MICK (Mobile Integrated Cognitive Kit) App for Concussion Assessment in a Youth Ice Hockey League.

BACKGROUND: Visual symptoms are common after concussion. Rapid automatized naming (RAN) tasks are simple performance measures that demonstrate worse time scores in the setting of acute or more remote injury. METHODS: We evaluated the capacity for the Mobile Universal Lexicon Evaluation System (MULES) and Staggered Uneven Number (SUN) testing to be feasibly administered during preseason testing in a cohort of youth ice hockey athletes using a novel computerized app, the Mobile Integrated Cognitive Kit (MICK). Participants from a youth hockey league underwent preseason testing. RESULTS: Among 60 participants, the median age was 13 years (range 6-17). The median best time for the MULES was 49.8 seconds (range = 34.2-141.0) and the median best time for the SUN was 70.1 (range = 36.6-200.0). As is characteristic of timed performance measures, there were learning effects between the first and second trials for both the MULES (median improvement = 10.6 seconds, range = -32.3 to 92.0, P < 0.001, Wilcoxon signed-rank test) and SUN (median improvement = 2.4 seconds, range= -8.0 to 15.1, P = 0.001, Wilcoxon signed-rank test). Age was a predictor of best baseline times, with longer (worse) times for younger participants for MULES (P < 0.001, rs = -0.67) and SUN (P < 0.001, rs = -0.54 Spearman rank correlation). Degrees of learning effect did not vary with age (P > 0.05, rs = -0.2). CONCLUSIONS: Vision-based RAN tasks, such as the MULES and SUN, can be feasibly administered using the MICK app during preseason baseline testing in youth sports teams. The results suggest that more frequent baseline tests are necessary for preadolescent athletes because of the relation of RAN task performance to age.

Testing the Validity and Reliability of a Standardized Virtual Examination for Concussion.

Background and Objectives: We determined inter-modality (in-person vs telemedicine examination) and inter-rater agreement for telemedicine assessments (2 different examiners) using the Telemedicine Buffalo Concussion Physical Examination (Tele-BCPE), a standardized concussion examination designed for remote use. Methods: Patients referred for an initial evaluation for concussion were invited to participate. Participants had a brief initial assessment by the treating neurologist. After a patient granted informed consent to participate in the study, the treating neurologist obtained a concussion-related history before leaving the examination room. Using the Tele-BCPE, 2 virtual examinations in no specific sequence were then performed from nearby rooms by the treating neurologist and another neurologist. After the 2 telemedicine examinations, the treating physician returned to the examination room to perform the in-person examination. Intraclass correlation coefficients (ICC) determined inter-modality validity (in-person vs remote examination by the same examiner) and inter-rater reliability (between remote examinations done by 2 examiners) of overall scores of the Tele-BCPE within the comparison datasets. Cohen's kappa, κ, measured levels of agreement of dichotomous ratings (abnormality present vs absent) on individual components of the Tele-BCPE to determine inter-modality and inter-rater agreement. Results: For total scores of the Tele-BCPE, both inter-modality agreement (ICC = 0.95 [95% CI 0.86-0.98, p < 0.001]) and inter-rater agreement (ICC = 0.88 [95% CI 0.71-0.95, p < 0.001]) were reliable (ICC >0.70). There was at least substantial inter-modality agreement (κ ≥ 0.61) for 25 of 29 examination elements. For inter-rater agreement (2 telemedicine examinations), there was at least substantial agreement for 8 of 29 examination elements. Discussion: Our study demonstrates that the Tele-BCPE yielded consistent clinical results, whether conducted in-person or virtually by the same examiner, or when performed virtually by 2 different examiners. The Tele-BCPE is a valid indicator of neurologic examination findings as determined by an in-person concussion assessment. The Tele-BCPE may also be performed with excellent levels of reliability by neurologists with different training and backgrounds in the virtual setting. These findings suggest that a combination of in-person and telemedicine modalities, or involvement of 2 telemedicine examiners for the same patient, can provide consistent concussion assessments across the continuum of care.

Obesity-associated epigenetic alterations and the obesity-breast cancer axis.

Both breast cancer and obesity can regulate epigenetic changes or be regulated by epigenetic changes. Due to the well-established link between obesity and an increased risk of developing breast cancer, understanding how obesity-mediated epigenetic changes affect breast cancer pathogenesis is critical. Researchers have described how obesity and breast cancer modulate the epigenome individually and synergistically. In this review, the epigenetic alterations that occur in obesity, including DNA methylation, histone, and chromatin modification, accelerated epigenetic age, carcinogenesis, metastasis, and tumor microenvironment modulation, are discussed. Delineating the relationship between obesity and epigenetic regulation is vital to furthering our understanding of breast cancer pathogenesis.

Measuring and understanding "quality of life" among emerging adults in a substance use program.

OBJECTIVE: This work focuses on understanding quality of life and evaluating a brief quality of life measure in an outpatient emerging adult (17-25 years of age) substance use program. METHOD: Mixed methods were used including: (a) psychometric evaluation of the adapted MyLifeTracker (MLT) based on assessments completed four times throughout treatment (n = 100) and (b) qualitative interviews with 12 emerging adults in the program. The study was codesigned, cofacilitated, and cointerpreted with emerging adults with lived experience. RESULTS: At intake, emerging adults reported quality of life scores of 3.7/10 on average and significantly improved (change M = 2.1 points, d = 0.86, p < .001) at the ∼12-week follow-up demonstrating program effects and sensitivity to change. Factor analysis suggested unidimensionality of the measure and internal consistency was high (ω = 0.81). MLT scores correlated in expected directions with other measures of quality of life, functioning, and mental health symptoms and demonstrated incremental validity in explaining variability in these measures over and above World Health Organization quality of life items. Emerging adults thought the five items (i.e., general well-being, day-to-day activities, relationships with friends, relationships with family, coping) generally captured the most important aspects of quality of life to them and had positive impressions regarding the use of this measure for measurement-based care. Other important aspects of quality of life included feeling a sense of meaning, purpose, motivation, and independence. CONCLUSION: Overall, the MLT demonstrated evidence of psychometric and content validity among emerging adults in substance use treatment. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Spastic Paraplegia Type 7-Associated Optic Neuropathy: A Case Series.

BACKGROUND: Hereditary optic neuropathies comprise a group of clinically and genetically heterogeneous disorders. Optic neuropathy has been previously reported in families with spastic paraplegia type 7 (SPG7) gene mutations. However, the typical time course and clinical presentation of SPG7-associated optic neuropathy is poorly understood. We report a series of 5 patients harboring pathogenic SPG7 mutations who originally presented to a neuro-ophthalmology clinic with symptoms of optic neuropathy. METHODS: Retrospective case series of 5 patients with pathogenic SPG7 mutations and optic atrophy from 3 neuro-ophthalmology clinics. Demographic, clinical, diagnostic, and treatment data were collected and reported by the clinician authors. RESULTS: Five patients ranging in age from 8 to 48 years were evaluated in the neuro-ophthalmology clinic. Although there were variable clinical presentations for each subject, all noted progressive vision loss, typically bilateral, and several also had previous diagnoses of peripheral neuropathy (e.g., Guillain-Barré Syndrome). Patients underwent neuro-ophthalmic examinations and testing with visual fields and optic coherence tomography of the retinal nerve fiber layer. Genetic testing revealed pathogenic variants in the SPG7 gene. CONCLUSIONS: Five patients presented to the neuro-ophthalmology clinic with progressive vision loss and were diagnosed with optic atrophy. Although each patient harbored an SPG7 mutation, this cohort was phenotypically and genotypically heterogeneous. Three patients carried the Ala510Val variant. The patients demonstrated varying degrees of visual acuity and visual field loss, although evaluations were completed during different stages of disease progression. Four patients had a previous diagnosis of peripheral neuropathy. This raises the prospect that a single pathogenic variant of SPG7 may be associated with peripheral neuropathy in addition to optic neuropathy. These results support the consideration of SPG7 testing in patients with high suspicion for genetic optic neuropathy, as manifested by symmetric papillomacular bundle damage without clear etiology on initial workup. Applied judiciously, genetic testing, including for SPG7, may help clarify the cause of unexplained progressive optic neuropathies.

Genomic analysis reveals HDAC1 regulates clinically relevant transcriptional programs in Pancreatic cancer.

Novel strategies are needed to combat multidrug resistance in pancreatic ductal adenocarcinoma (PDAC). We applied genomic approaches to understand mechanisms of resistance in order to better inform treatment and precision medicine. Altered function of chromatin remodeling complexes contribute to chemoresistance. Our study generates and analyzes genomic and biochemical data from PDAC cells overexpressing HDAC1, a histone deacetylase involved in several chromatin remodeling complexes. We characterized the impact of overexpression on drug response, gene expression, HDAC1 binding, and chromatin structure using RNA-sequencing and ChIP-sequencing for HDAC1 and H3K27 acetylation. Integrative genomic analysis shows that HDAC1 overexpression promotes activation of key resistance pathways including epithelial to mesenchymal transition, cell cycle, and apoptosis through global chromatin remodeling. Target genes are similarly altered in patient tissues and show correlation with patient survival. We also demonstrate that direct targets of HDAC1 that also show altered chromatin are enriched near genes associated with altered GTPase activity. HDAC1 target genes identified using in vitro methods and observed in patient tissues were used to develop a clinically relevant nine-transcript signature associated with patient prognosis. Integration of multiple genomic and biochemical data types enables understanding of multidrug resistance and tumorigenesis in PDAC, a disease in desperate need of novel treatment strategies.

Myeloid Heterogeneity Mediates Acute Exacerbations of Pulmonary Fibrosis.

Epidemiological evidence indicates that exposure to particulate matter is linked to the development of idiopathic pulmonary fibrosis (IPF) and increases the incidence of acute exacerbations of IPF. In addition to accelerating the rate of lung function decline, exposure to fine particulate matter (particulate matter smaller than 2.5 µm [PM2.5]) is a risk factor for increased mortality in subjects with IPF. In this article, we show that exposure to PM2.5 mediates monocyte recruitment and fibrotic progression in mice with established fibrosis. In mice with established fibrosis, bronchoalveolar lavage cells showed monocyte/macrophage heterogeneity after exposure to PM2.5. These cells had a significant inflammatory and anti-inflammatory signature. The mixed heterogeneity of cells contributed to the proinflammatory and anti-inflammatory response. Although monocyte-derived macrophages were recruited to the lung in bleomycin-injured mice treated with PM2.5, recruitment of monocytes expressing Ly6Chi to the lung promoted progression of fibrosis, reduced lung aeration on computed tomography, and impacted lung compliance. Ly6Chi monocytes isolated from PM2.5-exposed fibrotic mice showed enhanced expression of proinflammatory markers compared with fibrotic mice exposed to vehicle. Moreover, IPF bronchoalveolar lavage cells treated ex vivo with PM2.5 showed an exaggerated inflammatory response. Targeting Ly6Chi monocyte recruitment inhibited fibrotic progression in mice. Moreover, the adoptive transfer of Ly6Chi monocytes exacerbated established fibrosis. These observations suggest that enhanced recruitment of Ly6Chi monocytes with a proinflammatory phenotype mediates acute exacerbations of pulmonary fibrosis, and targeting these cells may provide a potential novel therapeutic target to protect against acute exacerbations of IPF.

Measurements of neutrino oscillation parameters from the T2K experiment using 3.6×1021 protons on target.

The T2K experiment presents new measurements of neutrino oscillation parameters using 19.7(16.3)×1020 protons on target (POT) in (anti-)neutrino mode at the far detector (FD). Compared to the previous analysis, an additional 4.7×1020 POT neutrino data was collected at the FD. Significant improvements were made to the analysis methodology, with the near-detector analysis introducing new selections and using more than double the data. Additionally, this is the first T2K oscillation analysis to use NA61/SHINE data on a replica of the T2K target to tune the neutrino flux model, and the neutrino interaction model was improved to include new nuclear effects and calculations. Frequentist and Bayesian analyses are presented, including results on sin2θ13 and the impact of priors on the δCP measurement. Both analyses prefer the normal mass ordering and upper octant of sin2θ23 with a nearly maximally CP-violating phase. Assuming the normal ordering and using the constraint on sin2θ13 from reactors, sin2θ23=0.561-0.032+0.021 using Feldman-Cousins corrected intervals, and Δm322=2.494-0.058+0.041×10-3eV2 using constant Δχ2 intervals. The CP-violating phase is constrained to δCP=-1.97-0.70+0.97 using Feldman-Cousins corrected intervals, and δCP=0,π is excluded at more than 90% confidence level. A Jarlskog invariant of zero is excluded at more than 2σ credible level using a flat prior in δCP, and just below 2σ using a flat prior in sinδCP. When the external constraint on sin2θ13 is removed, sin2θ13=28.0-6.5+2.8×10-3, in agreement with measurements from reactor experiments. These results are consistent with previous T2K analyses.

Hands-Free Analytical Urine Testing Technology Validated for Drug-Facilitated Crime Investigations.

Forensic laboratories need quick and simple technology to improve turnaround times, while delivering reliable results. The goal of this study is first to create a simplified workflow to meet new Academy Standards Board requirements for urine testing in drug-facilitated crime investigations and, second, to create "ready-to-go", "hands-free" testing technology to further streamline analytical procedures. A first of its kind, the ToxBox forensic test kit is used to validate a single analytical procedure for opioids, benzodiazepines, cannabinoids, antidepressants, and several other drug classes. Method performance indicators follow accreditation requirements and include accuracy, precision, measurement uncertainty, calibration models, reportable range, sensitivity, specificity, carryover, interference, ion suppression/enhancement, and analyte stability. "Hands-free" testing platforms require the use of new suspended-state technology to stabilize NIST-traceable standards premanufactured at precise concentrations in the presence of sample preparation reagents. By suspending all reaction components in the solid state, with air gaps between the phases, reference standards and process controls are built in a "ready-to-go" format and stabilized for long-term storage in the presence of a sample matrix, ß-d-glucuronidase, and enzymatic buffers. "Hands-free" test kits are removed from storage, incubated at either ambient temperature or 60 °C, and assayed using validated methods. This is the first example of how complex forensic testing workflows can be streamlined with new "hands-free" testing strategies to meet analytical challenges associated with quantitative and confirmatory analyses.

Vegetative fragment production as a means of propagule dispersal for tropical seagrass meadows.

BACKGROUND AND AIMS: Long distance dispersal (LDD) contributes to the replenishment and recovery of tropical seagrass habitats exposed to disturbance, such as cyclones and infrastructure development. However, our current knowledge regarding the physical attributes of seagrass fragments that influence LDD predominantly stems from temperate species and regions. The goal of this paper is to measure seagrass fragment density and viability in two tropical species, assessing various factors influencing their distribution. METHODS: We measured the density and viability of floating seagrass fragments for two tropical seagrass species (Zostera muelleri and Halodule uninervis) in two coastal seagrass meadows in the central Great Barrier Reef World Heritage Area, Australia. We assessed the effect of wind speed, wind direction, seagrass growing/senescent season, seagrass meadow density, meadow location and dugong foraging intensity on fragment density. We also measured seagrass fragment structure and fragment viability; i.e., potential to establish into a new plant. KEY RESULTS: We found that seagrass meadow density, season, wind direction and wind speed influenced total fragment density, while season and wind speed influenced the density of viable fragments. Dugong foraging intensity did not influence fragment density. Our results indicate that wave action from winds combined with high seagrass meadow density increases seagrass fragment creation, and that more fragments are produced during the growing than the senescent season. Seagrass fragments classified as viable for Z. muelleri and H. uninervis had significantly more shoots and leaves than non-viable fragments. We collected 0.63 (±0.08 SE) floating viable fragments 100 m-2 in the growing season, and 0.13 (±0.03 SE) viable fragments 100 m-2 in the senescent season. Over a third (38%) of all fragments collected were viable. CONCLUSION: There is likely to be a large number of viable seagrass fragments available for long distance dispersal. This study's outputs can inform dispersal and connectivity models that are used to direct seagrass ecosystem management and conservation strategies.

Precision Concussion Management: Approaches to Quantifying Head Injury Severity and Recovery.

Mitigating the substantial public health impact of concussion is a particularly difficult challenge. This is partly because concussion is a highly prevalent condition, and diagnosis is predominantly symptom-based. Much of contemporary concussion management relies on symptom interpretation and accurate reporting by patients. These types of reports may be influenced by a variety of factors for each individual, such as preexisting mental health conditions, headache disorders, and sleep conditions, among other factors. This can all be contributory to non-specific and potentially misleading clinical manifestations in the aftermath of a concussion. This review aimed to conduct an examination of the existing literature on emerging approaches for objectively evaluating potential concussion, as well as to highlight current gaps in understanding where further research is necessary. Objective assessments of visual and ocular motor concussion symptoms, specialized imaging techniques, and tissue-based concentrations of specific biomarkers have all shown promise for specifically characterizing diffuse brain injuries, and will be important to the future of concussion diagnosis and management. The consolidation of these approaches into a comprehensive examination progression will be the next horizon for increased precision in concussion diagnosis and treatment.

Initial insights from a quality improvement initiative to develop an evidence-informed young adult substance use program.

High rates of substance misuse during emerging adulthood (~17-25 years of age, also referred to as young adulthood) require developmentally appropriate clinical programs. This article outlines: 1) the development of an evidence-informed young adult outpatient substance use program that takes a biopsychosocial patient-centred approach to care; 2) a quality improvement process and protocol; and 3) the patient characteristics of an initial cohort. Literature reviews, program reviews, environmental scans, and consultations with interested parties (including individuals with lived expertise) were used to develop the program. A 12-week measurement-based care program was developed comprising: 1) individual measurement-based care and motivational enhancement therapy sessions; 2) group programming focused on cognitive behavioural therapy, mindfulness, distress tolerance, and emotional regulation; 3) clinical consultations for diagnostic clarification and/or medication review; and 4) an independent Community Reinforcement Approach Family Training (CRAFT) group for loved ones. A measurement system was concurrently created to collect clinical and program evaluation data at six time points. In the first 21 months of the program, 152 young adults enrolled in the program (mean age = 21 years old, 47% female gender) primarily reporting treatment targets of cannabis (68%) and alcohol (63%) and almost all presenting with co-occurring mental health concerns (95%). The initial cohort who completed the program showed symptom improvements. Collectively, the program demonstrates the feasibility of developing an evidence-informed young adult substance use program using measurement-based care, but also the need for flexibility and ongoing monitoring to meet local needs.

Des taux élevés d'abus de substances durant la vie d'adulte émergente (~17­25 ans d'âge, aussi nommé jeune âge adulte) nécessitent des programmes cliniques appropriés au développement. Cet article présente: 1) le développement d'un programme fondé sur des données probantes sur l'utilisation de substances des jeunes patients ambulatoires qui adopte une approche biopsychosociale axée sur les patients; 2) un processus et un protocole d'amélioration de la qualité; et 3) les caractéristiques du patient d'une cohorte initiale. Les revues de la littérature, les examens de programme, les analyses de l'environnement, et les consultations avec les parties intéressées (notamment les personnes ayant une expertise vécue) ont servi à élaborer le programme. Un programme de soins de 12 semaines basés sur la mesure a été élaboré qui comprend: 1) ides soins individuels basés sur la mesure et des séances de thérapie d'amélioration de la motivation; 2) une programmation de groupe axée sur la thérapie cognitivo-comportementale, la pleine conscience, la tolérance à la détresse, et la régulation émotionnelle; 3) les consultations cliniques pour la clarification du diagnostic et/ou la revue des médicaments; et (4) un groupe indépendant d'Approche de renforcement communautaire Formation familiale (ARCFF) pour les êtres chers. Un système de mesure a été créé simultanément pour recueillir les données cliniques et d'évaluation du programme à six points dans le temps. Dans les 21 premiers mois du programme, 152 jeunes adultes s'y sont inscrits (âge moyen = 21 ans, 47 % de sexe féminin) et déclaraient principalement que les cibles du traitement étaient le cannabis (68 %) et l'alcool (63 %) et presque tous présentaient des problèmes de santé mentale co-occurrents (95 %). La cohorte initiale qui a terminé le programme présentait des améliorations des symptômes. Collectivement, le programme démontre la faisabilité de développer un programme d'utilisation de substances pour jeunes adultes fondé sur des données probantes et utilisant des soins basés sur la mesure, mais également le besoin de flexibilité et de surveillance constante pour répondre aux besoins locaux.

Mother knows best: nest-site choice homogenizes embryo thermal environments among populations in a widespread ectotherm.

Species with large geographical ranges provide an excellent model for studying how different populations respond to dissimilar local conditions, particularly with respect to variation in climate. Maternal effects, such as nest-site choice greatly affect offspring phenotypes and survival. Thus, maternal behaviour has the potential to mitigate the effects of divergent climatic conditions across a species' range. We delineated natural nesting areas of six populations of painted turtles (Chrysemys picta) that span a broad latitudinal range and quantified spatial and temporal variation in nest characteristics. To quantify microhabitats available for females to choose, we also identified sites within the nesting area of each location that were representative of available thermal microhabitats. Across the range, females nested non-randomly and targeted microhabitats that generally had less canopy cover and thus higher nest temperatures. Nest microhabitats differed among locations but did not predictably vary with latitude or historic mean air temperature during embryonic development. In conjunction with other studies of these populations, our results suggest that nest-site choice is homogenizing nest environments, which buffers embryos from thermally induced selection and could slow embryonic evolution. Thus, although effective at a macroclimatic scale, nest-site choice is unlikely to compensate for novel stressors that rapidly increase local temperatures. This article is part of the theme issue 'The evolutionary ecology of nests: a cross-taxon approach'.

Contributions of rare and common variation to early-onset and atypical dementia risk.

We collected and analyzed genomic sequencing data from individuals with clinician-diagnosed early-onset or atypical dementia. Thirty-two patients were previously described, with 68 newly described in this report. Of those 68, 62 patients self-reported white, non-Hispanic ethnicity and 6 reported as African-American, non-Hispanic. Fifty-three percent of patients had a returnable variant. Five patients harbored a pathogenic variant as defined by the American College of Medical Genetics criteria for pathogenicity. A polygenic risk score (PRS) was calculated for Alzheimer's patients in the total cohort and compared to the scores of a late-onset Alzheimer's cohort and a control set. Patients with early-onset Alzheimer's had higher non-APOE PRSs than patients with late-onset Alzheimer's, supporting the conclusion that both rare and common genetic variation associate with early-onset neurodegenerative disease risk.

Transcriptomic and functional analysis of ANGPTL4 overexpression in pancreatic cancer nominates targets that reverse chemoresistance.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers based on five-year survival rates. Genes contributing to chemoresistance represent novel therapeutic targets that can improve treatment response. Increased expression of ANGPTL4 in tumors correlates with poor outcomes in pancreatic cancer. METHODS: We used statistical analysis of publicly available gene expression data (TCGA-PAAD) to test whether expression of ANGPTL4 and its downstream targets, ITGB4 and APOL1, were correlated with patient survival. We measured the impact of ANGPTL4 overexpression in a common pancreatic cancer cell line, MIA PaCa-2 cells, using CRISPRa for overexpression and DsiRNA for knockdown. We characterized global gene expression changes associated with high levels of ANGPTL4 and response to gemcitabine treatment using RNA-sequencing. Gemcitabine dose response curves were calculated on modified cell lines by measuring cell viability with CellTiter-Glo (Promega). Impacts on cell migration were measured using a time course scratch assay. RESULTS: We show that ANGPTL4 overexpression leads to in vitro resistance to gemcitabine and reduced survival times in patients. Overexpression of ANGPTL4 induces transcriptional signatures of tumor invasion and metastasis, proliferation and differentiation, and inhibition of apoptosis. Analyses revealed an overlapping signature of genes associated with both ANGPTL4 activation and gemcitabine response. Increased expression of the genes in this signature in patient PDAC tissues was significantly associated with shorter patient survival. We identified 42 genes that were both co-regulated with ANGPTL4 and were responsive to gemcitabine treatment. ITGB4 and APOL1 were among these genes. Knockdown of either of these genes in cell lines overexpressing ANGPTL4 reversed the observed gemcitabine resistance and inhibited cellular migration associated with epithelial to mesenchymal transition (EMT) and ANGPTL4 overexpression. CONCLUSIONS: These data suggest that ANGPTL4 promotes EMT and regulates the genes APOL1 and ITGB4. Importantly, we show that inhibition of both targets reverses chemoresistance and decreases migratory potential. Our findings have revealed a novel pathway regulating tumor response to treatment and suggest relevant therapeutic targets in pancreatic cancer.

Modeling the innate inflammatory cGAS/STING pathway: sexually dimorphic effects on microglia and cognition in obesity and prediabetes.

Introduction: The prevalence of obesity, prediabetes, and diabetes continues to grow worldwide. These metabolic dysfunctions predispose individuals to neurodegenerative diseases and cognitive impairment, including dementias such as Alzheimer's disease and Alzheimer's disease related dementias (AD/ADRD). The innate inflammatory cGAS/STING pathway plays a pivotal role in metabolic dysfunction and is an emerging target of interest in multiple neurodegenerative diseases, including AD/ADRD. Therefore, our goal was to establish a murine model to specifically target the cGAS/STING pathway to study obesity- and prediabetes-induced cognitive impairment. Methods: We performed two pilot studies in cGAS knockout (cGAS-/-) male and female mice designed to characterize basic metabolic and inflammatory phenotypes and examine the impact of high-fat diet (HFD) on metabolic, inflammatory, and cognitive parameters. Results: cGAS-/- mice displayed normal metabolic profiles and retained the ability to respond to inflammatory stimuli, as indicated by an increase in plasma inflammatory cytokine production in response to lipopolysaccharide injection. HFD feeding caused expected increases in body weight and decreases in glucose tolerance, although onset was accelerated in females versus males. While HFD did not increase plasma or hippocampal inflammatory cytokine production, it did alter microglial morphology to a state indicative of activation, particularly in female cGAS-/- mice. However, HFD negatively impacted cognitive outcomes in male, but not female animals. Discussion: Collectively, these results suggest that cGAS-/- mice display sexually dimorphic responses to HFD, possibly based on differences in microglial morphology and cognition.

NOX4-TIM23 interaction regulates NOX4 mitochondrial import and metabolic reprogramming.

Pulmonary fibrosis is a progressive lung disease characterized by macrophage activation. Asbestos-induced expression of nicotinamide adenine dinucleotide phosphate hydrogen oxidase 4 (NOX4) in lung macrophages mediates fibrotic progression by the generation of mitochondrial reactive oxygen species (ROS), modulating mitochondrial biogenesis, and promoting apoptosis resistance; however, the mechanism(s) by which NOX4 localizes to mitochondria during fibrosis is not known. Here, we show that NOX4 localized to the mitochondrial matrix following asbestos exposure in lung macrophages via direct interaction with TIM23. TIM23 and NOX4 interaction was found in lung macrophages from human subjects with asbestosis, while it was absent in mice harboring a conditional deletion of NOX4 in lung macrophages. This interaction was localized to the proximal transmembrane region of NOX4. Mechanistically, TIM23 augmented NOX4-induced mitochondrial ROS and metabolic reprogramming to oxidative phosphorylation. Silencing TIM23 decreased mitochondrial ROS and oxidative phosphorylation. These observations highlight the important role of the mitochondrial translocase TIM23 interaction with NOX4. Moreover, this interaction is required for mitochondrial redox signaling and metabolic reprogramming in lung macrophages.

Impaired PPARγ activation by cadmium exacerbates infection-induced lung injury.

Emerging data indicate an association between environmental heavy metal exposure and lung disease, including lower respiratory tract infections (LRTIs). Here, we show by single-cell RNA sequencing an increase in Pparg gene expression in lung macrophages from mice exposed to cadmium and/or infected with Streptococcus pneumoniae. However, the heavy metal cadmium or infection mediated an inhibitory posttranslational modification of peroxisome proliferator-activated receptor γ (PPARγ) to exacerbate LRTIs. Cadmium and infection increased ERK activation to regulate PPARγ degradation in monocyte-derived macrophages. Mice harboring a conditional deletion of Pparg in monocyte-derived macrophages had more severe S. pneumoniae infection after cadmium exposure, showed greater lung injury, and had increased mortality. Inhibition of ERK activation with BVD-523 protected mice from lung injury after cadmium exposure or infection. Moreover, individuals residing in areas of high air cadmium levels had increased cadmium concentration in their bronchoalveolar lavage (BAL) fluid, increased barrier dysfunction, and showed PPARγ inhibition that was mediated, at least in part, by ERK activation in isolated BAL cells. These observations suggest that impaired activation of PPARγ in monocyte-derived macrophages exacerbates lung injury and the severity of LRTIs.