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Characterization of Missense Variants in the RNA Exosome Associated with Pontocerebellar Hypoplasia
No full textIUIHigh-throughput sequencing has been essential in identifying genetic variants associated with disease. However, protein-level characterization of identified genetic variants is lacking, especially for rare genetic diseases. RNA sequencing and proteomics techniques were used to characterize missense variants associated with the rare neurodegenerative disorder pontocerebellar hypoplasia 1b (PCH1b). Several variants of EXOSC3, a subunit of the RNA exosome, have been identified in patients with PCH1b. We investigated three missense variants of EXOSC3, including one variant of uncertain significance (VUS). We compared the VUS with two pathogenic variants, one of which is the most common in the general population by allele frequency. The RNA exosome complex consists of 9 core subunits and 2 catalytic subunits and cooperates with several cofactors to guide its function. The RNA exosome is involved in diverse cellular functions including general RNA turnover, rRNA processing, and regulation of RNA splicing. We focused on variants in the EXOSC3 core subunit, identifying differences in protein abundance and stability changes within missense variant cell lines generated by CRISPR. While overall RNA-level changes were limited, we observed differences in rRNA processing and RNA abundance. Proteomics revealed significant decreases in RNA exosome subunit protein abundance, and interestingly, four spatially proximal subunits displayed a greater degree of reduced abundance suggesting altered interactions between / assembly of these subunits. We see potential compensation with increased protein abundance of the catalytic subunit DIS3 and several rRNA processing proteins. Comparison of the VUS with the known pathogenic variants highlights the similarities in the molecular phenotypes but determined that the effects are not as pronounced in the VUS. Ongoing experiments seek to rescue the phenotypes caused by the missense variants by proteasome inhibition and exogenous overexpression of reference or variant EXOSC3. Overall, these experiments illustrate that disease associated EXOSC3 variants have a continuum of functional changes that could explain the range of severity observed in PCH1b patients. By obtaining protein-level insights into exosome complex dynamics, we can design rescue experiments to alleviate dysfunction
Acute Exposure to Ozone Affects Circulating Estradiol Levels and Gonadotropin Gene Expression in Female Mice
No full textOzone, a critical air pollutant, has been shown to lead to systemic inflammation that can alter bodily functions, including hormone secretion, fertility, and the hypothalamic-pituitary-gonadal (HPG) axis. This study aimed to quantify changes in hormone production and follicle development after acute exposure to ozone using an animal model to identify the potential mechanisms underlying the observed effects of air pollution exposures on fertility and hormone secretion. To accomplish this, regularly cycling 8-week-old female C57BL/6J mice were exposed to 2 ppm of ozone or filtered air (control) for 3 h on the day of proestrus. Blood, ovaries, brain tissues, and pituitary glands were collected at 4 h after exposure to evaluate hormone levels, ovarian follicle distribution, and gene expression. Ovaries were also harvested at 24 h post-exposure. We found that at 4 h after ozone exposure, mice had significantly higher (30%) circulating estradiol levels than mice exposed to filtered air. This effect was accompanied by a decrease in mRNA expression of gonadotropin genes (LH, FSH) and gonadotropin-releasing hormone in the pituitary gland. Analysis of ovarian tissue at 4 h and 24 h after exposure showed no significant changes in follicle composition or the expression of steroidogenesis genes. We conclude that acute ozone exposure affects sex hormone levels and disrupts the HPG axis. Future studies addressing chronic or long-term effects of air pollution exposure are needed to elucidate the mechanisms by which ambient ozone affects endocrine function
IL-9 Intrinsically Alters Gene Expression and Chromatin Structure in Pulmonary Macrophages to Enhance Lung Tumor Growth
No full textIUITumor-associated macrophages are an abundant, tumor-infiltrating cell population that support tumor progression through mechanisms such as extracellular matrix remodeling, immunosuppression, and metabolic reprogramming. The cytokine milieu is a factor that influences the functional phenotype of TAMs within the tumor microenvironment. Among these, interleukin-9 (IL-9) is a pleiotropic cytokine with both tumor-promoting and tumor-suppressing roles depending on the cancer type and responding cell. Importantly, mechanistic understanding of IL-9 in cancer is largely undefined. The work described in this thesis mechanistically defines the role of IL-9-responsive macrophages in the progression and metastasis of lung tumors. We demonstrate that IL-9 expands lung interstitial macrophage populations and induces the expression of Arginase 1 (ARG1), a critical enzyme in arginine to polyamine metabolism that is associated with poor survival in patients. Therapeutically, targeting ARG1-expressing macrophages using Arg1 siRNA-loaded nanoparticles significantly reduced polyamine levels and tumor burden. Additionally, bulk RNA sequencing and single-nuclei multi-modal ATAC and RNA sequencing in mixed-bone marrow chimeric mice revealed that IL-9 intrinsically reprograms the epigenetic and transcriptomic landscape of lung interstitial macrophages. Dysregulation of key genes, including Pdl1 and several cathepsins (Ctsd, Ctse, and Ctss), was identified and linked to increased tumor growth and an impaired anti-tumor immune response. In summary, this work identifies a critical vii
pro-tumor mechanism of IL-9 in lung interstitial macrophages, characterized by dysregulated arginine metabolism, altered macrophage gene expression, and reduced anti-tumor immune responses. These findings underscore the potential of targeting IL-9-mediated pathways in macrophages as a potential therapeutic approach in lung cancer and metastasis
The evolution of serious health-related suffering from 1990 to 2021: an update to The Lancet Commission on global access to palliative care and pain relief
No full textBackground: The Lancet Commission on global access to palliative care and pain relief introduced the concept of serious health-related suffering (SHS) to measure the worldwide dearth of palliative care. This Article provides an extended analysis of SHS from 1990 to 2021 and the corresponding global palliative care need.
Methods: This Article is the first to apply the SHS 2·0 method published in 2024, incorporating prevalence data from the Global Burden of Diseases, Injuries, and Risk Factors Study to improve non-decedent estimates that account for country-level epidemiological variation; adjusting for non-decedent double counting of HIV/AIDS, cancer, cerebrovascular disease, and dementia; improving the non-decedent estimates for cancer using survivorship data from the Global Cancer Observatory and for HIV/AIDS incorporating access to antiretroviral therapy; differentiating by sex; considering more specific age groups allowing for better estimates, especially in children; and adding endocrine, metabolic, blood, and immune disorders to the health conditions causing SHS. We describe SHS trends globally and within country income groups, differentiating among decedents and non-decedents, by health conditions, sex, and across child and adult age groups.
Findings: The SHS global burden increased by 74% between 1990 and 2021 to almost 73·5 million individuals, with population growth accounting for only half of that increase. Low-income and middle-income countries (LMICs) accounted for 80% of SHS, with an increase of 83% from 1990 to 2021 compared with a 46% increase in high-income countries (HICs). Between 1990 and 2021, the decedent burden increased by 35%, whereas SHS in non-decedents more than doubled, accounting for 63% of SHS by 2021. The proportion of SHS from communicable diseases declined, especially in LMICs; however, the absolute number stayed relatively stable and even increased from 2019 to 2021 with the start of the COVID-19 pandemic. SHS from non-communicable diseases drastically increased, led by cancer (excluding leukaemia), cardiovascular diseases, and dementia in HICs. HIV/AIDS continued to be a major contributor, accounting for a substantial share of SHS in sub-Saharan Africa. The share of SHS in children decreased from 25% of SHS in 1990 to 14% in 2021 and accounted for 33% of SHS in low-income countries, compared with 2% in HICs. In 2021, SHS in low-income countries was concentrated in female individuals aged 20-49 years (affecting 59% of this population); in HICs, SHS was concentrated in female individuals aged 70 years and older (affecting 54% of this population and probably related to dementia).
Interpretation: SHS and the associated need for palliative care is a major and persistent but not insurmountable challenge for health systems worldwide. Our findings highlight the urgency to both reduce the avoidable SHS burden through prevention and treatment, and guarantee comprehensive, universal access to palliative care as an equity and health system imperative, especially in LMICs
Comparing Barriers and Facilitators to Physical Activity Among Underrepresented Minorities: Preliminary Outcomes from a Mixed-Methods Study
No full textPhysical activity (PA)'s benefits are well established, yet many U.S. adults fail to meet PA guidelines. This is especially true for minorities facing social inequities. This study explored PA's barriers and facilitators among urban Midwestern minorities using a mixed-methods approach framed on the socio-ecological model. A cross-sectional survey was conducted between January and June 2024 among community-dwelling minorities. Participants were grouped as completing low (LLPA) or high (HLPA) weekly leisure-time PA for comparison. Quantitative analysis included MANOVA, follow-up ANOVAs, and calculation of effect sizes. Qualitative data were assessed using inductive thematic analysis. Twenty-nine adults (44.83% Black, 41.37% Latino) participated in the study. The HLPA group (n = 18) reported higher leisure-time PA (p = 0.001, d = 2.21) and total PA (p = 0.02, d = 1.00) compared to the LLPA group (n = 11). LLPA participants faced more personal barriers to PA (p = 0.02, d = -0.92). Common barriers identified in the interviews included a lack of time and financial costs. Facilitators included social support and available PA facilities. Both groups achieved the USPA guidelines through different PA domains. Increasing social support and lowering PA-related costs could enhance participation. Addressing barriers and leveraging existing facilitators are crucial to increasing PA among minorities
A 4-Site Public Deliberation Project on the Acceptability of Youth Self-Consent in Biomedical HIV Prevention Trials: Assessment of Facilitator Fidelity to Key Principles
No full textBackground: Public deliberation is an approach used to engage persons with diverse perspectives in discussions and decision-making about issues affecting the public that are controversial or value laden. Because experts have identified the need to evaluate facilitator performance, our research team developed a framework to assess the fidelity of facilitator remarks to key principles of public deliberation.
Objective: This report describes how the framework was used to assess facilitator fidelity in a 4-site public deliberation project on the acceptability of minor self-consent in biomedical HIV prevention research.
Methods: A total of 88 individuals participated in 4 deliberation sessions held in 4 cities throughout the United States. The sessions, facilitated by 18 team members, were recorded and transcribed verbatim. Facilitator remarks were highlighted, and predetermined coding rules were used to code the remarks to 1 of 6 principles of quality deliberations. A variety of display tables were used to organize the codes and calculate the number of facilitator remarks that were consistent or inconsistent with each principle during each session across all sites. A content analysis was conducted on the remarks to describe how facilitator remarks aligned or failed to align with each principle.
Results: In total, 735 remarks were coded to one of the principles; 516 (70.2%) were coded as consistent with a principle, and 219 (29.8%) were coded as inconsistent. A total of 185 remarks were coded to the principle of equal participation (n=138, 74.6% as consistent; n=185, 25.4% as inconsistent), 158 were coded to expression of diverse opinions (n=110, 69.6% as consistent; n=48, 30.4% as inconsistent), 27 were coded to respect for others (n=27, 100% as consistent), 24 were coded to adoption of a societal perspective (n=11, 46% as consistent; n=13, 54% as inconsistent), 99 were coded to reasoned justification of ideas (n=81, 82% as consistent; n=18, 18% as inconsistent), and 242 were coded to compromise or movement toward consensus (n=149, 61.6% as consistent; n=93, 38.4% as inconsistent). Therefore, the counts provided affirmation that most of the facilitator remarks were aligned with the principles of deliberation, suggesting good facilitator fidelity. By considering how the remarks aligned or failed to align with the principles, areas where facilitator fidelity can be strengthened were identified. The results indicated that facilitators should focus more on encouraging quieter members to participate, refraining from expressing personal opinions, promoting the adoption of a societal perspective and reasoned justification of opinions, and inviting deliberants to articulate their areas of common ground.
Conclusions: The results provide an example of how a framework for assessing facilitator fidelity was used in a 4-site deliberation project. The framework will be refined to better address issues related to balancing personal and public perspectives, managing plurality, and mitigating social inequalities
The effect of Alzheimer's disease genetic factors on limbic white matter microstructure
No full textIntroduction: White matter (WM) microstructure is essential for brain function but deteriorates with age and in neurodegenerative conditions such as Alzheimer's disease (AD). Diffusion MRI, enhanced by advanced bi-tensor models accounting for free water (FW), enables in vivo quantification of WM microstructural differences.
Methods: To evaluate how AD genetic risk factors affect limbic WM microstructure - crucial for memory and early impacted in disease - we conducted linear regression analyses in a cohort of 2,614 non-Hispanic White aging adults (aged 50.12 to 100.85 years). The study evaluated 36 AD risk variants across 26 genes, the association between AD polygenic scores (PGSs) and WM metrics, and interactions with cognitive status.
Results: AD PGSs, variants in TMEM106B, PTK2B, WNT3, and apolipoprotein E (APOE), and interactions involving MS4A6A were significantly linked to WM microstructure.
Discussion: These findings implicate AD-related genetic factors related to neurodevelopment (WNT3), lipid metabolism (APOE), and inflammation (TMEM106B, PTK2B, MS4A6A) that contribute to alternations in WM microstructure in older adults.
Highlights: AD risk variants in TMEM106B, PTK2B, WNT3, and APOE genes showed distinct associations with limbic FW-corrected WM microstructure metrics. Interaction effects were observed between MS4A6A variants and cognitive status. PGS for AD was associated with higher FW content in the limbic system
Taking the Next Step in Neurologic Rehabilitation: Contributions of Intensity and Variability of Stepping Tasks During Locomotor Training
No full textResearch over the past 20 years indicates the amount of task-specific walking practice provided to individuals with stroke, brain injury, or incomplete spinal cord injury can strongly influence walking recovery. However, more recent data suggest that attention toward 2 other training parameters, including the intensity and variability of walking practice, may maximize walking recovery and facilitate gains in non-walking outcomes. The combination of these training parameters represents a stark contrast from traditional strategies, and confusion regarding the potential benefits and perceived risks may limit their implementation in clinical practice. The purpose of this perspective is to delineate the evidence regarding the contributions of intensity and variability of locomotor training to improve mobility outcomes in individuals with acute-onset brain and spinal cord injury. The rationale and evidence supporting the utility of these training parameters in controlled laboratory settings is first described by integrating concepts in the field of neuroscience, motor learning, biomechanics, and exercise physiology into a rehabilitation intervention. Subsequently, the evidence supporting the efficacy of this paradigm is addressed, including discussions of some of the misconceptions regarding perceived negative consequences of these strategies in an effort to mitigate common clinical concerns. Finally, the utility of these strategies implemented during inpatient rehabilitation is delineated to facilitate a more comprehensive understanding of the feasibility and potential benefits early following neurologic injury. A greater understanding of how and why to integrate higher intensity, variable stepping practice will support therapists to take the next step to maximize mobility in the patients they serve
Promoting Family Centered Care in the Neonatal Intensive Care Unit (NICU)
No full textIUIWhile the neonatal intensive care unit (NICU) is often medically necessary, it can contribute significantly to stress for both infants and their families. Weber and Harrison (2019) identifies stress in the NICU to result from the physical environment, the psychosocial environment, and the medical complex requirements. Family centered care has been established as best practice in NICU settings, with increased evidence supporting its positive impact on infants and families (Lee, 2024). This capstone project was conducted in a level III NICU in central Indiana with the goal of enhancing caregiver education to promote greater caregiver participation and to foster a positive healing environment for infants. In collaboration with the site, the student identified a gap between the literature and the practical implementation of family centered care. A mixed-methods data collection approach, including a pre- and post-survey completed by NICU staff, was utilized to evaluate the project’s effectiveness. Evidence-based educational resources were developed, supporting a more therapeutic and family-inclusive NICU experience. Project evaluation results indicated a positive impact on caregiver education, staff knowledge, and the student’s clinical practice development.Occupational Therap
A clear approach: Hemostatic gel as a novel adjunct for pediatric upper gastrointestinal bleeding
No full textPediatric upper gastrointestinal bleeding (UGIB) is a significant clinical concern, with a mortality rate of approximately 2%. Endoscopic management of UGIB in children includes various techniques such as injections, mechanical devices, thermal therapies, and topical agents. PuraStat®, a clear hemostatic gel, has been used in adults to create a physical barrier for hemostasis without obscuring the endoscopic view. However, its use in pediatric UGIB has not been well-documented. A review of four pediatric cases where PuraStat® was used to treat UGIB showed that it was applied as an adjunct to other hemostatic methods like clip placement or epinephrine injections, and in one case, as monotherapy for a large duodenal ulcer/site of recently contained perforation. The gel was easy to use, appeared to be beneficial, and was well-tolerated in this small cohort, although conclusions regarding its safety and efficacy are limited by the sample size