51886 research outputs found
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From Access to Impact: Assessing the Utility of Participant Trainings and Resources (2021–2025)
No full textThis project evaluated the effectiveness and relevance of training sessions offered through the Local Community Cadres (LCC) and Make-It-Take-It (MITI) programs by HANDS in Autism® between 2021 and 2025. Structured participant feedback was collected through REDCap surveys and analyzed using Excel and Power BI to assess knowledge gains, content utility, and satisfaction. Among 443 responses, “Increased Knowledge” consistently ranked highest across both programs, highlighting their educational value. Topics such as "Tasks, Adaptations, and Data-Driven Decision-Making" received the most favorable ratings, especially within the MITI sessions. Findings guided actionable recommendations for expanding high-impact topics and tailoring future training to participant backgrounds. This project enhanced skills in data cleaning, visualization, and survey analysis while supporting data-driven improvements for community-based autism training programs
Sugammadex for Neuromuscular Blockade Reversal: A Narrative Review
No full textSugammadex represents a significant advancement in neuromuscular blockade management, enabling rapid, predictable, and highly effective reversal of steroidal neuromuscular blockers such as rocuronium and vecuronium. This review critically examines recent advances in sugammadex research, particularly over the last decade, detailing its pharmacological profile, clinical efficacy, and safety compared to traditional reversal agents, like neostigmine. Its expanding clinical applications across operating rooms, critical care units, and emergency medicine are discussed, emphasizing dosing recommendations and clinical utility in special patient populations, including individuals with renal impairment, pediatric, obstetric, and obese patients. Economic considerations are explored, highlighting sugammadex's cost-effectiveness through reduced postoperative complications and enhanced operational efficiency, despite higher initial costs. Finally, the review outlines ongoing research directions, including emerging reversal agents, advanced neuromuscular monitoring technologies, and potential future clinical applications, underscoring sugammadex's evolving role in improving patient safety and anesthetic practice
Investigating the role of MMP9 in anti‐Abeta immunotherapy‐associated ARIA
No full textBackground:
Amyloid related imaging abnormalities (ARIA) remain a major obstacle to the widespread use of anti‐amyloid immunotherapy. Data has indicated an association of neuroinflammation and subsequent MMP activation as being associated with anti‐amyloid immunotherapy. We therefore performed a co‐administration study of anti‐amyloid immunotherapy (3D6) with marimastat, an MMP inhibitor that targets MMP1, 2, 3, 7 and 9, with the highest affinity for MMP9.
Method:
We initiated treatment with both agents in 19 mo hAbetaSAA knockin mice. Monthly MRI imaging was performed and, upon euthanasia, we performed scRNAseq on the frontal cortex using a glial enrichment preparation, and histological analysis for microhemorrhages.
Result:
We found that anti‐amyloid immunotherapy‐mediated Prussian blue microhemorrhages were not significantly reduced by marimastat co‐administration. However, MRI detected microhemorrhages were reduced by marimastat treatment. In our scRNAseq dataset we found significant shifts in microglial state with anti‐amyloid immunotherapy not detected with the control IgG.
Conclusion:
MMP inhibition does not appear to impact small microhemorrhages detected histologically. However, the reduced microhemorrhages detected using MRI suggests that marimastat prevented the development of larger sized microhemorrhage events. Data analysis continues to gain further insights from this study
Combining phenomics with transcriptomics reveals cell-type-specific morphological and molecular signatures of the 22q11.2 deletion
No full textNeuropsychiatric disorders remain difficult to treat due to complex and poorly understood mechanisms. NeuroPainting is a high-content morphological profiling assay based on Cell Painting and optimized for human stem cell–derived neural cell types, including neurons, progenitors, and astrocytes. The assay quantifies over 4000 features of cell structure and organelle organization, generating a dataset suitable for phenotypic screening in neural models. Here, we show that, in studies of the 22q11.2 deletion—a strong genetic risk factor for schizophrenia—we observe cell-type-specific effects, particularly in astrocytes, including mitochondrial disruption, altered endoplasmic reticulum organization, and cytoskeletal changes. Transcriptomic analysis shows reduced expression of cell adhesion genes in deletion astrocytes, consistent with post-mortem brain data. Integration of RNA and morphology data suggests a link between adhesion gene dysregulation and mitochondrial abnormalities. These results illustrate how combining image-based profiling with gene expression analysis can reveal cellular mechanisms associated with genetic risk in neuropsychiatric disease
Directed Differentiation Of Human Induced Pluripotent Stem Cells Through Neurogenin 2 as a Platform for Investigating Alzheimer's Disease Mechanisms
No full textIUIStudies involving human neurological diseases are often limited by the availability of patient-derived neurons. While direct differentiation of neurons from fibroblasts or other somatic cells is viable, the directed differentiation of human induced pluripotent stem cells (iPSCs) offers a renewable and scalable source of patient-specific neurons. However, current growth factor-based protocols for iPSC neuronal differentiation are cumbersome and require weeks to yield mature neurons and typically result in mixed cell populations. Thus, the manual isolation of desired neurons not only reduces their yield but also compromises specificity. Moreover, growth factor-induced neuronal differentiation tends to be highly variable, further compromising reproducibility. To overcome these shortcomings, we utilized a rapid single-step induced neuron (iN) methodology from iPSCs. Using a lentiviral delivery system, we induced constitutive tetracycline expression to overexpress exogeneous neurogenin-2 (NGN2) driven by the tetO promoter. The forced NGN2 expression aided in the direct lineage conversion of iPSCs into neuronal cells. The lentiviral construct also encoded eGFP and a puromycin resistance gene to enable both visualization and selection of successfully transduced cells. Within one-week post-transduction, surviving cells exhibited characteristic neuronal morphologies. To better model Alzheimer’s disease (AD), we generated neurons from patient-derived iPSCs with varying polygenic risk scores (PRS) based on ADNI samples. We confirmed the neuronal identity of these induced cells via immunostaining of key neuronal markers, demonstrating the protocol’s robustness and reproducibility. We confirmed that the NGN2-derived neurons were functionally active using multi-electrode array recordings, which showed differences in activity patterns across patient-derived lines. In parallel, molecular testing was used to examine AD-related features, specifically Aβ and pTau, with elevated levels observed so far in lines with high polygenic risk scores. Early findings suggest this model may aid in capturing patient-specific aspects of AD pathology and how genetic changes contribute to disease-related changes in neurons. Standardization of iPSCs-derived induced-neurons protocol will contribute to increasing the yield and specificity of isolated neurons with low cell-to-cell variability, which is necessary for determining disease pathogenesis and drug targets
Genetic analysis of triplicated genes affecting sex-specific skeletal deficits in Down syndrome model mice
No full textDown syndrome (DS) is caused by triplication of human chromosome 21 (Hsa21), resulting in skeletal insufficiency and altered postnatal bone development in individuals with DS. DS mouse models have shown similar deficits to humans with DS, mimicking differences between ages, sexes, and bone compartments. The historic mouse model, Ts65Dn, has provided much of the mechanistic insight behind these DS-related skeletal deficits, but there are concerns over its genetic construct validity. Ts65Dn mice have an additional 60 trisomic genes that are homologous to Hsa6. These genes, acting either directly or through interactions with trisomic, Hsa21-homologous or disomic genes, may produce phenotypes not related to DS; so, Ts66Yah mice were derived to remove these genes. After assessing individual densitometric and morphometric parameters in femurs, skeletal phenotypes were directly compared between male and female Ts65Dn and Ts66Yah mice at postnatal day (P) 36 and 6-weeks and between male mice at 16-weeks using multivariate principal components analyses on these parameters. These comparisons confirmed male Ts66Yah mice have trabecular and cortical deficits similar to male Ts65Dn mice at all ages. In contrast, female Ts66Yah mice lacked trabecular deficits evident in female Ts65Dn mice at P36, but both ages had similar cortical deficits. Copy number normalization of Dyrk1a, a trisomic, Hsa21-orthologous gene, failed to rescue deficits in male or improve trabecular bone in female Ts66Yah mice at P36 as observed in Ts65Dn mice. Thus, mechanisms behind trabecular phenotypes in both sexes of Ts66Yah mice likely differ from those of Ts65Dn mice. Overall, the trisomic, Hsa6-homologous genes in Ts65Dn mice may result in differences in trabecular phenotypes or mechanisms prior to 6 weeks but do not impact later trabecular or cortical phenotypes
Potency of human hematopoietic cells from a novel CD34+ isolation technique
No full textHematopoietic stem and progenitor cells are responsible for maintenance of the immune system and can be a source of cells for therapies. A critical step in studying or utilizing hematopoietic cells is subpopulation isolation. FerroBio is an emerging technology that uses a streamlined, semi-automated approach to isolate CD34+ cells, which are highly enriched for hematopoietic stem and progenitors. This technology also results in isolation of bead-free CD34+ cell samples, in contrast to traditional kits where beads persist following isolation. Here, we showed a side-by-side comparison of FerroBio isolated cells with CD34+ cells isolated by traditional column-based kits. We showed that FerroBio yields similar numbers of CD34+ cells with similar viability, yield, and gated purity and higher overall purity compared to control kits. FerroBio isolated similar numbers of progenitor cells but significantly higher stem cells. Ex vivo, cells isolated by FerroBio showed the same ability to form colonies in culture, but FerroBio colony-forming units expanded to a greater extent in liquid culture compared to control. Critically, FerroBio isolated cells had equivalent long-term engraftment capacity with significantly better intermediate-term engraftment compared to control in mouse models of transplantation. Based on microscopy images showing altered morphology co-localized with beads, we inferred that the persistence of magnetic microbeads may be associated with the observed differences. These data demonstrated that specific subpopulations of progenitors from FerroBio isolated CD34+ cells have better potency compared to cells isolated with column-based kits. Thus, FerroBio is a viable strategy for isolating CD34+ cells for research and potentially translational utility
Therapeutic Potential of Niacin in PS19 Tauopathy Mice
No full textBackground:
Alzheimer's disease (AD) is characterized by the presence of extracellular amyloid‐b plaques, intraneuronal neurofibrillary tangles, and a robust immune response. Dietary intake of niacin (nicotinic acid) has been correlated with decreased risk of AD and age‐related cognitive decline. We have recently shown that niacin stimulates the receptor HCAR2 to induce a protective microglial phenotype and attenuated disease severity in an amyloid mouse model of AD. However, the therapeutic potential of HCAR2 in tauopathy remains unknown.
Methods:
To investigate the contribution of HCAR2 on tau pathology, we used the tauopathy mouse model PS19. We employed two different strategies of niacin treatment, daily oral gavage (100 mg/kg) for 30 days between 9‐10 months of age, and a niacin‐enriched diet between 6‐9 months of age. To assess the effect of niacin on tau pathology, we analyzed motor phenotype, microglial and synaptic markers, as well as the levels of tau species in PS19 mice.
Results:
Our preliminary findings indicate that HCAR2 expression is significantly elevated in hippocampal microglia of PS19 mice. Oral niacin treatment ameliorates motor coordination deficits and prevents neuronal loss, suggesting a restoration of synaptic integrity. Furthermore, genetic deletion of the HCAR2 receptor in PS19 mice, accelerated the onset of motor deficits and exacerbated the accumulation of pathogenic species of tau. These results suggest that HCAR2 is protective in tau pathology and activating this receptor could serve as a promising pharmacological strategy to mitigate disease severity.
Conclusion:
Our findings suggest that alterations in hippocampal HCAR2 expression may play a role in tau pathology. Niacin treatment improved motor coordination but did not affect the clasping reflex. In addition, niacin improved expression patterns of structural synaptic proteins. These results indicate that HCAR2 activation may help reduce disease severity. However, further studies are needed to clarify the underlying mechanisms. Overall, this research highlights a novel role for HCAR2 in tauopathies and supports the potential repurposing of existing niacin formulations as a therapeutic approach for Alzheimer's disease
Personalized and real time hemodynamic management in critical care using Dynamic Cohort Ensemble Learning (DynaCEL)
No full textEffective hemodynamic management in the intensive care unit requires individualized targets that adapt to dynamic clinical conditions. We developed Dynamic Cohort Ensemble Learning (DynaCEL), a real-time framework that recommends personalized heart rate and systolic blood pressure targets by modeling each time point post-intensive care unit admission as a distinct temporal cohort. Trained on eICU data and validated on MIMIC-IV and Indiana University Health datasets, DynaCEL demonstrated robust predictive performance (AUCs 0.83-0.91). In the MIMIC-IV cohort, proximity to DynaCEL-predicted targets was associated with lower 24-hour mortality compared to fixed targets, after adjustment using propensity score matching. Dose-response and comparative analyses revealed that greater deviations from personalized targets were associated with higher mortality. Case studies illustrated temporal and inter-individual variation in optimal targets. DynaCEL offers interpretable and scalable support for exploring precision hemodynamic management, although its clinical utility remains to be established in prospective trials