome subunit genes, that disrupt protein homeostasis and brain development through poorly characterized mechanisms. Here, we report 26 distinct variants in PSMC5, encoding the AAA⁺ ATPase subunit PSMC5/RPT6, in individuals with syndromic neurodevelopmental conditions. Combining genetic, multi-omics and biochemical approaches across cellular models and Drosophila, we unveil the essential role of proteasomes in sustaining key cellular processes. Loss of PSMC5/RPT6 function impairs proteasome activity, leading to protein aggregation, disruption of mitochondrial homeostasis, and dysregulation of lipid metabolism and immune signaling. It also compromises synaptic balance, neuritogenesis, and neural progenitor …

The Pitfalls Of Multiple-Choice Questions In Generative Ai And Medical Education, Shrutika Singh, Anton Alyakin, Daniel Alexander Alber, Jaden Stryker, Ai Phuong S Tong, Karl Sangwon, Nicolas Goff, Mathew De La Paz, Miguel Hernandez-Rovira, Ki Yun Park, Eric Claude Leuthardt, Eric Karl Oermann

2020-Current year OA Pubs

The performance of Large Language Models (LLMs) on multiple-choice question (MCQ) benchmarks is frequently cited as proof of their medical capabilities. We hypothesized that LLM performance on medical MCQs may in part be illusory and driven by factors beyond medical content knowledge and reasoning capabilities. To assess this, we created a novel benchmark of free-response questions with paired MCQs (FreeMedQA). Using this benchmark, we evaluated three state-of-the-art LLMs (GPT-4o, GPT-3.5, and LLama-3-70B-instruct) and found an average absolute deterioration of 39.43% in performance on free-response questions relative to multiple-choice (p = 1.3 * 10

Implementation Outcomes From The Hypertension Treatment In Nigeria Program: Results From A Type 2 Hybrid Interrupted Time Series Trial, Jiancheng Ye, Erica L Jamro, Guhan Iyer, Mark D Huffman, Et Al.

2020-Current year OA Pubs

BACKGROUND: The Hypertension Treatment in Nigeria Program was implemented across 60 primary healthcare centers (PHCs) in Nigeria to improve hypertension treatment and control using the World Health Organization's HEARTS package. This study reports the program's implementation outcomes.

METHODS: The Hypertension Treatment in Nigeria Program used a type 2 hybrid interrupted time series design, and data were collected from January 2020 to December 2023. The RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) framework guided the evaluation, focusing on key metrics such as patients' and clinics' characteristics, prescription rate of fixed dose combination (FDC) drugs, medication availability, and retention.

RESULTS: Among 21,922 …

Molecular Basis Of Nfib-Mediated Regulation Of Oncogenic Transcription, Ci Zhu, Ding Xiao, Yueyu Wang, Hong Han, Chengxiao Qin, Shuang Liu, Xi Chen, Hejin Xiao, Xin Chen, Junfeng Shi, Juyu Tang, Jie Shen, He Song

2020-Current year OA Pubs

The Nuclear Factor I (NFI) family of transcription factors orchestrates key regulatory programs in development, differentiation, and metabolism, with dysregulation implicated in diverse pathological conditions, including cancer. Among the paralogs, NFIB has emerged as an oncogenic driver in multiple tumor types, yet the mechanisms through which it engages DNA and directs oncogenic transcriptional programs remain undefined. Here, using cancer cells with high NFIB expression, we demonstrate that NFIB promotes malignant phenotypes, as CRISPR-Cas9 knockout impairs proliferation, migration, and invasion. Transcriptomic profiling reveals that NFIB regulates a cancer-enriched gene network that includes FGFR3 and PDGFRB. Biophysical analyses show that NFIB, including …

Exploring Experiences Of Mental Health Challenges In Under-Represented Young People (Aged 16–24 Years) In England: A Narrative Inquiry Protocol, Rebecca Syed Sheriff, Jason Arday, Rohit Shankar, Roisin Mooney, Louise Chandler, Helen Adams, Lili Z Nagy, Roger Farrell, Daisy Fancourt, Scott Weich, Catherine Henderson, Shaima Hassan, Joe Langley, Kamaldeep Bhui

Peninsula Medical School

Introduction Three-quarters of mental health problems start before the age of 25. However, young people are the least likely to receive mental healthcare. Some young people (such as those from ethnic minorities) are even less likely to receive mental healthcare than others. Long-term impacts of mental health problems include poorer physical health, relationships, education and employment. We aim to elicit the views, experiences and needs of diverse young people (aged 16–24 years), to better understand (1) their experiences of under-representation, mental health and coping, (2) mechanisms that shape mental health trajectories and (3) how online arts and culture might be …

Metabolomic And Lipidomic Atlas Of Human Hair Across Its Length., Maria Van De Lavoir, Yuanye Chi, Ting Zeng, Rani Robeyns, Maria Del Mar Delgado Povedano, Leen Jacobs, Celine Gys, Hugo Neels, Shuzhao Li, Alexander L N Van Nuijs, Adrian Covaci

Faculty Research 2025

The stable structure and growth cycle of human hair enables the accumulation of both endogenous and exogenous compounds, making hair an ideal matrix for long-term profiling. However, its exact molecular composition, shaped by root-to-tip variations, remains poorly understood. Here, we present a metabolome and lipidome atlas of human hair originating from a healthy cohort. The Human Hair Atlas maps over 1200 unique molecular species and highlights compounds prone to significant longitudinal variations. Metabolite and lipid levels vary by up to 50% along the length of the hair, underscoring the importance of accounting for segmental differences. We categorized 122 molecules as …

Host-Specific Bacterial Modulation Of Airway Gene Expression And Alternative Splicing., Mian Horvath, Hyeon Gu Kang, Te-Chia Wu, Elizabeth Aiken, Diana Cadena Castaneda, Sema Akkurt, Florentina Marches, Olga Anczuków, Karolina Palucka, Julia Oh

Faculty Research 2025

The human microbiome varies extensively between individuals. While there are numerous studies investigating the effects of inter-individual differences on microbiome composition, there are few studies investigating inter-individual effects on microbial modulation of the host or host-specific effects. To address this knowledge gap, we colonized human bronchial epithelial air-liquid interface tissue cultures generated from six different adults with one of three phylogenetically diverse bacteria and compared how each microbe differentially modulated host gene expression in each of the six donors. Microbial treatment had the strongest effect on transcription, followed by donor-specific effects. Gene pathways differed markedly in their donor and microbe …

Optimizing Lower Intensity Triplet Therapy In Acute Myeloid Leukemia: A Practical Guide, Wei-Ying Jen, Curtis A Lachowiez, Jennifer Marvin-Peek, Jessica K Altman, Musa Yilmaz, Jacqueline S Garcia, Yasmin Abaza, Nicholas J Short, Joshua F Zeidner, Naval G Daver, Andrew H Wei, Ghayas C Issa, Courtney D Dinardo

Faculty, Staff and Student Publications

Venetoclax-based doublets with azacitidine or low dose cytarabine are the standard of care for the treatment of acute myeloid leukemia (AML) in older patients or those unfit for intensive chemotherapy. However, some patients do not attain complete remission, and over time, most patients relapse. Frontline triplet therapy incorporating a targeted therapy (FLT3, IDH or menin inhibitor) is an emerging treatment concept under investigation for this population. Initial triplet regimens have yielded encouraging composite complete remission and measurable residual disease negativity rates, enabling the transition to allogeneic stem cell transplantation for eligible patients. While effective, triplets are associated with myelosuppression and …

Targeting The Hepatic Circadian Clock Concomitant With Tyrosine Kinase Inhibition Reverses Late-Stage Hepatocellular Carcinoma, Baharan Fekry, Savera Aggarwal, Rachel Van Drunen, Rafael Bravo, Andy Escalante, Constance Atkins, Sheng Pan, Zheng Chen, Kai Sun, David R Hall, Mamoun Younes, Kristin Eckel-Mahan

Faculty, Staff and Student Publications

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths. Most patients present at advanced stages, and the effectiveness of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors is constrained by limited patient response. A subset of HCC shows elevated expression of the promoter 2 ("P2")-driven hepatocyte nuclear factor 4 alpha (HNF4α) isoform, which directly transcriptionally represses the circadian brain and muscle ARNT-like protein 1 (BMAL1) transcription factor. This subtype of HCC is robustly inhibited by the plant-based flavonoid nobiletin (NOB), a circadian-fortifying compound. Using patient-matched human HCC and serum, we show that BMAL1-deficient HCC shows exaggerated carnitine palmitoyl transferase …

Coordinated Transfer Of Dna Between Pol Θ And Pol Δ Resets Microhomology Choice During Double-Strand Break Repair, Yuzhen Li, Mark Returan, Adele T Guerin, April M Averill, Dorcas Oladapo, Sylvie Doublié, Richard D Wood

Faculty, Staff and Student Publications

DNA polymerase theta (Pol θ)-mediated end joining (TMEJ) initiates DNA double-strand break repair by using short homologies (microhomologies) between single-stranded DNA tails. This repair process is particularly important in cancer cells defective in homologous recombination. The exonuclease function of DNA polymerase delta (Pol δ) has been identified as an essential component for TMEJ, functioning to remove unpaired bases flanking a microhomology (MH). It is not known if the exonuclease removes all unpaired bases at once and how this removal might affect subsequent MH selection. Here, we reconstituted a functional TMEJ repair process using purified human Pol θ and Pol δ. …