Medical Molecular Biology Commons^™

Mtorc2-Nav1.2 Signaling Drives Early Hyperexcitability In Alzheimer’S Disease Mouse Model, Nolan M Dvorak, Jeffrey L Noebels

Faculty, Staff and Students Publications

Hyperexcitability is a biomarker of early-stage Alzheimer’s Disease (AD) and hastens cognitive decline later in its course. Mechanistic target of rapamycin (mTOR) signaling contributes to the slope of this trajectory, as evidenced by early increased brain expression and the rescue of hyperexcitability by genetic deletion of mTOR complex 2 (mTORC2); however, a molecular mechanism directly linking mTOR signaling to membrane hyperexcitability in early-stage AD remains elusive. Here, we show that hyperactive mTOR signaling stimulates the voltage-gated Na+ channel 1.2 (Nav1.2), a previously identified downstream phosphorylation target of mTORC2 and a key regulator of membrane electrogenesis. Augmented Nav1.2 channel function induced …

Brain Perivascular Macrophages Regulate Endothelial Cell Function Via A Cmaf-Dependent Transcriptional Program In Mouse And Human, Simone Brioschi, Julia A Belk, Steffen E Storck, Yue Wu, Zhuoying Wang, Ziang Feng, Lynn Van Olst, Josie L Emery, Raki Sudan, Junjie Wu, Siling Du, Marco Genua, Federica La Terza, Alex J Edwards, Khai M Nguyen, Jessie Sanford, Daniel D Lee, Mattia Bugatti, Arnold J Federico, Yun Chen, Zuoxu Wang, Silvia Penati, Patrick Fernandes Rodrigues, Alina Ulezko Antonova, Hui Qi Loo, Igor Smirnov, Susan Gilfillan, Carmen M Halabi, Jennifer Ponce, Jun Yan, Howard Y Chang, Gwendalyn J Randolph, William Vermi, Marina Cella, Michael Meers, Renato Ostuni, David Gate, Aivi T Nguyen, Carlos Cruchaga, Song Hu, Jonathan Kipnis, Marco Colonna

The Brown Foundation: Institute of Molecular Medicine

Brain perivascular macrophages maintain brain physiology, yet their transcriptional regulators and functions in health and disease remain unclear. Using single-cell multi-omics and functional experiments, we identify cellular musculoaponeurotic fibrosarcoma oncogene (cMAF) as a key transcription factor for brain perivascular macrophages, and conditional deletion of cMAF disrupts their phenotype in vivo. Functionally, cMAF drives insulin-like growth factor-1 (IGF1) expression in perivascular macrophages, enabling communication with endothelial cells. Consistently, cMAF deletion in perivascular macrophages causes transcriptional alterations in cerebral arteries, affecting vascular functions. Notably, cMAF emerges as the main transcription factor for human perivascular macrophages, suggesting conservation of this transcriptional module. During …

Telomere-To-Telomere Genome Assembly And A Pangenome For The Rat, Kai Li, Julia L Ciosek, Sergey Koren, Adam M Phillippy, Yaming Zhu, William A Lauer, Shelise Y Brooks, Gerard G Bouffard, Brandon D Pickett, Beth L Dumont, Melissa L Smith, Theodore S Kalbfleisch, Peter A Doris

The Brown Foundation: Institute of Molecular Medicine

We report a complete rodent telomere-to-telomere genome assembly from the brown rat, Rattus norvegicus. Annotation was enriched with multi-tissue long-read RNA sequencing and uncovered numerous novel genes. Assembly of both sex chromosomes reveals the absence of gene coding in the presumed pseudo-autosomal regions and the presence of centromeric satellite repeats on distal chromosome Y (chrY). We provide evidence of meiotic conjunction between Xp and Yq. The genome assembly reveals several expanded autosomal regions enriched for testis-expressed genes. Finally, we have generated a pangenome from recent high-quality assemblies of 8 distinct inbred rat strain genomes. This allows the strain-specific distribution of …

Runx1+23 Enhancer Marks Erythro-Megakaryocyte Lineages In Early Waves Of Hematopoiesis In Human Esc Differentiation, Chika Nishida, Michihiro Kobayashi, Alina Syed, Philipp Kramer, Haizi Cheng, Pamela L Wenzel, Motomi Osato, Jason David Chobirko, Andrew Grimson, Igor I Slukvin, Brian R Davis, Momoko Yoshimoto

The Brown Foundation: Institute of Molecular Medicine

No abstract provided.

A Distinct Form Of Fat Fibrosis Is Linked To Insulin Resistance In People With Hiv, Diana L Alba, Alaa Abdellatif, Moon Kyung Choi, Stephen M Brown Mayfield, Thuy An T Pham, David I Berrios, Antonio E Rodriguez, Marin Ewing, Tony R Figueroa, Judy Gonzalez-Vargas, Ningyan Zhang, Zhiqiang An, Dawei Bu, Steven G Deeks, Philipp E Scherer, Peter W Hunt, Suneil K Koliwad

The Brown Foundation: Institute of Molecular Medicine

BACKGROUND

Despite antiretroviral therapy (ART), people with HIV (PWH) are at heightened risk for insulin resistance (IR) and type 2 diabetes (T2D). Subcutaneous adipose tissue (SAT) fibrosis contributes to metabolic disease, but its role in IR among PWH is unknown. We investigated the relationship between SAT fibrosis and IR in PWH, along with transcriptional signatures to distinguish it from SAT fibrosis due to obesity.

METHODS

We analyzed body composition and SAT fibrosis (hydroxyproline) in 46 PWH and 74 people without HIV (PWoH), excluding individuals with T2D. We examined fibrosis-related gene transcription in the SAT using a targeted panel and measured …

Terahertz Electromagnetic Effects And Chirality-Induced Spin Selectivity In Dna, F. Matthew Mihelic Md

Faculty Publications

The effects of terahertz electromagnetic stimulation of the DNA molecule can be understood through modeling of the quantum logical mechanics of the DNA molecule.  Coherent conduction of electron spin states along the aromatic nucleotide base pairs and chirality-induced spin selectivity are two characteristics of the DNA molecule that are involved in the precise separation of the double-stranded DNA molecule at a specific location.  Such modeling can inform predictions of DNA strand separation and has significant implications for understanding DNA transcription bubble formation.

De Novo Complex Genomic Rearrangement Spanning 2q31.1 In A Proband With Congenital Malformations: Genotype-Phenotype Correlation And Development Of A Cgr Detection Pipeline, Katherine Helle, Jesse D Bengtsson, Mira Gandhi, Christopher M Grochowski, Ming Yin Lun, Neha Sudhir, Shalini N Jhangiani, Fritz J Sedlazeck, Seema R Lalani, Neil A Hanchard, Claudia M B Carvalho

Faculty, Staff and Students Publications

The 2q31 region is commonly associated with pathogenic alleles of the HOXD cluster leading to various clinical phenotypes related to skeletal development. We present a proband with tetralogy of Fallot and multiple congenital anomalies. Genomic variant screening including an in-house CGR detection pipeline pairing genome sequencing (GS) structural variant calls with read-depth data revealed a de novo complex genomic rearrangement (CGR) spanning 2.7 Mb across 2q31 characterized by a series of duplications and triplications including the HOXD gene cluster. The genomic structure was assembled by applying combined methodologies including short-read and long-read GS, and optical genome mapping (OGM). This in-house …

Systemic Corticosteroids In The Management Of Sinonasal Disease: An Evidence-Based Expert Review, Andrew Thamboo, Deanna Gigliotti, Eugenio De Corso, Stella Lee, Benjamin S Bleier, Christopher J Chin, Marie-Noelle Corriveau, Valerie Hox, Claire Hopkins, Peter H Hwang, Arif Janjua, Ludger Klimek, Daniel Lee, John Lee, Amber Luong, Geoffrey Mortuaire, Joaquim Mullol, Zara M Patel, John Scott, Doron Sommer, Leigh Sowerby, Marc Tewfik, Beatrice Voizard, Martin Wagenmannm, Sarah K Wise, Jonathan Yip, Quirina Thompson, Martin Desrosiers, Yvonne Chan

The Brown Foundation: Institute of Molecular Medicine

Background: Chronic rhinosinusitis (CRS) is a prevalent, heterogeneous inflammatory disease associated with significant morbidity. Systemic corticosteroids (SCS) are commonly prescribed for their anti-inflammatory effects, but cumulative exposure carries risks, including metabolic, cardiovascular, and skeletal complications. Despite widespread use, evidence-based guidance on optimal indications, timing, and duration of SCS in CRS remains inconsistent.

Methodology/principal: An evidence-based review was performed using MEDLINE, EMBASE, and Cochrane databases (2013-2023). Studies were screened and categorized into two primary groups: CRS with (CRSwNP) or without (CRSsNP) nasal polyps. Within CRSwNP, evidence was subcategorized by indication, including (1) polyp size reduction, (2) olfactory dysfunction, (3) comorbid disease, …

Understanding Hypertensive Renal Injury: A Well-Structured Approach, Peter A Doris

The Brown Foundation: Institute of Molecular Medicine

No abstract provided.

Notch Signaling Regulates The Secretion Of Pro-Metastatic Factors In Extracellular Vesicles In Liposarcoma, Menchus Quan, Yi-Kai Liu, Ying Zhao, Madeline Kay, Kai Sun, Timothy P Gavin, Raphael E Pollock, W Andy Tao, Shihuan Kuang

The Brown Foundation: Institute of Molecular Medicine

Notch signaling is an emerging regulator of liposarcoma (LPS), but its role in mediating communication with the tumor microenvironment (TME) is unclear. Here, we investigate how Notch activation (NICD overexpression) alters the proteomes of LPS-derived extracellular vesicles (EVs). We used quantitative mass spectrometry to profile the EV proteome in multiple contexts: cultured LPS cells, LPS tumor, circulating EVs of LPS-bearing mice, and human LPS samples. We found that Notch signaling increases the secretion of EV proteins that favor tumor progression and metastasis but suppresses immune responses in murine LPS cells. Overlapping murine and human LPS data identifies 18 proteins that …

Myeloid Mmp14 Couples Extracellular Proteolysis To Inflammatory And Metabolic Remodeling During Obesity, Long J Shao, Fathima Elizondo, Feng Gao, Elizabeth L Lieu, Bharati Reddi, Maryam Elizondo, Iqbal Mahmud, Kristin Eckel-Mahan, Philipp E Scherer, Xin Ge, Huaizhu Wu, Sean Hartig, Kai Sun

The Brown Foundation: Institute of Molecular Medicine

Macrophages orchestrate tissue remodeling, inflammation, and metabolic dysfunction in obesity, but the role of macrophage-intrinsic extracellular proteolysis in immunometabolic regulation remains unclear. Matrix metalloproteinase-14 (MMP14), a membrane-bound protease, is strongly induced during monocyte-to-macrophage differentiation and further elevated in adipose tissue macrophages from high-fat diet (HFD)-fed mice. Pharmacological inhibition or myeloid-specific deletion of Mmp14 impaired macrophage differentiation, proliferation, migration, phagocytosis, and inflammatory activation in response to obesity-associated adipose tissue signals. Mechanistically, MMP14 promoted inflammatory programming by increasing endotrophin generation and enhancing TLR4-NFκB signaling. MMP14 also reprogrammed macrophage lipid metabolism by suppressing lipolysis and promoting lipid accumulation, altering metabolic communication with neighboring …

Simbinder-If: Structure-Aware Antibody Affinity Optimization Via Efficient Preference Learning, Xinyan Zhao, Yi-Ching Tang, Rivaaj Monsia, Victor J Cantu, Ashwin Kumar Ramesh, Siyu Yang, Xiaozhong Liu, Zhiqiang An, Xiaoqian Jiang, Yejin Kim

The Brown Foundation: Institute of Molecular Medicine

Motivation: Antibody therapeutic efficacy depends on high-affinity target engagement, yet laboratory affinity maturation is slow and costly. Most protein language models (PLMs) lack explicit training for high affinity, and current preference optimization methods introduce computational overhead without clear affinity improvements. Therefore, structure-aware and parameter-efficient approaches for antibody affinity optimization are urgently needed.

Results: We propose SimBinder-IF, a structure-aware antibody optimization model trained by freezing the Evolutionary Scale Modeling inverse folding (ESM-IF) structure encoder and fine-tuning only its decoder via Simple Preference Optimization (SimPO) to prefer stronger binders. In generalization tests across seven held-out complexes (93 477 mutants), SimBinder-IF shows a …

Kras-Independent Factors Drive Pi3k Signaling And Circumvent The Necessity Of Kras-Driven Pi3k Activation In Pdac, Lucas Christopher Bialousow

MUSC Theses and Dissertations

Pancreatic ductal adenocarcinoma (PDAC) has one of the lowest five-year survival rates among cancers and is characterized by near-ubiquitous occurrence of oncogenic KRAS mutations. Oncogenic KRAS activates several downstream pathways, including ERK 1/2 MAPK and PI3K, which are critical for PDAC. However, accumulating evidence suggests that PI3K activity can be maintained independent of oncogenic KRAS. The high prevalence of KRAS^G12R in PDAC challenges the prevailing model of KRAS-driven PI3K activation, as this mutant is defective in direct engagement with PI3Kα. These observations raise important questions regarding how PI3K signaling is sustained in PDAC. Here, we investigated KRAS-independent mechanisms that …

Dupilumab For Patients With Allergic Fungal Rhinosinusitis, Amber U Luong, Joshua M Levy, Sarah K Wise, Joseph K Han, Mamoru Yoshikawa, Luo Zhang, Rodney Schlosser, Prerna Ranganathan, Paula Dakin, Jennifer Maloney, George D Yancopoulos, Andrew P Fontenot, Neelam A Phadke, Lacey R Robinson

The Brown Foundation: Institute of Molecular Medicine

Background: Allergic fungal rhinosinusitis (AFRS) is a severe subtype of chronic rhinosinusitis characterized by fungal hypersensitivity and accentuated type 2 inflammation. Dupilumab-a fully human mAb blocking IL-4/13, approved for type 2 inflammatory diseases, including chronic rhinosinusitis with nasal polyps-may benefit patients with AFRS.

Objective: We sought to understand the effect of dupilumab in AFRS.

Methods: In this phase 3 trial, patients with AFRS age ≥6 years were randomized to dupilumab or matched placebo for 52 weeks. The primary end point was Lund-Mackay computed tomography score, quantifying sinus opacification, at 52 weeks. Secondary end points were multiplicity-controlled and hierarchically tested.

Results: …

Overcoming Igf1r-Mediated Resistance To Oncolytic Hsv1 And Radiotherapy Via Triple Combination Therapy, Alexandra A Miller, Min-Hye Noh, Jin Muk Kang, Jiyeon Kim, Lily Nguyen, Amanda S Kouaho, Grace Nguyen, Minxin Huang, Stephanie M Bean, Joshua Davis, Matthew P Mullarkey, Sunil Krishnan, Zhongming Zhao, E Antonio Chiocca, Tae Jin Lee, Ji Young Yoo

The Brown Foundation: Institute of Molecular Medicine

FDA-approved oncolytic herpes simplex virus-1 (oHSV) therapy has emerged as a promising viro-immunotherapy for solid tumors. However, tumor- and tumor microenvironment (TME)-associated adaptations following viral treatment, such as feedback immune suppression, neoangiogenesis, and enhanced tumor aggressiveness, often hinder complete tumor eradication. A deeper understanding of the molecular mechanisms underlying resistance to oHSV is crucial to enhancing its clinical impact. We recently discovered that oHSV induces Insulin-like growth factor 2 (IGF2) secretion, shaping an immunosuppressive TME. Similarly, radiotherapy (RTx) activates the IGF1/IGF1R and YAP1 signaling pathways, further promoting therapeutic resistance. In this study, we investigated how oHSV-induced Insulin-like growth factor 1 …

Unbiased Avidity-Based Isolation Of Antigen-Specific T Cells, Amanda Montoya, Meredith L Frank, Peixin Jiang, Hui Nie, Minying Zhang, Emily Bontekoe, Jared K Slone, Ludovica L Posta, Sofia Rosy Caterina Sorice, Tina Cascone, Maura Gillison, Don L Gibbons, Jianjun Zhang, Eleonora Dondossola, Lydia Kavraki, Pamela L Wenzel, John V Heymach, Alexandre Reuben

The Brown Foundation: Institute of Molecular Medicine

Background: Cancer immunotherapies have significantly improved treatment efficacy and patient survival by exploiting antigen-specific T cells to eliminate cancer cells. However, current approaches for identifying and isolating antigen-specific T cells typically require prior knowledge of target antigens, limiting discovery, and reducing the ability to consistently detect rare tumor-reactive T cells. We therefore sought to develop an unbiased platform for the identification and enrichment of antigen-specific T cells using naturally processed and presented tumor antigens.

Methods: We developed ATTACH (Assessment of T cells Tethered to Antigen Class I Histocompatibility), a microfluidic platform that applies controlled shear stress and leverages tumor cells …

Tau Pathology In Epilepsy: Emerging Mechanisms And Translational Opportunities, Arjune Sen, Xin You Tai, Aristea Galanopoulou, Maria Thom, Eleonora Aronica, Lucy Vivash, Martin Hardmeier, Action Amos, Stephan Rueegg, Matthias Koepp, Yaroslav Winter, Christoph Helmstaedter, Jeffrey L Noebels, Hilal A Lashuel, Terence J O'Brien

Faculty, Staff and Students Publications

The onset of epilepsy in adulthood occurs most commonly after 55 years of age. Given the ageing global population, this disorder represents an increasing burden on healthcare and society. The bidirectional link between epilepsy and dementia is a focus of intense research with underlying tau pathology highlighted as a potential mechanistic link. In this review, we examine the evidence for tau-related neurodegenerative processes in epilepsy beginning with how changes in biochemical and structural properties of the tau protein can lead to abnormal phosphorylation and pathological aggregation. We consider the role of tau in seizure occurrence and cognitive difficulties in experimental …

Single-Nucleotide Rna M6a Mapping In Bovine Preimplantation Development Reveals Site-Specific Regulation Of Rpl12 At Zygotic Genome Activation, Rajan Iyyappan, Yichi Niu, Yang Li, Hao Ming, Kinga Pajdzik, Noah R Rakestraw, Piyush K Jain, Chuan He, Chenghang Zong, Zongliang Jiang

Faculty, Staff and Students Publications

RNA N6-methyladenosine (m6A) is a key regulator of gene expression during early embryogenesis. Using SAC-seq (m6A-selective allyl chemical labeling and sequencing), an antibody-independent m6A profiling method, we generated the first single-nucleotide-resolution m6A map of bovine oocytes and preimplantation embryos. We observed both coordinated and uncoupled relationships between m6A modification and expression of protein-coding and noncoding genes. Integrative analysis of the transcriptome, m6A epitranscriptome, and translatome revealed dynamic m6A remodeling, particularly in ribosomal protein genes. Functional interrogation of a specific m6A site within the RPL12 transcript demonstrated that loss of this modification reduces protein synthesis, disrupts translation-related gene expression, impairs zygotic …

Antibody-Oligonucleotide Conjugates: An Emerging Modality For Precision Rna Therapeutics, Chen-Hsu Yu, Summer Y Y Ha, Zhiqiang An, Kyoji Tsuchikama, Wenbo Li

The Brown Foundation: Institute of Molecular Medicine

RNA-targeting therapeutics have enormous potential to precisely target disease-causing RNAs, extending beyond the traditional limits of "druggability" for small molecules, antibodies, and protein-targeting cell therapies. However, one crucial limitation is that RNA-targeting drug modalities (such as oligonucleotides) cannot effectively reach diseased tissue or cell types. Antibody-oligonucleotide conjugates (AOCs) emerge as a promising frontier in aiding RNA therapeutics by harnessing antibodies to deliver drug modalities to target specific RNAs in desired tissues or cells. In this Review, we summarize the critical components of AOCs, key considerations for their design and manufacturing, ongoing AOCs in preclinical/clinical development, and disease indications. We discuss …

Genetics Of Cerebrotendinous Xanthomatosis, Jennifer Hanson, Penelope E Bonnen

Faculty, Staff and Students Publications

Cerebrotendinous xanthomatosis (CTX) is rare, autosomal recessive inborn error of metabolism caused by biallelic pathogenic variants in CYP27A1, which encodes sterile 27 hydroxylase, a key enzyme in bile acid biosynthesis. Enzyme deficiency results in reduced cholic and chenodeoxycholic acid synthesis with accumulation of cholestanol, bile acid intermediates, and bile alcohols, producing a progressive multisystem disorder characterized by chronic diarrhea, juvenile-onset cataracts, tendons xanthomas, and neurological dysfunction. Although CTX typically begins in childhood, diagnosis is frequently delayed until adulthood, limiting the benefit of effective disease modifying therapy with chenodeoxycholic acid. Since the identification of CYP27A1, more than 200 pathogenic variants have …

Evidence-Based Classification Of Genes Implicated In Skeletal Disorders Using The Clingen Curation Framework, Ryan F Webb, Hannah Mccurry, Amanda Girod, Madeline Hughes, Emma Wilcox, Mayher Patel, Eleanor C Broeren, Kezang C Tshering, Marina Distefano, Lorenzo D Botto, Lindsay C Burrage, Valérie Cormier-Daire, Juan Dong, Nadja Ehmke, Deborah Krakow, Shahida Moosa, Geert Mortier, Sandesh Nagamani, Loren Pena, Pedro A Sanchez-Lara, Andrea Superti-Furga, Sheila Unger, Danita Velasco, Matthew L Warman, Kerry Brown, Deepika D'Cunha Burkardt, Carlos R Ferreira

Faculty, Staff and Students Publications

More than 770 genetic skeletal disorders have been described, most with disease-causing variants reported in 1 of over 550 different genes. The ClinGen Skeletal Disorders Gene Curation Expert Panel was established to determine the strength of the evidence that supports specific gene-disease relationships (GDRs). Such information can assist clinical testing laboratories in choosing genes that should be included on diagnostic panels. Nine genes accounting for the most frequently encountered skeletal dysplasias (COL1A1, COL1A2, COL2A1, FGFR3, SLC26A2, TRPV4, COMP, ALPL, and SOX9) associated in the medical literature with 26 different skeletal disorders were reviewed using a semi-quantitative scoring framework. This framework …

Jak Inhibition In Pnpt1-Related Mitochondrial Interferonopathy: A Case Report And Review Of Mitochondrial-Immune Crosstalk, Dan Ross Brooks, Hyun Yong Koh, Taylor Martin Kerrins, Steven Lang, Emily Bland, Rui Yang, Sarah Kogan Nicholas, Stephanie Jean Sikkink, Stephen Kralik, Christine Eng, Chaya Nautiyal Murali, Seema Lalani, Pilar Lenglet Magoulas, Lisa Emrick, Kristen Sydney Fisher, Fernando Scaglia

Faculty, Staff and Students Publications

Biallelic pathogenic variants in PNPT1 cause combined oxidative phosphorylation deficiency 13 (COXPD13) (MIM #614932), linking mitochondrial dysfunction to type I interferon (IFN) activation through cytosolic leakage of mitochondrial double‐stranded RNA (mt‐dsRNA). This mechanism connects mitochondrial disease to interferonopathies such as Aicardi–Goutières syndrome (AGS). We describe a 7‐month‐old female infant with compound heterozygous PNPT1 variants presenting with severe hypotonia, feeding difficulties necessitating gastrostomy, dystonia, and elevated serum lactate. Brain magnetic resonance imaging (MRI) demonstrated marked cerebellar, brainstem, and basal ganglia atrophy, with a lactate peak on MR spectroscopy (consistent with an inverted doublet). Serum immune profiling revealed a mild but elevated …

Author Correction: Plasticity And Language In The Anaesthetized Human Hippocampus, Kalman A Katlowitz, Eric R Cole, Elizabeth A Mickiewicz, Shraddha Shah, Melissa Franch, Joshua A Adkinson, James L Belanger, Raissa K Mathura, Domokos Meszéna, Matthew Mcginley, William Muñoz, Garrett P Banks, Sydney S Cash, Chih-Wei Hsu, Angelique C Paulk, Nicole R Provenza, Andrew J Watrous, Ziv Williams, Alica M Goldman, Vaishnav Krishnan, Atul Maheshwari, Sarah R Heilbronner, Robert Kim, Nuttida Rungratsameetaweemana, Benjamin Y Hayden, Sameer A Sheth

Faculty, Staff and Students Publications

This corrects the article "Plasticity and language in the anaesthetized human hippocampus" in volume 654 on page 714.

Biphasic Sleep Is A Feature Of Sleep Disturbance In Syngap1-Rd, Aida Doucoure, Het Patel, Mark A Abboud, Alice Sperry, Sarah K Wanigatunga, Deana Crocetti, Heather Volk, Adam P Spira, Stewart H Mostofsky, Vaishnav Krishnan, Constance Smith-Hicks

Faculty, Staff and Students Publications

Study objectives: Sleep problems are common in children with SYNGAP1-Related Disorder (SYNGAP1-RD). The use of devices that objectively estimate sleep are complicated by co-occurring sensory disorders in this population. We examined the feasibility and validity of wrist actigraphy to examine sleep and rest-activity rhythms (RAR).

Methods: Data from five children with SYNGAP1-RD and 42 typically developing children were analyzed. All children were asked to wear the Actiwatch-2 for 14 continuous days and caregivers were asked to complete a sleep diary and the Children Sleep Health Questionnaire (CSHQ). Parametric (alpha, beta, acrophase, amplitude, up/down mesor, mesor), nonparametric (intradaily variability, interdaily stability, …

Antibody-Oligonucleotide Conjugates: An Emerging Modality For Precision Rna Therapeutics, Chen-Hsu Yu, Summer Y Y Ha, Zhiqiang An, Kyoji Tsuchikama, Wenbo Li

The Brown Foundation: Institute of Molecular Medicine

RNA-targeting therapeutics have enormous potential to precisely target disease-causing RNAs, extending beyond the traditional limits of "druggability" for small molecules, antibodies, and protein-targeting cell therapies. However, one crucial limitation is that RNA-targeting drug modalities (such as oligonucleotides) cannot effectively reach diseased tissue or cell types. Antibody-oligonucleotide conjugates (AOCs) emerge as a promising frontier in aiding RNA therapeutics by harnessing antibodies to deliver drug modalities to target specific RNAs in desired tissues or cells. In this Review, we summarize the critical components of AOCs, key considerations for their design and manufacturing, ongoing AOCs in preclinical/clinical development, and disease indications. We discuss …

Nano-Bio Interfacial Effects Modulating Protein Adsorption In Dialdehyde Lentinan-Crosslinked Polysaccharide Sponges Reinforced With Zein Nanoflowers, Dorota Chelminiak-Dudkiewicz, Miloslav Machacek, Hana Janová, Klara Konecna, Ondrej Jandourek, Jana Kejmarová, Kinga Mylkie, Aleksander Smolarkiewicz-Wyczachowski, Marta Ziegler-Borowska

The Brown Foundation: Institute of Molecular Medicine

The interfacial organization of porous biomaterials critically influences protein adsorption and subsequent cell-material interactions at hydrated biointerfaces relevant to wound-contacting environments. Herein, hybrid sponges were developed by rationally assembling chitosan, lentinan, levan, and fucoidan into a covalently defined macromolecular network featuring nano-bio interfacial effects. The materials were designed to modulate interfacial biological performance via engineered pore-wall structures, with protein-layer formation at sponge interfaces associated with downstream cell-material responses. A dialdehyde lentinan was deliberately employed to establish a chemically defined pore-wall interface via dense Schiff-base junctions with chitosan. The incorporation of zein nanoflowers introduced additional nanoscale structure features, providing additional anchoring …

Cost Utility Analysis Of Fluticasone Exhalation Delivery System Versus Budesonide Nasal Irrigation For Chronic Rhinosinusitis With Nasal Polyps, Daniel Xiao, Martin J Citardi, William C Yao, Amber U Luong

The Brown Foundation: Institute of Molecular Medicine

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is managed after sinus surgery with topical corticosteroids. Given limited distribution of nasal steroid sprays, patients have the option of either steroid nasal irrigation (SNI) or exhalation delivery system with fluticasone (EDS-FLU). This study evaluates the cost-effectiveness of EDS-FLU compared to SNI for CRSwNP.

Methods: A cohort-style Markov decision-tree economic model with a 33-year time horizon was developed in TreeAgePro. Because EDS-FLU is not currently covered by Medicare, costs of medications were estimated using retail pricing. A willingness-to-pay threshold of $50,000/quality adjusted life year (QALY) was used to determine cost-effectiveness. One-way and probabilistic …

Functional Characterization Of Uhrf1 Variants In Facilitating Dna Methylation, Bigang Liu, Kaila Nayvelt, Swanand Hardikar, Kimie Kondo, Marcos R Estecio, Xiaodong Cheng, Taiping Chen

The Brown Foundation: Institute of Molecular Medicine

Ubiquitin-like with plant homeodomain (PHD) and really interesting new gene (RING) finger domains 1 (UHRF1) is essential for DNA methylation inheritance. However, the functional impacts of several natural and engineered UHRF1 variants are either insufficiently characterized or obscured by conflicting results, with some discrepancies likely stemming from cellular toxicity and adaptive responses induced by DNA methylation changes. In this study, we utilized mouse embryonic stem cells (mESCs)-which uniquely tolerate the complete loss of DNA methylation-to evaluate the functional consequences of clinical mutations, isoform variation, and epitope tagging. Using rescue experiments in Uhrf1-deficient mESCs, we characterized two UHRF1 mutations identified in …

Kmt2d As An Epigenetic Target In Cervical Cancer: A Literature Review On Polyclonal Antibody Therapeutics And Translational Prospects, Farsya Hidayah Septiananda, Taurisma Aulia Nanda Wibisono, Rajendra Aulya Gilardino, Andreas Budi Wijaya

Preventia: The Indonesian Journal of Public Health

Cervical cancer remains a significant global health burden, particularly in regions with limited access to advanced therapeutics. Beyond viral oncogenesis, accumulating evidence highlights the crucial role of epigenetic dysregulation, particularly KMT2D, in tumor initiation and progression. This literature review aimed to critically synthesize current evidence regarding the biological role of KMT2D in cervical cancer and to explore the opportunities and limitations of antibody-based approaches for future epigenetic intervention. A structured narrative literature review was conducted using PubMed, Scopus, and Web of Science to identify relevant studies published between January 2020 and May 2025. Literature selection was guided by a modified …

Comprehensive Prediction Analysis Of Novel Noncoding Regulatory Variants Identified In The Microrna Binding Regions In Complement System Genes, Anthony Shadid, Haydn E Rich, Kathryn D Hok, Marie-Francoise Doursout, Marcos I Restrepo, Nirmal K Banda, Lavanya Gunamalai, Pooja Shivshankar

The Brown Foundation: Institute of Molecular Medicine

The complement system is a central component of innate immunity that coordinates host defense, immune surveillance, and inflammatory responses through tightly regulated proteolytic cascades. Genetic variation within complement genes contributes substantially to interindividual differences in complement activity and disease susceptibility. While coding variants directly alter complement protein structure and function, the microRNA (miRNA)-mediated control and post-transcriptional regulation is not fully understood in shaping complement gene expression across immune and inflammatory mechanisms. Complement pathway genes exhibit extensive and heterogeneous 3'-untranslated regions (3'UTRs), which serve as primary platforms for miRNA binding and RNA-binding protein interactions. Both common and rare single-nucleotide polymorphisms within …