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Cryo-EM Reveals How Cardiomyopathy Therapeutic Drugs Modulate the Myosin Motors of the Heart [preprint]
Get PDFThis article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.Genetic mutations in myosin, the motor protein that powers the heartbeat, are linked to inherited hypertrophic and dilated cardiomyopathies. Mavacamten and omecamtiv mecarbil are therapeutic, myosin-targeted drugs designed to treat these myopathies, but their mechanism of action has remained unclear. Using single-particle cryo-EM, we determined near-atomic resolution structures of wild-type, mavacamten-bound, and omecamtiv mecarbil-bound myosin molecules. Across all conditions, two conformations of myosin were observed. We show how mavacamten stabilizes one conformation by reinforcing key electrostatic interfaces in the molecule, whereas omecamtiv mecarbil weakens these interfaces, favoring the second structure. This remodeling elucidates previously unclear allosteric mechanisms through which these drugs either inhibit or enhance myosin activity, countering the deleterious impacts of disease. These findings reveal how drugs modulate myosin structure to control cardiac contractility.No embarg
Social media use, risk behavior engagement, and mental health among middle adolescents in the Caribbean
Get PDFBackground: Social media plays a pivotal role in adolescents’ lives. Social media encounters, including online risk behaviors, may influence real-world risk behaviors and mental health. This study explored the magnitude and patterns of social media use, risk behaviors, and mental health among boys and girls and examined associations between these factors.
Methods: A survey was administered to Grade 9 students in New Providence, The Bahamas, in 2023 to assess their social media use, including platforms used, online activities, and experiences of online risk behavior, as well as their risk behavior engagement and mental health. We analyzed data from 1,563 students using generalized linear mixed models.
Results: Two-thirds of the students spent three hours or more on social media daily. Online risk behaviors, such as cyberbullying and sexting (sending, receiving, or forwarding sexually explicit messages), were also prevalent. Approximately 48% had suicidal ideation during their lifetime. Girls reported higher rates of social media usage, active and passive engagement on social media, cyberbullying experiences, and mental health issues, while boys were more likely to engage in sexting and offline risk behaviors. Factors associated with suicidal ideation included being female, experiencing sexting or cyberbullying, using X, and engaging in risk behaviors such as inappropriate touching and weapon carrying.
Conclusions: Future studies should clarify the complex interplay among the content consumed by adolescents, their online activities, and gender-specific effects on mental health. This study highlights the need for programs that can both foster a positive and supportive online environment and provide targeted assistance for victims of online harm.
Supplementary Information: The online version contains supplementary material available at 10.1186/s12889-025-23646-8.No embarg
Diabetes Medical Group Visits and Type 2 Diabetes Outcomes: Mediation Analysis of Diabetes Distress
Get PDFBackground: Group-based diabetes care, both technology-enabled and in-person, can improve diabetes outcomes in low-income minority women, but the mechanism remains unclear.
Objective: We tested whether diabetes group medical visits (GMVs) reduced hemoglobin A1c (HbA1c) by mitigating diabetes distress (DD), an emotional response affecting nearly half of adults with type 2 diabetes in community settings.
Methods: We conducted a mediation and moderation analysis of data from the Women in Control 2.0 comparative effectiveness study, which showed that both technology-enabled and in-person diabetes GMVs improve HbA1c. We tested whether DD mediated the relationship between diabetes GMV engagement and reductions in HbA1c. We also tested whether this relationship was moderated by depressive symptoms and social support. Participants were 309 low-income and minority women. Diabetes GMV engagement was measured using the Group Climate Questionnaire. The mediator, DD, was measured using the Diabetes Distress Screening Scale. The outcome was the 6-month change in HbA1c. Social support was measured using the Medical Outcomes Study Social Support Survey.
Results: DD mediated the relationship between engagement and 6-month HbA1c. Specifically, group engagement affected HbA1c by reducing distress associated with the regimen of diabetes self-management (P=.04), and possibly the emotional burden of diabetes (P=.09). The relationship between engagement and 6-month HbA1c was moderated by depressive symptoms (P=.02), and possibly social support (P=.08).
Conclusions: Engagement in diabetes GMVs improved HbA1c because it helped reduce diabetes-related distress, especially related to the regimen of diabetes management and possibly related to its emotional burden, and especially for women without depressive symptoms and possibly for women who lacked social support.No embarg
Central-variant posterior reversible encephalopathy syndrome in association with adrenal insufficiency: A case report
No full textRationale: Posterior reversible encephalopathy syndrome (PRES) is a neurotoxic condition often linked to hypertension, eclampsia, or renal failure. PRES typically presenting with seizures, headaches, visual disturbances, and altered mental status. A rarer form, the central variant of PRES, involves atypical radiologic findings such as edema in central brain structures. PRES has not been previously associated with adrenal insufficiency, making this case novel and significant.
Patient concerns: A 59-year-old woman with a history of hypertension, chronic obstructive pulmonary disease, and previous COVID-19 infection presented to the emergency department with seizures and altered mental status. She exhibited a fluctuating systolic blood pressure (79-195 mm Hg) and had a Glasgow Coma Scale (GCS) score of 7.
Diagnoses: Initial imaging and laboratory tests were inconclusive. Continuous electroencephalogram indicated focal cortical irritability, raising concerns about seizures. Brain magnetic resonance imaging revealed increased T2-weighted signals in the bilateral cerebellar hemispheres, consistent with central variant PRES. Endocrine evaluation showed primary adrenal insufficiency, confirmed by low AM cortisol levels and a positive cosyntropin stimulation test.
Interventions: The patient was started on levetiracetam for seizure management and hydrocortisone for adrenal insufficiency. She was intubated for airway protection but later extubated as her condition stabilized.
Outcomes: Follow-up magnetic resonance imaging showed progressive resolution of the cerebellar T2 hyperintensities. The patient was discharged on day 15 with no residual neurological deficits. At a 3-month follow-up, she remained seizure-free and continued oral hydrocortisone and levetiracetam.
Lessons: This case highlights adrenal insufficiency as a possible novel precipitant of the central variant of PRES, emphasizing the need for prompt diagnosis and treatment to prevent serious neurological outcomes. The underlying pathophysiological mechanism of PRES from adrenal insufficiency is most likely labile blood pressure causing rapid alterations in cerebral perfusion pressure (CPP) precipitating PRES.No embarg
Impact of smoking on recurrence rates among wide-neck intracranial aneurysms treated with Woven EndoBridge: a multicenter retrospective study
No full textObjective: Tobacco smoking is among the factors known to significantly augment the risk of untreated intracranial aneurysm (IA) growth and rupture. Smoking appears to have a variable effect on different endovascular treatment modalities. The impact of smoking on the safety, efficacy, and outcomes of Woven EndoBridge (WEB) device use for wide-neck IAs has not been evaluated. This study aimed to investigate the outcomes of WEB devices by smoking status.
Methods: A retrospective multicenter analysis was conducted on the data of patients from 36 sites worldwide treated with the WEB device for intracranial saccular aneurysms. Patients were stratified based on smoking status (current, former, and never smokers). The Student t-test and chi-square test were performed for continuous and categorical variables, respectively. Multivariable logistic regression was used to adjust for confounders.
Results: Of 1376 patients with available smoking status, 504 were current smokers, 358 were former smokers, and 514 were never smokers. Upon adjusting for significant confounders, no association was found between smoking and recurrence outcomes (OR 1.39, 95% CI 0.69-2.80; p = 0.36), thromboembolic and hemorrhagic complications, and mortality among IAs treated with the WEB device. There was no statistically significant difference in outcomes between former and never smokers (OR 1.23, 95% CI 0.70-2.18; p = 0.46). The location of aneurysms differed between smoking groups, with former smokers having more anterior circulation aneurysms compared with current and never smokers (99.0% vs 96.9% vs 95.3%; p = 0.01). In terms of clinical symptoms, headache and dizziness were more common in the never smokers compared with current and former smokers (13.9% vs 8.9% vs 7.7%, p = 0.01).
Conclusions: This large-scale study suggests no significant correlation between smoking and the recurrence of IAs treated with the WEB device. Biological studies are warranted to better understand the biological impact of smoking on the growth and rupture of treated IAs.No embarg
Cerebrospinal Fluid Flow Enhancement (CFE) Increases the Spatial Distribution of Methotrexate after Intracerebroventricular Administration in a Sheep Model
No full textFor the treatment of central nervous system (CNS) neoplasias, achieving widespread chemotherapy distribution throughout the brain remains a major challenge. Direct infusion of substances into the cerebrospinal fluid (CSF) is one method to bypass the blood-brain barrier (BBB) and increase the exposure of CNS tissues to therapeutic molecules. As of 2024, only a handful of drugs are FDA-approved for CSF administration, including morphine, baclofen, ziconotide, and methotrexate. However, despite the use of these approaches in clinical practice, relatively little is understood regarding the spatial distribution of CSF-administered agents, and these distributions remain to be optimized. Here, we focus on methotrexate (MTX), which is an antifolate antineoplastic agent that has been administered intrathecally to treat numerous conditions, including inflammatory and oncologic diseases. We examined the time course of the distribution of MTX to gain insight into the flow dynamics and hypothesized that CSF flow enhancement (CFE), i.e., manipulation of the pattern by which CSF moves within the CNS, would alter the spatial distribution of MTX in the CNS following CSF administration. This hypothesis was tested with a recirculating device, which we used to continuously recirculate fluid from the intracerebral lateral ventricles (ICV) to the cisterna magna (CM). Our experimental results provide detailed maps of the spatial distribution of MTX following CSF administration in sheep and support our expectation that CFE is an effective method to manipulate CNS drug distribution.No embarg
High-speed wide-field fluorescence lifetime imaging for intraoperative tumor visualization and in vivo multiplexing
Get PDFWe present a technique for fast wide-field fluorescence lifetime (FLT) imaging using simultaneous steady-state and time- (or frequency-) domain measurements acquired in a single shot and exploiting the theoretical dependence of fluorescence intensity on FLT. Using theory, simulations, and experiments, we show that the single-shot FLT (S-FLT) method can provide absolute FLTs at a higher signal-to-noise ratio compared to other high-speed FLT imaging techniques, without the need for sample-dependent system calibration or model training. We demonstrate that S-FLT can provide accurate tumor delineation in real-time during surgical resections in preclinical tumor models and in clinical patient specimens . We also extend S-FLT for real-time multiplexing and demonstrate this technique for quantifying dynamic FLT changes and for multiplexing of organ-targeted NIR fluorophores . Our results suggest that S-FLT can enable real-time quantitative high-throughput studies in preclinical applications and accurate tumor margin delineation in real-time during surgeries.No embarg
Screening the human druggable genome identifies ABHD17B as an anti-fibrotic target in hepatic stellate cells
Get PDFHepatic stellate cells (HSCs) are activated with chronic liver injury and transdifferentiate into myofibroblasts, which produce excessive extracellular matrices that form the fibrotic scar. While the progression of fibrosis is understood to be the cause of end-stage liver disease, there are no approved therapies directed at interfering with the activity of HSC myofibroblasts. Here, we perform a high-throughput small interfering RNA (siRNA) screen in primary human HSC myofibroblasts to identify gene products necessary for the fibrotic phenotype of HSCs. We find that depletion of ABHD17B promotes the inactivation of HSCs, characterized by reduced COL1A1 and ACTA2 expression and accumulation of lipid droplets. Mice deficient in Abhd17b are also protected from fibrosis in the setting of in vivo liver injury. While ABHD17B is a depalmitoylase, our data suggest that ABHD17B promotes fibrosis through pathways independent of depalmitoylation that include interaction with MYO1B to modulate gene expression and HSC migration. Together, our results provide an analysis of the phenotypic consequences for siRNAs targeting RNAs from >9500 genes in primary human HSCs and identify ABHD17B as a potential therapeutic target to inhibit liver fibrosis.No embarg
Unifying community whole-brain imaging datasets enables robust neuron identification and reveals determinants of neuron position in C. elegans
Get PDFWe develop a data harmonization approach for C. elegans volumetric microscopy data, consisting of a standardized format, pre-processing techniques, and human-in-the-loop machine-learning-based analysis tools. Using this approach, we unify a diverse collection of 118 whole-brain neural activity imaging datasets from five labs, storing these and accompanying tools in an online repository WormID (wormid.org). With this repository, we train three existing automated cell-identification algorithms, CPD, StatAtlas, and CRF_ID, to enable accuracy that generalizes across labs, recovering all human-labeled neurons in some cases. We mine this repository to identify factors that influence the developmental positioning of neurons. This growing resource of data, code, apps, and tutorials enables users to (1) study neuroanatomical organization and neural activity across diverse experimental paradigms, (2) develop and benchmark algorithms for automated neuron detection, segmentation, cell identification, tracking, and activity extraction, and (3) share data with the community and comply with data-sharing policies.No embarg
Moving the dial on diagnostics: an update from the Lancet Commission on diagnostics
No full textThe Lancet Commission on diagnostics made recommendations for ten topics: national strategy (including national essential diagnostics lists), access in primary care, workforce, regulatory framework, national financing, affordability, appropriate use of technology, needs in conflict or fragile situations, advocacy, and an international alliance with oversight capabilities. Since 2021, progress in these areas has benefitted greatly from the adoption of a World Health Assembly resolution on diagnostics and the work of a broad coalition, as assessed by literature surveys by subject matter experts, quantitative findings (where feasible), and an anonymous survey of knowledgeable and engaged individuals. Greater progress was observed where there was political will and the production of diagnostics coincided with industrial policy goals, also in areas where changing the legal and health policy frameworks was involved. Progress was slower on recommendations with substantial resource implications (eg, labour force, affordability, and diagnostics for conflict situations). It is expected that the Global Diagnostics Coalition will consolidate and accelerate progress.No embarg