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Mitochondrial DNA (mtDNA) is highly polymorphic, and host mtDNA variation has been associated with altered cancer severity. To determine the basis of this mtDNA-cancer association, we analyzed conplastic mice with the C57BL/6J (B6) nucleus but two naturally occurring mtDNA lineages, mtDNAB6 and mtDNANZB, where mtDNANZB mitochondria generate more oxidative phosphorylation (OXPHOS)-derived reactive oxygen species (mROS). In a cardiac transplant model, mtDNAB6 Foxp3+ T regulatory (Treg) cells supported long-term allograft survival, whereas mtDNANZB Treg cells failed to suppress host T effector (Teff) cells, leading to acute rejection. When challenged with melanoma or colon cancer cells, the mtDNANZB mice exhibited strikingly impaired tumor growth while mtDNAB6 mice showed Treg-dependent inhibition of Teff cells and allowed rapid tumor growth. Transcriptional analysis showed that activation of mtDNANZB Teff cells increased mitochondrial gene expression while activation of mtDNANZB Treg cells impaired mitochondrial gene expression and resulted in mtDNANZB Treg cell exhaustion. Induction of the mitochondrially targeted catalytic antioxidant, mCAT, in hematopoietic cells normalized mtDNANZB Treg function in both transplant and tumor models, indicating a key role for mROS in promoting Treg dysfunction. Anti-PD-L1 therapy did not modulate these effects, indicating that modulation of host mitochondrial function provides an independent approach for enhancing tumor cell destruction.

BackgroundApolipoprotein E ε4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD). A recent case report identified a rare variant in APOE, APOE3-R136S (Christchurch), proposed to confer resistance to autosomal dominant Alzheimer's Disease (AD). However, it remains unclear whether and how this variant exerts its protective effects.MethodsWe introduced the R136S variant into mouse Apoe (ApoeCh) and investigated its effect on the development of AD-related pathology using the 5xFAD model of amyloidosis and the PS19 model of tauopathy. We used immunohistochemical and biochemical analysis along with single-cell spatial omics and bulk proteomics to explore the impact of the ApoeCh variant on AD pathological development and the brain's response to plaques and tau.ResultsIn 5xFAD mice, ApoeCh enhances a Disease-Associated Microglia (DAM) phenotype in microglia surrounding plaques, and reduces plaque load, dystrophic neurites, and plasma neurofilament light chain. By contrast, in PS19 mice, ApoeCh suppresses the microglial and astrocytic responses to tau-laden neurons and does not reduce tau accumulation or phosphorylation, but partially rescues tau-induced synaptic and myelin loss. We compared how microglia responses differ between the two mouse models to elucidate the distinct DAM signatures induced by ApoeCh. We identified upregulation of antigen presentation-related genes in the DAM response in a PS19 compared to a 5xFAD background, suggesting a differential response to amyloid versus tau pathology that is modulated by the presence of ApoeCh. Bulk proteomics show upregulated mitochondrial protein abundance with ApoeCh in 5xFAD mice, but reductions in mitochondrial and translation associated proteins in PS19 mice.ConclusionsThese findings highlight the ability of the ApoeCh variant to modulate microglial responses based on the type of pathology, enhancing DAM reactivity in amyloid models and dampening neuroinflammation to promote protection in tau models. This suggests that the Christchurch variant's protective effects likely involve multiple mechanisms, including changes in receptor binding and microglial programming.

Finding ways to move knowledge-to-impact is a key priority for research funding agencies, universities, and academics. However, academic engagement with the broader community is not without tensions and challenges, including arriving at mutual benefit and relevance, and addressing power dynamics and often incompatible communication practices. This study used a mixed-methods approach to examine a unique event series of public dialogues that brought together diverse community and academic perspectives around health equity issues. Findings suggest the series successfully merged strategies from both the knowledge mobilization and citizen engagement/public involvement domains to spark conversations in one community regarding health equity and social justice. We provide initial descriptive evidence that the format was successful in achieving its proximate goals, and was appreciated by those who participated and attended. We position this type of activity as a promising strategy to effectively bring academic research to the broader local community.

Students with autism are enrolling in college more frequently, yet graduation rates for these students remain low. One reason posited is a lack of self-determination (SD) skills, which help students communicate with faculty and staff and act on goals. This study investigated how faculty at a community college support students in developing these skills, the nature of their communication with disability resource professionals and site directors, and the experiences of faculty and disability resource professionals with accommodations. The study employed basic qualitative methods, specifically semi-structured interviews with 31 faculty, disability resource professionals, and site directors. Findings show that faculty use specific strategies to communicate with students yet struggle with helping them to regulate behaviors and giving them autonomy. Faculty, disability resource professionals, and site directors indicate that rapport and trust are important in communications between all three groups about how to help students with autism. Yet when these qualities are not present, faculty find safe spaces to access the help they need through informal supports. All groups of participants indicated that while accommodation letters are a good place to start when supporting students with autism, they provide little help in reinforcing SD skills. Thus, accommodations are supplemented by faculty being willing to work with students beyond the accommodation letter.

Calls to improve relationships between education research and practice abound, among them efforts to help researchers work in partnership with and communicate more effectively with policy and practice audiences. Recognizing this need, the U.S. National Academies of Science, Engineering, and Medicine have emphasized the importance of integrating knowledge mobilization (KMb) into education research funding frameworks to ensure that research outcomes are both impactful and responsive to the needs of policymakers and practitioners. In our study, we seek to identify and clarify effective strategies for bridging the divide between education research and practice, contributing to the scholarship on educational change by highlighting the potential of KMb to drive research impact. Using a mixed-methods approach, we conducted an inquiry into the KMb practices of education researchers, beginning with a national survey followed by in-depth case studies of ten research projects identified through the survey. Our analysis examines how knowledge is mobilized from the inception of research through its dissemination and identifies the key factors that support effective KMb in these projects. We demonstrate that Kmb has the potential to generate significant impact when research is practice-centered, when stakeholders are actively engaged throughout the research process, and when KMb strategies are tailored to meet the needs of policy and practice audiences. We also highlight examples of how education research has achieved impact. Additionally, we identify key barriers to KMb, including institutional and systemic challenges that hinder its integration into the research process. We conclude that for education research to be truly impactful, it must prioritize relevance to practice from its inception. We advocate for systemic changes such as incorporating KMb training into doctoral programs, recognizing the value of engaged research within institutions, and diversifying funding mechanisms to support KMb activities.

The cryo-electron microscopy (cryoEM) method has enabled high-resolution structure determination of numerous biomolecules and complexes. Nevertheless, cryoEM sample preparation of challenging proteins and complexes, especially those with low abundance or with preferential orientation, remains a major hurdle. We developed an affinity-grid method employing monodispersed single particle streptavidin on a lipid monolayer to enhance particle absorption on the grid surface and alleviate sample exposure to the air-water interface. Using this approach, we successfully enriched the Thermococcus kodakarensis mini-chromosome maintenance complex 3 (MCM3) on cryoEM grids through biotinylation and resolved its structure. We further utilized this affinity method to tether the biotin-tagged dsDNA to selectively enrich a stable MCM3-ATP-dsDNA complex for cryoEM structure determination. Intriguingly, both MCM3 apo and dsDNA bound structures exhibit left-handed open spiral conformations, distinct from other reported MCM structures. The large open gate is sufficient to accommodate a dsDNA which could potentially be melted. The value of mspSA affinity method was further demonstrated by mitigating the issue of preferential angular distribution of HIV-1 capsid protein hexamer and RNA polymerase II elongation complex from Saccharomyces cerevisiae.

BACKGROUND: We evaluated sociodemographic and clinical predictors of financial toxicity (FT) among patients with breast cancer with higher risk clinical factors warranting regional nodal irradiation (RNI). METHODS: Among 183 participants in a clinical trial of conventional vs. hypofractionated treatment with RNI, 125 (68 %) completed a pilot survey of FT measured using the validated Economic Strain and Resilience in Cancer (ENRICh) instrument, scored from 0 (minimal) to 10 (severe) FT. Associations with predictors were evaluated using Pearson correlation coefficients and Kruskal Wallis, Mann-Whitney U, and Jonckheere-Terpstra tests. Predictors of severe FT (ENRICh≥5) were tested using multivariable logistic regression with odds ratios converted to relative risks (RR). RESULTS: Of the sample, all received RNI, 92 % chemotherapy, 67 % axillary dissection, 26 % mastectomy without reconstruction, and 32 % mastectomy with reconstruction. At a median follow up of 1.48 years, median FT score was 2.13 (IQR 0.93-4.6), with 20.8 % of patients experiencing severe FT. Unadjusted worse FT score was associated with younger age (P = 0.003), Hispanic ethnicity (P = 0.006), lower income (P = 0.02), shorter interval from diagnosis to FT assessment (P = 0.02), and chemotherapy receipt (P = 0.05), but not with breast surgery type (P = 0.42), axillary surgery type (P = 0.33), or pathologic T (P = 0.68) or N stage (P = 0.47). In multivariable analysis, triple negative subtype was the sole clinical factor predicting severe FT (RR = 3.38; 95 % CI 1.48-4.99; P = 0.01). CONCLUSION: Among patients with breast cancer receiving RNI, triple negative subtype was associated with severe FT, suggesting that tumor receptor subtype may help identify a key breast cancer subpopulation for early FT intervention.

The HEALthy Brain and Child Development (HBCD) Study, a multi-site prospective longitudinal cohort study, will examine human brain, cognitive, behavioral, social, and emotional development beginning prenatally and planned through early childhood. The acquisition of multimodal magnetic resonance-based brain development data is central to the studys core protocol. However, application of Magnetic Resonance Imaging (MRI) methods in this population is complicated by technical challenges and difficulties of imaging in early life. Overcoming these challenges requires an innovative and harmonized approach, combining age-appropriate acquisition protocols together with specialized pediatric neuroimaging strategies. The HBCD MRI Working Group aimed to establish a core acquisition protocol for all 27 HBCD Study recruitment sites to measure brain structure, function, microstructure, and metabolites. Acquisition parameters of individual modalities have been matched across MRI scanner platforms for harmonized acquisitions and state-of-the-art technologies are employed to enable faster and motion-robust imaging. Here, we provide an overview of the HBCD MRI protocol, including decisions of individual modalities and preliminary data. The result will be an unparalleled resource for examining early neurodevelopment which enables the larger scientific community to assess normative trajectories from birth through childhood and to examine the genetic, biological, and environmental factors that help shape the developing brain.

IntroductionEmerging evidence links changes in the gut microbiome to late-onset Alzheimer's disease (LOAD), necessitating examination of AD mouse models with consideration of the microbiome.MethodsWe used shotgun metagenomics and untargeted metabolomics to study the human amyloid beta knock-in (hAβ-KI) murine model for LOAD compared to both wild-type (WT) mice and a model for early-onset AD (3xTg-AD).ResultsEighteen-month female (but not male) hAβ-KI microbiomes were distinct from WT microbiomes, with AD genotype accounting for 18% of the variance by permutational multivariate analysis of variance (PERMANOVA). Metabolomic diversity differences were observed in females, however no individual metabolites were differentially abundant. hAβ-KI mice microbiomes were distinguishable from 3xTg-AD animals (81% accuracy by random forest modeling), with separation primarily driven by Romboutsia ilealis and Turicibacter species. Microbiomes were highly cage specific, with cage assignment accounting for more than 40% of the PERMANOVA variance between the groups.DiscussionThese findings highlight a sex-dependent variation in the microbiomes of hAβ-KI mice and underscore the importance of considering the microbiome when designing studies that use murine models for AD.HighlightsMicrobial diversity and the abundance of several species differed in human amyloid beta knock-in (hAβ-KI) females but not males. Correlations to Alzheimer's disease (AD) genotype were stronger for the microbiome than the metabolome. Microbiomes from hAβ-KI mice were distinct from 3xTg-AD mice. Cage effects accounted for most of the variance in the microbiome and metabolome.

BackgroundVariants in ABCA7, a member of the ABC transporter superfamily, have been associated with increased risk for developing late onset Alzheimer's disease (LOAD).MethodsCRISPR-Cas9 was used to generate an Abca7V1613M variant in mice, modeling the homologous human ABCA7V1599M variant, and extensive characterization was performed.ResultsAbca7V1613M microglia show differential gene expression profiles upon lipopolysaccharide challenge and increased phagocytic capacity. Homozygous Abca7V1613M mice display elevated circulating cholesterol and altered brain lipid composition. When crossed with 5xFAD mice, homozygous Abca7V1613M mice display fewer Thioflavin S-positive plaques, decreased amyloid beta (Aβ) peptides, and altered amyloid precursor protein processing and trafficking. They also exhibit reduced Aβ-associated inflammation, gliosis, and neuronal damage.DiscussionOverall, homozygosity for the Abca7V1613M variant influences phagocytosis, response to inflammation, lipid metabolism, Aβ pathology, and neuronal damage in mice. This variant may confer a gain of function and offer a protective effect against Alzheimer's disease-related pathology.HighlightsABCA7 recognized as a top 10 risk gene for developing Alzheimer's disease. Loss of function mutations result in increased risk for LOAD. V1613M variant reduces amyloid beta plaque burden in 5xFAD mice. V1613M variant modulates APP processing and trafficking in 5xFAD mice. V1613M variant reduces amyloid beta-associated damage in 5xFAD mice.

IntroductionAlzheimer's disease (AD) is a neurodegenerative disorder with multifactorial etiology, including genetic factors that play a significant role in disease risk and resilience. However, the role of genetic diversity in preclinical AD studies has received limited attention.MethodsWe crossed five Collaborative Cross strains with 5xFAD C57BL/6J female mice to generate F1 mice with and without the 5xFAD transgene. Amyloid plaque pathology, microglial and astrocytic responses, neurofilament light chain levels, and gene expression were assessed at various ages.ResultsGenetic diversity significantly impacts AD-related pathology. Hybrid strains showed resistance to amyloid plaque formation and neuronal damage. Transcriptome diversity was maintained across ages and sexes, with observable strain-specific variations in AD-related phenotypes. Comparative gene expression analysis indicated correlations between mouse strains and human AD.DiscussionIncreasing genetic diversity promotes resilience to AD-related pathogenesis, relative to an inbred C57BL/6J background, reinforcing the importance of genetic diversity in uncovering resilience in the development of AD.HighlightsGenetic diversity's impact on AD in mice was explored. Diverse F1 mouse strains were used for AD study, via the Collaborative Cross. Strain-specific variations in AD pathology, glia, and transcription were found. Strains resilient to plaque formation and plasma neurofilament light chain (NfL) increases were identified. Correlations with human AD transcriptomics were observed.

IntroductionThe BIN1 coding variant rs138047593 (K358R) is linked to Late-Onset Alzheimer's Disease (LOAD) via targeted exome sequencing.MethodsTo elucidate the functional consequences of this rare coding variant on brain amyloidosis and neuroinflammation, we generated BIN1K358R knock-in mice using CRISPR/Cas9 technology. These mice were subsequently bred with 5xFAD transgenic mice, which serve as a model for Alzheimer's pathology.ResultsThe presence of the BIN1K358R variant leads to increased cerebral amyloid deposition, with a dampened response of astrocytes and oligodendrocytes, but not microglia, at both the cellular and transcriptional levels. This correlates with decreased neurofilament light chain in both plasma and brain tissue. Synaptic densities are significantly increased in both wild-type and 5xFAD backgrounds homozygous for the BIN1K358R variant.DiscussionThe BIN1 K358R variant modulates amyloid pathology in 5xFAD mice, attenuates the astrocytic and oligodendrocytic responses to amyloid plaques, decreases damage markers, and elevates synaptic densities.HighlightsBIN1 rs138047593 (K358R) coding variant is associated with increased risk of LOAD. BIN1 K358R variant increases amyloid plaque load in 12-month-old 5xFAD mice. BIN1 K358R variant dampens astrocytic and oligodendrocytic response to plaques. BIN1 K358R variant decreases neuronal damage in 5xFAD mice. BIN1 K358R upregulates synaptic densities and modulates synaptic transmission.

Abstract This paper explores the development of a collaborative and customer-centric business model for sustainable innovation in rare earth magnet recycling. Rare earth elements have become crucial to various electronics and renewable energy systems. Due to their finite nature and the supply risk they pose as they are available in a few countries, recycling these magnets is becoming increasingly important as demand increases. This study highlights the importance of developing business models that prioritize resource sufficiency, economic viability and environmental conservation. It emphasizes customer discovery, a critical component in understanding market needs and consumer behavior. Through detailed case studies as part of the NSF I-Corps program, this paper presents evidence from over 130 stakeholder interviews, completed with individuals from rare earth magnet companies, rare earth magnet recycling companies, National laboratories, metal alloy companies, and metal recycling companies. These case studies highlight best practices, challenges, and lessons learned, providing a comprehensive blueprint for other businesses to follow. In addition, this paper explores policy implications, advocating for regulatory frameworks that support sustainable practices and incentivize recycling initiatives. Ultimately, this research aims to contribute to the circular economy by demonstrating how sufficiency-driven business models can lead to sustainable growth and resilience in the rare earth recycling industry. By integrating stakeholder collaboration and customer discovery, businesses can innovate effectively, ensuring the sustainability of both their operations and the environment.

Abstract Background Apolipoprotein E ε4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer’s disease (LOAD). A recent case report identified a rare variant in APOE, APOE3-R136S (Christchurch), proposed to confer resistance to autosomal dominant Alzheimer’s Disease (AD). However, it remains unclear whether and how this variant exerts its protective effects. Methods We introduced the R136S variant into mouse Apoe (ApoeCh) and investigated its effect on the development of AD-related pathology using the 5xFAD model of amyloidosis and the PS19 model of tauopathy. We used immunohistochemical and biochemical analysis along with single-cell spatial omics and bulk proteomics to explore the impact of the ApoeCh variant on AD pathological development and the brain’s response to plaques and tau. Results In 5xFAD mice, ApoeCh enhances a Disease-Associated Microglia (DAM) phenotype in microglia surrounding plaques, and reduces plaque load, dystrophic neurites, and plasma neurofilament light chain. By contrast, in PS19 mice, ApoeCh suppresses the microglial and astrocytic responses to tau-laden neurons and does not reduce tau accumulation or phosphorylation, but partially rescues tau-induced synaptic and myelin loss. We compared how microglia responses differ between the two mouse models to elucidate the distinct DAM signatures induced by ApoeCh. We identified upregulation of antigen presentation-related genes in the DAM response in a PS19 compared to a 5xFAD background, suggesting a differential response to amyloid versus tau pathology that is modulated by the presence of ApoeCh. Bulk proteomics show upregulated mitochondrial protein abundance with ApoeCh in 5xFAD mice, but reductions in mitochondrial and translation associated proteins in PS19 mice. Conclusions These findings highlight the ability of the ApoeCh variant to modulate microglial responses based on the type of pathology, enhancing DAM reactivity in amyloid models and dampening neuroinflammation to promote protection in tau models. This suggests that the Christchurch variant's protective effects likely involve multiple mechanisms, including changes in receptor binding and microglial programming. Graphical Abstract

Abstract Background Global re-emergence of the zoonotic viral disease, Mpox (Monkeypox) has drawn global attention, leading to its declaration as a Public Health Emergency of International Concern (PHEIC) by World Health Organisation (WHO) in July 2022. Nigeria is a spotlight identified for the viral disease outbreak, with attention drawn on its transmission to non-endemic nations. With the country’s healthcare challenges, care seeking practices particularly amongst low-income urban informal settlement populations are diverse – presenting challenges to both case identification and management during an outbreak. In this study, we examine the social, economic, and behavioural context of Mpox therapeutics. Methods This was an ethnographic study conducted between September 2022 and March 2023, with the purposive selection of urban informal settlements and interlocutors in Oyo, Ogun and Lagos States. We interviewed a total of 28 interlocutors who were either confirmed or suspected cases of Mpox or parents of children who are confirmed or suspected Mpox cases identified by the public health workers. Data were elicited through In-depth interviews and observations technique on the interlocutor’s local knowledge and their lived experiences on the therapeutics of Mpox. Analysis of the transcript was done inductively using thematic analysis process. Findings The study revealed awareness and vague knowledge of Mpox. Furthermore, the behavioural practices on how ailments are understood and managed revealed a commonality in their social actions in terms of local diagnosis and management. Mpox was perceived to be a mild disease, and this had implications on the local characteristics of the PHEIC in the endemic regions. Conclusion Our paper contributes to a more nuanced understanding of not only the health care access barriers, but the complex geographical, economic, and sociocultural factors that shape how and when people seek care for Mpox within the context of urban informal settlements. This further draws attention to behavioral dispositions to the nomenclature of what is perceived as PHEIC. Thus, the global health and security paradigm should give room to local context, expertise, and global politics in shaping epidemic responses.