Infantile-onset cardiomyopathy due to mitochondrial dysfunction is a severe condition frequently associated with poor prognosis. Biallelic pathogenic variants in ELAC2, an essential mitochondrial tRNA processing gene, have been implicated in this phenotype. This study investigates the clinical and genetic spectrum of ELAC2-related disease in a national cohort from Kuwait. We conducted a retrospective cohort study using data from the Kuwait Medical Genetics Center registry, including individuals with genetically confirmed or clinically suspected ELAC2-related cardiomyopathy. Clinical, metabolic, and molecular data were reviewed. Exome sequencing or targeted mutation testing was performed in affected individuals and at-risk family members. A total of 34 individuals from 23 consanguineous families were identified, of whom 30 were genetically confirmed to harbor the homozygous ELAC2 founder variant c.460T>C; p.(Phe154Leu). All individuals presented in infancy with severe cardiomyopathy and refractory lactic acidosis. Neurological involvement was observed in 39% of cases. The majority exhibited hypertrophic cardiomyopathy, with variable dilated features and pericardial effusion. The disease course was fatal in all, with most patients dying in infancy. This is the largest single-country cohort reported to date with ELAC2-related mitochondrial cardiomyopathy, raising the global case total to over 70. The uniform presence of the Phe154Leu variant across unrelated Bedouin families highlights a strong founder effect. Given the rapid disease progression and high mortality, we recommend targeted ELAC2 screening in infants with idiopathic cardiomyopathy and persistent lactic acidosis, particularly in consanguineous populations. Premarital carrier testing and early family counseling should be prioritized to support preventive strategies.
Using human pluripotent stem cell differentiation in vitro has significantly broadened the understanding of lineage specification events that occur during early development in vivo, a period that is extremely challenging to investigate. One of the first embryonic lineages to be specified in the human embryo is the germ cell lineage, marked by the induction of the primordial germ cells (PGCs). The PGCs are the sole founder population of the gametes later in life, and their specification is a critical first step towards the organism's fertility. Here, a robust protocol for generating PGC-like cells (PGCLCs) from human induced pluripotent stem cells (hiPSCs) is described, starting with the initial evaluation of the pluripotent state and cellular characteristics of the hiPSCs to ensure effective PGCLC differentiation. For this, the effects of different cell densities, plate coatings, and hiPSCs used for PGCLC differentiation are discussed. Finally, a workflow for characterization and quantification of hPGCLCs, using immunofluorescence and flow cytometry, is provided. The differentiation protocol focuses on conditions that are easy to establish and test in most laboratories and can be adjusted as necessary. Moreover, this protocol is fast, allowing determination of whether hiPSCs are suitable for PGCLC differentiation. The protocol aims to promote consistency and compatibility in hPGCLC outcomes across different hiPSC lines and culture platforms, ensuring robust yields that support reliable characterization and further optimization of downstream differentiation steps toward successful in vitro gametogenesis in humans.
Online lending marketplaces have emerged as potentially disruptive players in the financial industry by digitally connecting borrowers and lenders. However, little is known about the emergence of dominant business model patterns in this regulated, platform-based service industry. Drawing on dominant design theory, this study examines the international convergence of business model components in online lending since 2005. Using a comparative, longitudinal case study of the market leaders Funding Circle (the UK), LendingClub (the USA), and auxmoney (Germany), we analyze the Business Model Canvas components "customer segments" and "value propositions." Our findings reveal a convergence toward peer-to-institution models, shaped by regulatory pressures, technological advances, and institutional capital. All marketplaces now address underserved borrower segments such as SMEs, the self-employed, and founders, while excluding retail investors. This indicates the emergence of internationally dominant business model components in potentially disruptive two-sided platform markets. We synthesize these findings into a generic, process-oriented model explaining how platform convergence unfolds across national contexts. This study extends dominant design theory to business models in regulated service industries and highlights external forces as key drivers of standardization. It offers practical insights for policymakers, institutional investors, and marketplace operators navigating scalability, regulation, and financial integration.
Longitudinal studies have shown an association between diet quality and depression. However, reverse causality, unmeasured confounding, and selection bias remained important limitations. We aim to examine the relationship between diet quality and depression in older adults while addressing these issues and explore modification role of genetic predisposition to depression and low-grade inflammation. We emulated a target trial of dietary interventions using data from the ASPREE cohort. An ultra-processed food (UPF) index and an anti-inflammatory diet measure were extracted from a food frequency questionnaire to quantify diet quality. Depressive symptoms were assessed annually with a Center for Epidemiologic Studies-Depression 10-item score of ≥8. A polygenic score was derived using the latest Psychiatric Genomics Consortium data for major depression. Systemic inflammation was assessed using circulating high-sensitivity C-reactive protein. Inverse probability treatment weighting was applied to balance measured confounders. The effects of diet quality on depressive symptoms were estimated using generalised estimating equations. A total of 7220 participants (52.7% female), aged 70+ years, were followed for a median of 5.7 years. High UPF consumption was associated with a higher risk of depressive symptoms (RR: 1.12, 95% CI: 1.03-1.21), while an anti-inflammatory diet was associated with lower depressive symptoms (RR: 0.93, 95% CI: 0.86-1.00). Genetic predisposition or low-grade inflammation did not modify the observed associations. Higher diet quality is associated with a lower risk of depressive symptoms, independent of genetic predisposition or low-grade inflammation, which may support dietary interventions as a modifiable lifestyle strategy for mental health promotion and prevention in older adults.
Maturity-onset diabetes of the young (MODY) is a clinically and genetically heterogeneous group of monogenic diabetes subtypes that is frequently misdiagnosed as type 1 or type 2 diabetes, and accurate genetic diagnosis enables a precision-medicine treatment approach. Regional Turkish data are limited, and previous Turkish series have been pediatric only. We characterized the genetic spectrum and therapeutic consequences of next-generation sequencing (NGS)-based MODY testing in a combined adult-and-pediatric cohort from the eastern Black Sea region of Türkiye. We retrospectively analyzed 296 consecutive patients with clinically suspected MODY referred between January 2022 and June 2025. A targeted NGS panel covering 14 MODY genes was applied, variants were classified per 2015 ACMG/AMP criteria, and treatment changes attributable to the genetic diagnosis were extracted from medical records. Pathogenic or likely pathogenic (P/LP) variants were identified in 43 of 296 patients (14.5%); diagnostic yield rose to 26.0% with variants of uncertain significance included. GCK-MODY accounted for 72.1% of P/LP findings, with a recurrent frameshift c.1256del p.(Phe419SerfsTer12) across nine apparently unrelated families consistent with a regional founder allele. Rare subtypes included MODY4 (PDX1), MODY6 (NEUROD1), MODY8 (CEL), MODY10 (INS), MODY12 (ABCC8) and MODY13 (KCNJ11). The genetic diagnosis directly modified pharmacological therapy in 14 patients, including insulin discontinuation in three KATP-channel MODY and one INS-MODY case. NGS-based MODY testing yields actionable findings in approximately one in seven clinically selected patients in this region and supports inclusion of MODY testing in routine endocrinology practice.
Advances in DNA sequencing technology are increasing the rate of molecular diagnosis for patients and families with inherited Mendelian diseases. However, some patients remain unsolved following standard-of-care testing (typically either exome or genome sequencing), with structural variants (SVs) likely to account for a significant proportion of these missed diagnoses. We re-analysed ten research cases with the visual disorder foveal hypoplasia (FH) that were previously unsolved through whole exome sequencing (WES). We used SVRare, a tool that integrates outputs from Canvas and Manta and combines these with allele frequencies and information regarding their genomic context to highlight plausible pathogenic SVs. This analysis solved 2/10 cases. Expanding this strategy, we then used SVRare in a reverse genetics approach to analyse an FH-relevant gene panel in the 100,000 Genomes Project (100KGP) rare disease cohort. This identified potentially pathogenic SVs as the cause of disease in a further 11 previously unsolved cases with phenotypes overlapping FH. In total, 11 SVs in five genes were identified as the likely cause of FH in 13 patients: SLC38A8 (1 patient), PAX6 (3), OCA2 (3), GPR143 (5) and CACNA1F (1). This analysis also identified multiple carriers of an apparently novel deletion in OCA2. However, further analysis suggested that this is, in fact, the relatively common founder variant responsible for oculocutaneous albinism (OCA) in African populations, first identified over 30 years ago. These findings show that SVRare effectively identifies deleterious SVs and illustrates the challenges in reporting SVs, including the importance of accurate and consistent reporting of such variants.
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Senescent cells accumulate following chemotherapy and during aging, where they contribute to dysfunction through the pro-inflammatory arm of the senescence-associated secretory phenotype (SASP), termed NF-κB-associated SASP (NASP). Here we show that short-term inhibition of CDK4/6 with abemaciclib suppresses established NASP in pre-existing senescent cells both in vitro and in vivo. This senomorphic effect reduces the pro-tumorigenic activity of chemotherapy-induced senescent cells and improves physical function in mice following chemotherapy. Genetic knockdown of CDK4/6 phenocopied these effects, confirming a CDK4/6-dependent mechanism. Mechanistically, CDK4/6 inhibition suppressed retinoic acid signaling, and the RARα antagonist agn194310 similarly reduced NASP expression. CDK4 and CDK6 interacted with NF-κB, while CDK4 additionally bound RARα, and these interactions were disrupted by abemaciclib. In aged mice, abemaciclib and agn194310 reduced systemic NASP expression and improved physical performance. Together, these findings identify the CDK4/6-RARα-NF-κB axis as a therapeutic target for senomorphic interventions.
Postpartum depression (PPD) can be predicted by biomarkers of 3rd trimester methylation at two estrogen-responsive genes (TTC9B, HP1BP3), but the mechanism(s) by which these epigenetic changes lead to PPD are unknown. We investigated whether clinical characteristics (psychiatric histories, depression onset, stress/anxiety/trauma) differ between those with (BM+) and without (BM-) these biomarkers of PPD risk. Participants (N = 206) completed clinical diagnostic interviews and stress, anxiety, and trauma questionnaires at up to 7 visits during pregnancy and postpartum. Biomarker status was determined using 3rd trimester blood samples. Linear mixed effects models compared outcomes between biomarker groups (positive/negative). Mediation models assessed the average causal mediation effect of anxiety on the relationship between biomarker status and PPD. BM+ individuals were more likely to 1) have a prior history of generalized anxiety (X2 = 10.06, p = .003) and bipolar II disorder (X2 = 7.68, p = .01), 2) develop PPD (X2 = 3.97, p = .04), and 3) be depressed during both pregnancy and postpartum (X2 = 6.52, p = .02). BM+ individuals scored higher on the perinatal anxiety screening scale (PASS, p = .006), perceived stress scale (PSS, p = .001), and state-trait anxiety inventory (STAI)-trait subscale (p = .02). Anxiety outcomes on the PASS (95% CI: 0.01-0.10, p = .004), PSS (95% CI: 0.007-0.10, p = .03), and STAI-State (95% CI: -0.001-0.06, p = .06) mediated the relationship between biomarker status and PPD development. Findings suggest distinct clinical phenotypes between BM+ and BM- PPD, with BM+ individuals displaying significantly higher anxiety/stress, which may contribute to their higher risk of developing PPD. This presents an opportunity to investigate mechanisms in more homogenous groups based on biomarker status.
Individuals who wear Ankle Foot Orthoses (AFOs) express a desire for adaptability and improved stair ambulation. This exploratory study examined how the stiffness and neutral angle of a robotic AFO influence stair ambulation and preference in spastic cerebral palsy (CP) and compared robotic AFOs, solid AFOs, and shoes alone. Seven individuals with spastic CP completed modified Timed-Up-and-Down-Stairs (TUDS) tests under nine robotic AFO stiffness-neutral angle configurations, solid AFOs, and shoes alone. Outcomes included TUDS time, ankle kinematics, soleus and vastus lateralis activity, exertion, balance confidence, trunk instability, stiffness preference, and device power and torque. Mixed effects modeling assessed the effects of stiffness and neutral angle. Stiffness preference was evaluated during level walking, stair ascent, and descent. Repeated measures ANOVA compared robotic AFOs, solid AFOs, and shoes alone. Increased stiffness and more plantarflexed neutral angles decreased peak dorsiflexion (p < 0.05) and increased peak torque (p < 0.05). Few other outcomes were affected. Four of seven participants preferred low stiffness across all tasks. Robotic AFOs performed better than solid AFOs, by decreasing TUDs time (- 27%, d = - 0.66, p < 0.05) and increasing confidence (49%, d = 0.92, p < 0.05) in descent, but not better than shoes alone. During stair ascent, the only difference between the AFOs and shoes was a reduction in soleus activity between solid AFOs and shoes alone. Robotic AFO configuration influences stair descent and may improve descent speed and confidence over solid AFOs in a limited sample of spastic CP.
Structural brain changes and immune-metabolic alterations are widely reported in post-COVID condition (PCC), particularly among patients with depressive symptoms. Alterations in gray matter volume (GMV) and dysregulation of the peripheral kynurenine pathway have each been described independently in PCC; however, potential interactions remain unclear. This observational case-control study investigated associations between GMV and peripheral kynurenine-pathway metabolites in patients with PCC compared to unimpaired individuals who recovered after COVID-19. The analysis is based on a sub-cohort from a multicentre, population-based study of individuals who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) between October 2020 and April 2021. We compared 43 patients with PCC (age: M = 47.63 (SD = 13.01), 74.4% female) to 27 age- and sex-matched fully recovered controls (age: M = 47.44 (SD = 10.39), 77.8% female) on average 156 weeks after SARS-CoV-2 infection. GMV was assessed using isotropic T1-weighted magnetic resonance imaging (MRI) data (normalized to total intracranial volume, age, and sex). We analyzed the relation of normalized regional GMV to serum kynurenine-pathway metabolites (kynurenine, kynurenic acid, quinolinic acid, kynurenic/quinolinic acid ratio). Additionally, in patients with PCC, GMV and kynurenine-pathway metabolites were tested for correlations with the severity of depressive symptoms. No significant group-level differences in GMV were observed. Clinical case status moderated the association between the peripheral kynurenic acid/quinolinic acid ratio and GMV of the right cingulate gyrus and right parietal lobe. Post-hoc analyses showed a positive association in PCC. Furthermore, within the PCC group, 60.5% showed depressive symptoms according to the Patient Health Questionnaire-9, and larger bilateral hippocampal volumes were significantly associated with greater depressive symptom severity. None of the kynurenine pathway metabolites were significantly associated with depressive symptom severity. Our findings may indicate that the peripheral kynurenine metabolism is associated with GMV in PCC, suggesting the presence of facilitated immune-brain interactions. The association between higher hippocampal GMV and depressive symptom severity in PCC-associated depression points to a distinct neurobiological mechanism.
We aimed to investigate if reinforcement learning (RL) can detect clinical practice variations and if transfer learning (TL) can mitigate resulting distribution shifts across patient sexes and sites. Using data from over 41,000 patients with obstructive coronary artery disease (CAD) in Alberta, Canada from 2009 to 2019, we conducted three experiments: 1) evaluate physician behavior policies across stratified groups using off-policy evaluation (OPE); 2) develop and evaluate RL policies using conservative Q-learning and OPE for each group; and 3) apply TL to improve RL performance on target groups. Female patients had significantly lower expected rewards under their own physician policies compared to males. Applying the physician policies learned from male patients improved rewards for females but remained lower than those for males. RL policies outperformed physician policies. TL with only 10% of target group data effectively mitigated distribution shifts. Residual confounding warrants further research to validate our findings.
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Androgen abuse has been suggested to adversely affect sleep-disordered breathing, but prospective real-world data in androgen abusers are lacking. The aim of this study was to evaluate the effects of androgen abuse on sleep-disordered breathing. Adult men planning a self-initiated androgen cycle were evaluated before, at approximately week 8 of their cycle, and approximately three months after cycle cessation. Sleep was assessed using ambulatory WatchPAT monitoring. The primary outcome was change in the peripheral arterial tone-derived apnea-hypopnea index (pAHI). Secondary outcomes included peripheral arterial tone-derived respiratory distress index (pRDI) and oxygen desaturation index (pODI), sleep architecture and subjective sleep questionnaires as measured through the Epworth Sleepiness Scale (ESS) and Insomnia Severity Index (ISI). Longitudinal changes were analyzed using linear mixed-effects models. Twenty-three participants were included. Median cycle duration was 12 weeks with a median weekly dose of 678 mg. During the androgen cycle, pAHI did not increase significantly, whereas pRDI did increase (mean increase of 3.0 events/hour). At post-cycle follow-up, pAHI, pRDI, and pODI were significantly increased compared with baseline (mean increases of 2.7, 4.4, and 3.0 events/hour, respectively). Sleep architecture was largely preserved, although a modest reduction in deep sleep and an increase in heart rate was observed during androgen abuse. No significant changes were observed in total ESS or ISI scores across time points. These findings suggest that androgen abuse may exert subtle effects on sleep-disordered breathing parameters but are unlikely to translate into overt or clinically meaningful sleep apnea in most androgen abusers. Registration number P2117, study number NL77191.028.21.
The co-use of nicotine/tobacco products and cannabis among young adults is prevalent, yet little is known regarding the treatment impact of co-use and the underlying relationship between substances. No prospective treatment studies to date have evaluated the impact of cannabis use on nicotine cessation specifically among young adults, with an emphasis on dual-use substance patterns predicting outcomes. The overall goal of this protocol is to characterise the relationship between nicotine and cannabis and evaluate how patterns of co-use are associated with nicotine cessation outcomes through a behavioural economics framework to examine how cannabis co-use may be associated with nicotine cessation. This study protocol describes an ongoing, prospective nicotine cessation trial being conducted among young adults who co-use nicotine (vaping and/or cigarettes) and cannabis products to: (1) evaluate the association between behavioural economically derived measures of substance substitutability on end of treatment (EOT) nicotine abstinence, (2) examine whether changes in nicotine use are associated with changes in cannabis demand and use and (3) assess reciprocal prospective relationships between patterns of nicotine and cannabis use during treatment. This is a fully remote, prospective, 12-week nicotine cessation trial among young adults (ages 18-25; target N=350) across the USA who co-use nicotine and cannabis. Eligible participants vape nicotine and/or smoke cigarettes regularly (20+ days in the past 30) and use cannabis on 10+ out of the past 30 days. Participants receive comprehensive nicotine cessation treatment, which includes digital contingency management to reinforce nicotine abstinence, brief counselling and SMS-text based cessation support whereas cannabis use is monitored but not treated. Biochemical verification (through oral fluid samples) and self-reports (mobile daily diaries) of substance use are collected longitudinally. Study enrolment began in May 2024 and is expected to conclude in September 2027.Aim 1 (primary outcome) analyses will evaluate whether baseline behavioural economic indices of nicotine-cannabis substitutability predict EOT nicotine abstinence using logistic regression models. Aim 2 (exploratory outcome) analyses will use generalised linear mixed-effects models to examine within-person associations between changes in nicotine use (abstinence, reduction in use, nicotine withdrawal) and cannabis demand and use over time, and whether these associations are moderated by time-varying substitutability. Cross-lagged panel models will be used for Aim 3 (exploratory outcome) to assess reciprocal prospective relationships between nicotine and cannabis use during treatment. This study has received Institutional Review Board approval from the Medical University of South Carolina (reference ID: Pro00131124). All participants provide informed consent prior to study procedures. Findings will be disseminated through peer-reviewed publications, conference presentations and data sharing in accordance with National Institutes of Health and institutional guidelines. The manuscript reports protocol components according to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist. NCT06239350.
Biomolecular condensates formed via liquid-liquid phase separation regulate essential cellular processes, with dysregulation implicated in neurodegeneration and cancer. Nuclear magnetic resonance (NMR) spectroscopy provides label-free, atomic-resolution insights into condensate composition, stoichiometry, physicochemical properties (e.g., viscosity and water content), and molecular interactions, overcoming the limitations of imaging and bulk techniques. This review highlights NMR's capabilities in quantifying selective partitioning of proteins, RNAs, ions, and small molecules, as well as mapping interaction hotspots in scaffold proteins, and characterizing client molecule dynamics within condensates. Finally, we point to future applications, including the study of the modulation of the protein conformational landscape by condensates, drug development targeting pathological phase transitions, and integration with advanced techniques like dynamic nuclear polarization, single-molecule microscopy, and advanced computational models for studying complex physiological systems.
To evaluate the resection efficiency of the Aveta hysteroscopic tissue removal system and compare its performance with three established hysteroscopic morcellation devices using a standardized synthetic fibroid model designed to simulate the mechanical resistance of dense leiomyoma tissue. Prospective, multicenter comparative bench study with repeated measures in an incomplete blocks design. Simulated hysteroscopic fibroid resections under standardized conditions. Ninety-one Ob/Gyn practicing physicians routinely performing hysteroscopic myomectomy procedures participated in the study. Simulated hysteroscopic resections using four commercially available hysteroscopic tissue removal systems (Aveta Flex, MyoSure Reach, MyoSure XL, and TruClear Dense Tissue Shaver Plus (DTSP)) were performed in a synthetic fibroid analog tissue model with rheologic properties calibrated to simulate the mechanical resistance of highly fibrotic or partially calcified leiomyomas. Resection efficiency was quantified by measuring the mass of fibroid analog removed in g/min. Ninety-one physicians participated and a total of 220 device observations were included: Aveta Flex (n = 91), MyoSure Reach (n = 56), MyoSure XL (n = 37), and TruClear DTSP (n = 36). Least squares mean resection rates were 0.506 g/min for Aveta Flex, 0.184 g/min for MyoSure Reach, 0.274 g/min for MyoSure XL, and 0.389 g/min for TruClear DTSP. Parametric and nonparametric analyses demonstrated significantly higher resection rates for Aveta Flex compared with MyoSure Reach, MyoSure XL, and TruClear DTSP (mixed-effects model p < .005; Skillings-Mack p < .0001). In this prospective, multicenter study using a standardized synthetic fibroid analog model, the Aveta Flex hysteroscopic tissue removal system demonstrated significantly higher resection efficiency compared with established hysteroscopic morcellation devices. Given the importance of procedural efficiency in operative hysteroscopy, particularly within the limitations imposed by fluid deficit thresholds, these findings may have implications for operative duration, likelihood of complete resection, and overall procedural workflow in hysteroscopic myomectomy.
Current treatments for pancreatic ductal adenocarcinoma (PDAC) patients are typically restricted to (neo)adjuvant chemotherapy, surgery or palliative care. Mainly due to a late diagnosis and highly desmoplastic environment, these treatments have limited efficacy and patient prognosis is very poor. Intratumoral delivery of chemotherapeutic agents using hydrogel technology might boost treatment efficacy and reduce side effects. Here, we aimed to investigate the preclinical efficacy and tolerability of a novel thermosensitive hydrogel, ChemoGell, loaded with the chemotherapeutic agent gemcitabine. We explored this in vitro, using patient-derived organoids and surgically obtained tumor explants, and in vivo, using a human patient-derived xenograft (PDX) and syngeneic KPC3 mouse models. Upon intratumoral injections of gemcitabine-loaded ChemoGell, respective survival, peripheral blood and end-stage tumor histological analyses were performed. Intratumoral injection of gemcitabine-loaded ChemoGell in in vitro and in vivo models showed decreased tumor growth and increased cytotoxicity compared to blank ChemoGell and saline control intratumoral injections. In contrast, systemic administration of gemcitabine did not show therapeutic benefits. Intratumoral ChemoGell injections induced interesting lymphocyte and monocyte dynamics overtime, showing an intratumoral influx of NK cells and monocytes and an in-depot infiltration of activated fibroblasts, macrophages and activated CD8 + T cells. Our findings establish a foundation for integrating localized treatment modalities, addressing critical challenges in PDAC and improving patient prognosis through more effective, localized therapeutic strategies.
The glucagon-like peptide-1 receptor (GLP1R), a class B G protein-coupled receptor (GPCR), is a pivotal therapeutic target for type 2 diabetes mellitus and obesity. GLP1R agonists signal through both G protein and β-arrestin pathways, associated with distinct receptor conformational and trafficking states. Here, we develop G protein-biased GLP1R agonists through N-terminal modifications, including acetylation or amino acid substitutions, which exhibit preferential G protein signaling relative to the reference ligand. Cryo-EM structure of GLP1-Y11-GLP1R-Gs complex at 2.64 Å resolution reveals that outward displacement of extracellular loop 3 (ECL3) is the key structural feature associated with signaling bias, distinguishing the complex from β-arrestin-biased agonist-bound state. Ac-GLP1 and Ac-semaglutide display altered receptor trafficking, attenuated β-arrestin recruitment, and prolonged cAMP signaling. In diet-induced obese mice, Ac-semaglutide maintains glucose-lowering activity three days post-administration. These findings elucidate the structural basis of GLP1R biased agonism and provide mechanistic insights into class B GPCR signaling modulation.
Epidural spinal cord stimulation has been shown to be a promising neurotechnology to improve upper limb function in people affected by stroke. It is well established that spinal cord stimulation (SCS) targeting the dorsal root entry zone increases excitatory drive to α-motoneurons via the monosynaptic reflex pathway. However, the effects of SCS on inhibitory neural pathways remain unexplored. We hypothesized that SCS improves the neuromotor control of arm movement by strengthening both excitatory and inhibitory circuit function. We show in three individuals with post-stroke motor symptoms that SCS enhances postsynaptic Ia reciprocal inhibition. These changes correlate with enhanced muscle coordination and arm kinematics, resulting in smoother and faster trajectories. Our study provides further insights into the neural targets of spinal cord stimulation and the use of this technology to treat post-stroke motor deficits. This study was registered at ClinicalTrials.gov (NCT04512690).