Non-equivalent Atomic Vibrations at Interfaces in a Polar Superlattice.

In heterostructures made from polar materials, e.g., AlN-GaN-AlN, the non-equivalence of the two interfaces has long been recognized as a critical aspect of their electronic properties, in that they host different two-dimensional carrier gases. Interfaces play an important role in the vibrational properties of materials, where interface states enhance thermal conductivity and can generate unique infrared-optical activity. The non-equivalence of the corresponding interface atomic vibrations, however, has not been investigated so far due to a lack of experimental techniques with both high spatial and high spectral resolution. Herein we experimentally demonstrate the non-equivalence of AlN-(Al0.65Ga0.35)N and (Al0.65Ga0.35)N-AlN interface vibrations using monochromated electron energy-loss spectroscopy in the scanning transmission electron microscope (STEM-EELS) and employ density-functional-theory (DFT) calculations to gain insights in the physical origins of observations. We demonstrate that STEM-EELS possesses sensitivity to the displacement vector of the vibrational modes as well as the frequency, which is as critical to understanding vibrations as polarization in optical spectroscopies. The combination enables direct mapping of the non-equivalent interface phonons between materials with different phonon polarizations. The results demonstrate the capacity to carefully assess the vibrational properties of complex heterostructures where interface states dominate the functional properties. This article is protected by copyright. All rights reserved.

Ovarian Carcinosarcoma Mimicking Symptoms of Recurrent Diverticulitis: A Case Report.

Ovarian carcinosarcoma, also known as malignant mixed müllerian tumor, is a rare and highly aggressive form of ovarian cancer. This report discusses a case where initial misdiagnosis underscored the complexity of diagnosing this condition. The findings highlight the critical nature of considering ovarian malignancies in the differential diagnosis for postmenopausal women presenting with abdominal pain and altered bowel habits. The significance of utilizing advanced imaging techniques and tumor markers in the early detection of ovarian carcinosarcoma is emphasized, demonstrating how such strategies can substantially affect patient management and outcomes. This case also illustrates the effectiveness of a multidisciplinary approach in treating this challenging malignancy, contributing to our understanding and management of ovarian carcinosarcoma.

Improved cardiac auscultation competency interweaving visual, auditory, and tactile stimuli: a preliminary study.

Methods:   A pilot randomized controlled trial was conducted at our institution's simulation center with 32 first year medical students from a single medical institution. Participants were randomly divided into two equal groups and completed an educational module the identification and pathophysiology of five common cardiac sounds. The control group utilized traditional education methods, while the interventional group incorporated multisensory stimuli. Afterwards, participants listened to randomly selected cardiac sounds and competency data was collected through a multiple-choice post-assessment in both groups. Mann-Whitney U test was used to analyze the data. Results: Data were analyzed using the Mann-Whitney U test. Diagnostic accuracy was significantly higher in the multisensory group (Mdn=100%) compared to the control group (Mdn=60%) on the post-assessment (U=73.5, p<0.042). Likewise, knowledge acquisition was substantially better in the multisensory group (Mdn=80%) than in the control group (Mdn=50%) (U= 49, p<0.031). Conclusions: These findings suggest the incorporation of multisensory stimuli significantly improves cardiac auscultation competency. Given its cost-effectiveness and simplicity, this approach offers a viable alternative to more expensive simulation technologies like the Harvey simulator, particularly in settings with limited resources. Consequently, this teaching modality holds promise for global applicability, addressing the worldwide deterioration in cardiac auscultation skills and potentially leading to better patient outcomes. Future studies should broaden the sample size, span multiple institutions, and investigate long-term retention rates.

"We want to change the system": a qualitative study on emergency medicine physician leadership.

OBJECTIVE: The significance of physician leadership to help transform the healthcare system has been increasingly discussed. This study looked at the qualities of emergency medicine (EM) physicians that support or inhibit their work as healthcare leaders. METHODS: Through an iterative process of semi-structured interviews and then focus groups, we examined why EM physicians pursue leadership roles, the strengths they bring and the frustrations they encounter. Thematic analysis identified factors that facilitate and inhibit the work of EM physicians as they enter leadership roles. RESULTS: These findings can be summarized in four key themes. (1) A desire to improve the wider health system was often a prime motivator for entering a leadership role. (2) EM physicians' clinical skills such as confident decision-making, relationship building through communication, and comfort with uncertainty supported their successful transition to leadership. (3) EM physician leaders perceived shiftwork as both a potential benefit and a challenge in their leadership role and felt it needed to be carefully managed to ensure personal wellness and success. And (4) participants were not driven to take on leadership positions by financial remuneration but stated that the discrepancy between EM clinical and leadership compensation was a point of stress. CONCLUSION: As physician leadership is explored as a mechanism to support the healthcare system's success, this project provides insights into the realities experiences by EM physicians and considerations for healthcare professionals as they encourage physicians into leadership positions.

RéSUMé: OBJECTIF: L'importance du leadership des médecins pour aider à transformer le système de santé est de plus en plus discutée. Cette étude s'est penchée sur les qualités des médecins urgentistes (MU) qui soutiennent ou entravent leur travail en tant que leaders dans le domaine des soins de santé. MéTHODES: Grâce à un processus itératif d'entretiens semi-structurés puis de groupes de discussion, nous avons examiné les raisons pour lesquelles les médecins spécialistes en médecine d'urgence assument des fonctions de direction, les forces qu'ils apportent et les frustrations qu'ils rencontrent. L'analyse thématique a permis d'identifier les facteurs qui facilitent et inhibent le travail des médecins en médecine d'urgence lorsqu'ils accèdent à des fonctions de direction. RéSULTATS: Ces résultats peuvent être résumés en quatre thèmes principaux. 1) Le désir d'améliorer le système de santé dans son ensemble était souvent une motivation majeure pour accéder à un rôle de leadership. 2) Les compétences cliniques des médecins en médecine d'urgence, telles que la prise de décision en toute confiance, l'établissement de relations par la communication et l'aisance face à l'incertitude, ont favorisé leur transition réussie vers le leadership. 3) Les médecins leaders en médecine d'urgence percevaient le travail posté comme un avantage potentiel et un défi dans leur rôle de leadership et estimaient qu'il devait être géré avec soin pour assurer le bien-être et la réussite personnels. Et 4) les participants n'ont pas été incités à occuper des postes de direction par la rémunération financière, mais ont déclaré que l'écart entre la rémunération clinique et la rémunération de la direction de MU était un point de stress. CONCLUSIONS: Alors que le leadership des médecins est considéré comme un mécanisme de soutien au succès du système de santé, ce projet donne un aperçu des réalités vécues par les médecins en médecine d'urgence et des considérations pour les professionnels de la santé qui encouragent les médecins à occuper des postes de direction.

Single-cell RNA sequencing comparison of the human metastatic prostate spine tumor microenvironment.

Spinal column tumors can be difficult to process for single-cell omic studies, given the heterogeneity in tissue. Here, we present a protocol for operating room-to-benchtop single-cell processing of clinical specimens from a prostate cancer patient. We describe steps for sample homogenization, red blood cell lysis, cryopreservation, and single-cell sequencing analysis. This protocol can be used to identify prognostic markers and therapeutic targets for patients with osseous spine metastases and better inform eligibility for clinical trials.

Social Risk Determinants for Successful Same Calendar Day Discharge in Total Joint Arthroplasty.

Background: While many studies have examined the impact of comorbidities on the success of same calendar day discharge (SCDD) in total joint arthroplasty (TJA), literature surrounding the impact of social determinants is lacking. Purpose: We sought to investigate the relationship between various social determinants and success of SCDD after primary total hip arthroplasty (THA) and total knee arthroplasty (TKA). Methods: We conducted a retrospective review of 1160 THA and 1813 TKA performed at a single academic institution between November 2020 and August 2022. Social factors including substance use, occupation, marital status, income, and participation in physical exercise were included. In addition, aspects of discharge planning were reviewed such as living situation and transportation details. Results: Overall, 952 (32%) patients had successful SCDD, whereas 2021 (68%) patients were discharged on postoperative day 1 (POD1) or greater. Successful SCDD patients were more likely to have health care (4.8% vs 2.5%) and active (5.4% vs 4.6%) rather than sedentary occupations, be married (79.6% vs 67.4%), have access to transportation (95.6% vs 92.9%), live in a higher median income area ($64,044 [16,183] vs $61,572 [14,594]), and exercise weekly (62.6% vs 23.9%). Interestingly, the successful patients had more stories in their homes (1.62 [0.56] vs 1.43 [0.53]), more stairs to enter their homes (5.19 [5.22] vs 4.60 [5.24]), lived farther from the hospital (43.3 [138.0] vs 32.0 [75.9] miles), and a higher prevalence of alcohol use (60.7% vs 44.7%) and tobacco use (19.3% vs 17.3%). Conclusion: These findings may help arthroplasty surgeons to better understand the social factors that contribute to successful SCDD in TJA patients, ultimately aiding in patient selection and preoperative counseling.

Nucleosome conformation dictates the histone code.

Histone post-translational modifications (PTMs) play a critical role in chromatin regulation. It has been proposed that these PTMs form localized 'codes' that are read by specialized regions (reader domains) in chromatin-associated proteins (CAPs) to regulate downstream function. Substantial effort has been made to define [CAP: histone PTM] specificities, and thus decipher the histone code and guide epigenetic therapies. However, this has largely been done using the reductive approach of isolated reader domains and histone peptides, which cannot account for any higher-order factors. Here, we show that the [BPTF PHD finger and bromodomain: histone PTM] interaction is dependent on nucleosome context. The tandem reader selectively associates with nucleosomal H3K4me3 and H3K14ac or H3K18ac, a combinatorial engagement that despite being in cis is not predicted by peptides. This in vitro specificity of the BPTF tandem reader for PTM-defined nucleosomes is recapitulated in a cellular context. We propose that regulatable histone tail accessibility and its impact on the binding potential of reader domains necessitates we refine the 'histone code' concept and interrogate it at the nucleosome level.

Voltage-gated potassium channels control extended access cocaine seeking: a role for nucleus accumbens astrocytes.

Dopaminergic signaling in the nucleus accumbens shell (NAc) regulates neuronal activity relevant to reward-related learning, including cocaine-associated behaviors. Although astrocytes respond to dopamine and cocaine with structural changes, the impact of dopamine and cocaine on astrocyte functional plasticity has not been widely studied. Specifically, behavioral implications of voltage-gated channel activity in the canonically non-excitable astrocytes are not known. We characterized potassium channel function in NAc astrocytes following exposure to exogenous dopamine or cocaine self-administration training under short (2 h/day) and extended (6 h/day) access schedules. Electrophysiological, Ca2+ imaging, mRNA, and mass spectrometry tools were used for molecular characterization. Behavioral effects were examined after NAc-targeted microinjections of channel antagonists and astroglial toxins. Exogenous dopamine increased activity of currents mediated by voltage-gated (Kv7) channels in NAc astrocytes. This was associated with a ~5-fold increase in expression of Kcnq2 transcript level in homogenized NAc micropunches. Matrix-assisted laser desorption/ionization mass spectrometry revealed increased NAc dopamine levels in extended access, relative to short access, rats. Kv7 inhibition selectively increased frequency and amplitude of astrocyte intracellular Ca2+ transients in NAc of extended access rats. Inhibition of Kv7 channels in the NAc attenuated cocaine-seeking in extended access rats only, an effect that was occluded by microinjection of the astrocyte metabolic poison, fluorocitrate. These results suggest that voltage-gated K+ channel signaling in NAc astrocytes is behaviorally relevant, support Kv7-mediated regulation of astrocyte Ca2+ signals, and propose novel mechanisms of neuroglial interactions relevant to drug use.

MetaVision3D: Automated Framework for the Generation of Spatial Metabolome Atlas in 3D.

High-resolution spatial imaging is transforming our understanding of foundational biology. Spatial metabolomics is an emerging field that enables the dissection of the complex metabolic landscape and heterogeneity from a thin tissue section. Currently, spatial metabolism highlights the remarkable complexity in two-dimensional space and is poised to be extended into the three-dimensional world of biology. Here, we introduce MetaVision3D, a novel pipeline driven by computer vision techniques for the transformation of serial 2D MALDI mass spectrometry imaging sections into a high-resolution 3D spatial metabolome. Our framework employs advanced algorithms for image registration, normalization, and interpolation to enable the integration of serial 2D tissue sections, thereby generating a comprehensive 3D model of unique diverse metabolites across host tissues at mesoscale. As a proof of principle, MetaVision3D was utilized to generate the mouse brain 3D metabolome atlas (available at https://metavision3d.rc.ufl.edu/ ) as an interactive online database and web server to further advance brain metabolism and related research.

Modified realist evaluation of a complex, multi-centred, multi-intervention programme.

Well North was a complex, multi-intervention health improvement programme spanning 10 sites across the North of England. The aim was to address inequalities by improving the health of the poorest fastest, increasing resilience and reducing levels of worklessness. The intention of the programme was for all sites to have freedom and flexibility to conduct different interventions reflecting local priorities. Evaluation ran concurrently with the programme, and an iterative approach was required to ensure constant feedback, allowing the programme to be adapted and improved as necessary. Realist methodology was chosen for evaluation, as it provides insight into what works, for whom and in what circumstances. Due to the complex nature of the programme and diverse approaches, it was necessary to adapt the methodology to meet the needs of the evaluation. The Evaluation Team utilized a range of qualitative and quantitative techniques within the context of a Rapid Cycle Evaluation framework. For each project, Contexts, Mechanisms and Outcomes (CMOs) were identified at three stages and were incorporated into the CMO configuration, leading to the development of a middle range theory. Validation and testing of theory took place at every stage. Realist methodology was the most appropriate existing method. However, it still necessitated modification.

The Influence of Phosphorus Substituents on the Structures and Solution Speciation of Trivalent Uranium and Lanthanide Phosphinodiboranates.

Here, we report the mechanochemical synthesis and characterization of homoleptic uranium and lanthanide phosphinodiboranates with isopropyl and ethyl substituents attached to phosphorus. M(H3BPiPr2BH3)3 complexes with M = U, Nd, Sm, Tb, and Er were prepared by ball milling UI3(THF)4, SmBr3, or MI3 with three equivalents of K(H3BPiPr2BH3). M(H3BPEt2BH3)3 with M = U and Nd were prepared similarly using K(H3BPEt2BH3), and the complexes were purified by extraction and crystallization from Et2O or CH2Cl2. Single-crystal XRD studies revealed that all five M(H3BPiPr2BH3)3 crystallize as dimers, despite the significant differences in metal radii across the series. In contrast, Nd(H3BPEt2BH3)3 with smaller ethyl substituents crystallized as a coordination polymer. Crystals of U(H3BPEt2BH3)3 were not suitable for structural analysis, but crystals of U(H3BPMe2BH3)3 isolated in low yield by solution methods were isostructural with Nd(H3BPEt2BH3)3. 1H and 11B NMR studies in C6D6 revealed that all of the complexes form mixtures of monomer and oligomers when dissolved, and the extent of oligomerization was highly dependent on metal radius and phosphorus substituent size. A comprehensive analysis of all structurally characterized uranium and lanthanide phosphinodiboranate complexes reported to date, including those with larger Ph and tBu substituents, revealed that the degree of oligomerization in solution can be correlated to differences in B-P-B angles obtained from single-crystal XRD studies. Density functional theory calculations, which included structural optimizations in combination with conformational searches using tight binding methods, replicated the general experimental trends and revealed free energy differences that account for the different solution and solid-state structures. Collectively, these results reveal how steric changes to phosphorus substituents significantly removed from metal coordination sites can have a significant influence on solution speciation, deoligomerization energies, and the solid-state structure of homoleptic phosphinodiboranate complexes containing trivalent f-metals.

GPR84-mediated signal transduction affects metabolic function by promoting brown adipocyte activity.

The G protein-coupled receptor 84 (GPR84), a medium-chain fatty acid receptor, has garnered attention because of its potential involvement in a range of metabolic conditions. However, the precise mechanisms underlying this effect remain elusive. Our study has shed light on the pivotal role of GPR84, revealing its robust expression and functional significance within brown adipose tissue (BAT). Mice lacking GPR84 exhibited increased lipid accumulation in BAT, rendering them more susceptible to cold exposure and displaying reduced BAT activity compared with their WT counterparts. Our in vitro experiments with primary brown adipocytes from GPR84-KO mice revealed diminished expression of thermogenic genes and reduced O2 consumption. Furthermore, the application of the GPR84 agonist 6-n-octylaminouracil (6-OAU) counteracted these effects, effectively reinstating the brown adipocyte activity. These compelling in vivo and in vitro findings converge to highlight mitochondrial dysfunction as the primary cause of BAT anomalies in GPR84-KO mice. The activation of GPR84 induced an increase in intracellular Ca2+ levels, which intricately influenced mitochondrial respiration. By modulating mitochondrial Ca2+ levels and respiration, GPR84 acts as a potent molecule involved in BAT activity. These findings suggest that GPR84 is a potential therapeutic target for invigorating BAT and ameliorating metabolic disorders.

Celiac disease: mechanisms and emerging therapeutics.

Celiac disease (CeD) is a widespread, gluten-induced, autoimmune disorder that lacks any medicinal therapy. Towards the goal of developing non-dietary treatments for CeD, research has focused on elucidating its molecular and cellular etiology. A model of pathogenesis has emerged centered on interactions between three molecular families: specific class II MHC proteins on antigen-presenting cells (APCs), deamidated gluten-derived peptides, and T cell receptors (TCRs) on inflammatory CD4+ T cells. Growing evidence suggests that this pathogenic axis can be pharmacologically targeted to protect patients from some of the adverse effects of dietary gluten. Further studies have revealed the existence of additional host and environmental contributors to disease initiation and tissue damage. This review summarizes our current understanding of CeD pathogenesis and how it is being harnessed for therapeutic design and development.

RIT1 regulation of CNS lipids RIT1 deficiency Alters cerebral lipid metabolism and reduces white matter tract oligodendrocytes and conduction velocities.

Oligodendrocytes (OLs) generate lipid-rich myelin membranes that wrap axons to enable efficient transmission of electrical impulses. Using a RIT1 knockout mouse model and in situ high-resolution matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) coupled with MS-based lipidomic analysis to determine the contribution of RIT1 to lipid homeostasis. Here, we report that RIT1 loss is associated with altered lipid levels in the central nervous system (CNS), including myelin-associated lipids within the corpus callosum (CC). Perturbed lipid metabolism was correlated with reduced numbers of OLs, but increased numbers of GFAP+ glia, in the CC, but not in grey matter. This was accompanied by reduced myelin protein expression and axonal conduction deficits. Behavioral analyses revealed significant changes in voluntary locomotor activity and anxiety-like behavior in RIT1KO mice. Together, these data reveal an unexpected role for RIT1 in the regulation of cerebral lipid metabolism, which coincide with altered white matter tract oligodendrocyte levels, reduced axonal conduction velocity, and behavioral abnormalities in the CNS.

Upscaling the remediation of acidic landscapes - the coastal floodplain prioritisation method.

Over 24 million hectares of the world's coastal floodplains are underlain by acid sulfate soils (ASS). Drainage of these sediments has led to widespread environmental degradation, raising serious health concerns. To date, onsite rehabilitation has been complicated by differing stakeholder priorities, with resources often allocated to sites with more vocal proponents rather than those exposed to more significant environmental impacts. To address this issue, this paper introduces the Coastal Floodplain Prioritisation (CFP) Method; a novel, data driven and spatially explicit multi-criteria assessment that ranks floodplain catchment areas according to their risk of transferring acidic drainage waters to an estuary. Results can be used to prioritise where remediation actions are likely to have the greatest benefit. The method was applied across six different estuaries in south-east Australia, with major field campaigns undertaken at each site. Within each estuary, the largest acid fluxes and impacts are identified with relevant mitigation measures provided. On a catchment scale, the results reflect the broader hydrogeomorphic characteristics of each estuary, including the historic acid formation conditions and recent anthropogenic drainage activities. Low-lying backswamps were identified as the highest risk zones within each estuary. These areas are also the most vulnerable to sea level rise. Reinstatement of tidal inundation to these backswamps effectively remediates acid sulfate soil discharges and provides a nature-based solution for adaptation to sea level rise with a range of co-benefits to encourage further investment.

Sequence-Defined Conjugated Oligomers in Donor-Acceptor Dyads.

Conjugated macromolecules have a rich history in chemistry, owing to their chemical arrangements that intertwine physical and electronic properties. The continuing study and application of these systems, however, necessitates the development of atomically precise models that bridge the gap between molecules, polymers, and/or their blends. One class of conjugated polymers that have facilitated the advancement of structure-property relationships is discrete, precision oligomers that have remained an outstanding synthetic challenge with only a handful of reported examples. Here we show the first synthesis of molecular dyads featuring sequence-defined oligothiophene donors covalently linked a to small-molecule acceptor. These dyads serve as a platform for probing complex photophysical interactions involving sequence-defined oligomers. This assessment is facilitated through the unprecedented control of oligothiophene length- and sequence-dependent arrangement relative to the acceptor unit, made possible by the incorporation of hydroxyl-containing side chains at precise positions along the backbone through sequence-defined oligomerizations. We show that both the oligothiophene sequence and length play complementary roles in determining the transfer efficiency of photoexcited states. Overall, the work highlights the importance of the spatial arrangement of donor-acceptor systems that are commonly studied for a range of uses, including light harvesting and photocatalysis.

Loss of carnitine palmitoyltransferase 1a reduces docosahexaenoic acid-containing phospholipids and drives sexually dimorphic liver disease in mice.

BACKGROUND AND AIMS: Genome and epigenome wide association studies identified variants in carnitine palmitoyltransferase 1a (CPT1a) that associate with lipid traits. The goal of this study was to determine the role of liver-specific CPT1a on hepatic lipid metabolism. APPROACH AND RESULTS: Male and female liver-specific knockout (LKO) and littermate controls were placed on a low-fat or high-fat diet (60% kcal fat) for 15 weeks. Mice were necropsied after a 16 h fast, and tissues were collected for lipidomics, matrix-assisted laser desorption ionization mass spectrometry imaging, kinome analysis, RNA-sequencing, and protein expression by immunoblotting. Female LKO mice had increased serum alanine aminotransferase levels which were associated with greater deposition of hepatic lipids, while male mice were not affected by CPT1a deletion relative to male control mice. Mice with CPT1a deletion had reductions in DHA-containing phospholipids at the expense of monounsaturated fatty acids (MUFA)-containing phospholipids in whole liver and at the level of the lipid droplet (LD). Male and female LKO mice increased RNA levels of genes involved in LD lipolysis (Plin2, Cidec, G0S2) and in polyunsaturated fatty acid metabolism (Elovl5, Fads1, Elovl2), while only female LKO mice increased genes involved in inflammation (Ly6d, Mmp12, Cxcl2). Kinase profiling showed decreased protein kinase A activity, which coincided with increased PLIN2, PLIN5, and G0S2 protein levels and decreased triglyceride hydrolysis in LKO mice. CONCLUSIONS: Liver-specific deletion of CPT1a promotes sexually dimorphic steatotic liver disease (SLD) in mice, and here we have identified new mechanisms by which females are protected from HFD-induced liver injury.

A Novel Achilles Tendon Repair Technique Utilizing a Bio-Composite Scaffold for a Sub-Acute Tear.

Achilles tendon ruptures are prevalent musculoskeletal injuries accounting for 20% of all large tendon ruptures with a re-rupture rate of 2.1-8.8%. Ineffectual management of these injuries can lead to a significant loss in push-off strength and overall ankle function. The field of orthopedic surgery has shown an increasing interest in biologic augmentation. Encouraged by its success in various other applications, this approach holds promise for potentially enhancing outcomes in Achilles tendon repairs, especially in poor tendon tissue. The BioBrace® (ConMed, New Haven, Connecticut) is a biocomposite scaffold made of highly porous type I collagen and bioresorbable poly (L-Lactide) (PLLA) microfilaments. It can be applied in conjunction with Achilles tendon repair or reconstruction. It provides immediate strength to the augmented repair upon implantation and simultaneously promotes new, organized tissue growth throughout its resorptive phase. Here, we outline a technique to effectively augment an acute Achilles tendon repair utilizing the BioBrace® reinforced bio-inductive implant.

Gys1 Antisense Therapy Prevents Disease-Driving Aggregates and Epileptiform Discharges in a Lafora Disease Mouse Model.

Patients with Lafora disease have a mutation in EPM2A or EPM2B, resulting in dysregulation of glycogen metabolism throughout the body and aberrant glycogen molecules that aggregate into Lafora bodies. Lafora bodies are particularly damaging in the brain, where the aggregation drives seizures with increasing severity and frequency, coupled with neurodegeneration. Previous work employed mouse genetic models to reduce glycogen synthesis by approximately 50%, and this strategy significantly reduced Lafora body formation and disease phenotypes. Therefore, an antisense oligonucleotide (ASO) was developed to reduce glycogen synthesis in the brain by targeting glycogen synthase 1 (Gys1). To test the distribution and efficacy of this drug, the Gys1-ASO was administered to Epm2b-/- mice via intracerebroventricular administration at 4, 7, and 10 months. The mice were then sacrificed at 13 months and their brains analyzed for Gys1 expression, glycogen aggregation, and neuronal excitability. The mice treated with Gys1-ASO exhibited decreased Gys1 protein levels, decreased glycogen aggregation, and reduced epileptiform discharges compared to untreated Epm2b-/- mice. This work provides proof of concept that a Gys1-ASO halts disease progression of EPM2B mutations of Lafora disease.