Exploration of the tumorigenic, metabolic, and cognitive consequences of tau protein removal

Background: Tau accumulation causes tauopathies and drives cellular senescence, which can lead to inflammation, neurodegeneration, and cognitive impairment. The association between intracellular tau deposition and pathogenesis has prompted therapeutic strategies that reduce tau expression. However, tau is also critical in microtubule stabilization, synaptic plasticity, and maintaining DNA integrity. We investigated the impact of tau removal on brain cell senescence and associated neurocognitive behaviors in aged tau knockout (Mapt0/0) and wild type control (Mapt+/+) mice. We also assessed physical, metabolic, histological, and biochemical outcomes in Mapt0/0 and Mapt+/+ mice and in response to high fat diet (HFD), a stressor that drives DNA damage. Method: 20-month-old female Mapt0/0 and Mapt+/+ mice were subjected to the Elevated Plus Maze to assess anxiety-like behavior. Mice were then fed control (CTL) or HFD (60% kcal fat) for 9 weeks. Behavioral and physical measures were then assessed, and brain tissue was further analyzed via gene expression, biochemistry, and histological assays. Result: Tau knockout and HFD, separately and additively, caused weight gain and insulin resistance. Removing tau primed cells to proliferate, as Mapt0/0 mice had increased body size, organ size, and tumor burden compared to Mapt+/+. We observed no difference in senescence between genotypes on CTL diet. The HFD increased senescence only in Mapt+/+ mice, whereas Mapt0/0 mice displayed increased tumor burden. Mapt0/0 mice displayed anxiety- and depressive-like behaviors on both diets. Transcriptomic and protein expression data revealed that several molecules responded similarly to tau removal and HFD exposure, but Mapt+/+ and Mapt0/0 mice responded differently to HFD. Genotype differences in DNA damage and cell cycle dysregulation were also observed. Conclusion: Mapt0/0 mice did not accumulate senescent cells but demonstrated anxiety-like behaviors in the presence of elevated DNA damage; thus tau knockout may drive neuropsychiatric phenotypes which can be dissociated from obesity and senescence. Mapt0/0 mice also developed tumors, suggesting that tau plays a critical role in cell fate decisions, including senescence versus cancer. Overall, we found that tau removal prevents senescent cell accumulation with the tradeoff of tumorigenic, metabolic, and cognitive consequences. We caution against removing tau until a better understanding of its physiological roles are defined

Predictive Screening of M1 and M2 Macrophages Reveals the Immunomodulatory Effectiveness of Post Spinal Cord Injury Azithromycin Treatment

Spinal cord injury (SCI) triggers a heterogeneous macrophage response that when experimentally polarized toward alternative forms of activation (M2 macrophages) promotes tissue and functional recovery. There are limited pharmacological therapies that can drive this reparative inflammatory state. In the current study, we used in vitrosystems to comprehensively defined markers of macrophages with known pathological (M1) and reparative (M2) properties in SCI. We then used these markers to objectively define the macrophage activation states after SCI in response to delayed azithromycin treatment. Mice were subjected to moderate-severe thoracic contusion SCI. Azithromycin or vehicle was administered beginning 30 minutes post-SCI and then daily for 3 or 7 days post injury (dpi). We detected a dose-dependent polarization toward purportedly protective M2 macrophages with daily AZM treatment. Specifically, AZM doses of 10, 40, or 160 mg/kg decreased M1 macrophage gene expression at 3 dpi while the lowest (10 mg/kg) and highest (160 mg/kg) doses increased M2 macrophage gene expression at 7 dpi. Azithromycin has documented immunomodulatory properties and is commonly prescribed to treat infections in SCI individuals. This work demonstrates the utility of objective, comprehensive macrophage gene profiling for evaluating immunomodulatory SCI therapies and highlights azithromycin as a promising agent for SCI treatment

Mouse cytomegalovirus-experienced ILC1s acquire a memory response dependent on the viral glycoprotein m12.

Innate lymphoid cells (ILCs) are tissue-resident sentinels that are essential for early host protection from pathogens at initial sites of infection. However, whether pathogen-derived antigens directly modulate the responses of tissue-resident ILCs has remained unclear. In the present study, it was found that liver-resident type 1 ILCs (ILC1s) expanded locally and persisted after the resolution of infection with mouse cytomegalovirus (MCMV). ILC1s acquired stable transcriptional, epigenetic and phenotypic changes a month after the resolution of MCMV infection, and showed an enhanced protective effector response to secondary challenge with MCMV consistent with a memory lymphocyte response. Memory ILC1 responses were dependent on the MCMV-encoded glycoprotein m12, and were independent of bystander activation by proinflammatory cytokines after heterologous infection. Thus, liver ILC1s acquire adaptive features in an MCMV-specific manner

Azithromycin Drives Alternative Macrophage Activation and Improves Recovery and Tissue Sparing in Contusion Spinal Cord Injury

BACKGROUND: Macrophages persist indefinitely at sites of spinal cord injury (SCI) and contribute to both pathological and reparative processes. While the alternative, anti-inflammatory (M2) phenotype is believed to promote cell protection, regeneration, and plasticity, pro-inflammatory (M1) macrophages persist after SCI and contribute to protracted cell and tissue loss. Thus, identifying non-invasive, clinically viable, pharmacological therapies for altering macrophage phenotype is a challenging, yet promising, approach for treating SCI. Azithromycin (AZM), a commonly used macrolide antibiotic, drives anti-inflammatory macrophage activation in rodent models of inflammation and in humans with cystic fibrosis. METHODS: We hypothesized that AZM treatment can alter the macrophage response to SCI and reduce progressive tissue pathology. To test this hypothesis, mice (C57BL/6J, 3-month-old) received daily doses of AZM (160 mg/kg) or vehicle treatment via oral gavage for 3 days prior and up to 7 days after a moderate-severe thoracic contusion SCI (75-kdyn force injury). Fluorescent-activated cell sorting was used in combination with real-time PCR (rtPCR) to evaluate the disposition and activation status of microglia, monocytes, and neutrophils, as well as macrophage phenotype in response to AZM treatment. An open-field locomotor rating scale (Basso Mouse Scale) and gridwalk task were used to determine the effects of AZM treatment on SCI recovery. Bone marrow-derived macrophages (BMDMs) were used to determine the effect of AZM treatment on macrophage phenotype in vitro. RESULTS: In accordance with our hypothesis, SCI mice exhibited significantly increased anti-inflammatory and decreased pro-inflammatory macrophage activation in response to AZM treatment. In addition, AZM treatment led to improved tissue sparing and recovery of gross and coordinated locomotor function. Furthermore, AZM treatment altered macrophage phenotype in vitro and lowered the neurotoxic potential of pro-inflammatory, M1 macrophages. CONCLUSIONS: Taken together, these data suggest that pharmacologically intervening with AZM can alter SCI macrophage polarization toward a beneficial phenotype that, in turn, may potentially limit secondary injury processes. Given that pro-inflammatory macrophage activation is a hallmark of many neurological pathologies and that AZM is non-invasive and clinically viable, these data highlight a novel approach for treating SCI and other maladaptive neuroinflammatory conditions

Not Only How Much but How: The Importance of Diversifying Funding Streams in a Reimagined Public Health System

Revenue diversification may be a synergistic strategy for transforming public health, yet few national or trend data are available. This study quantified and identified patterns in revenue diversification in public health before and during the COVID-19 pandemic. We used National Association of County and City Health Officials’ National Profile of Local Health Departments study data for 2013, 2016, 2019, and 2022 to calculate a yearly diversification index for local health departments. Respondents’ revenue portfolios changed fairly little between 2016 and 2022. Compared with less-diversified local health departments, well-diversified departments reported a balanced portfolio with local, state, federal, and clinical sources of revenue and higher per capita revenues. Less-diversified local health departments relied heavily on local sources and saw lower revenues. The COVID-19 period exacerbated these differences, with less-diversified departments seeing little revenue growth from 2019 to 2022. Revenue portfolios are an underexamined aspect of the public health system, and this study suggests that some organizations may be under financial strain by not having diverse revenue portfolios. Practitioners have ways of enhancing diversification, and policy attention is needed to incentivize and support revenue diversification to enhance the financial resilience and sustainability of local health departments

Revisiting experimental methods for studies of acidity-dependent ocean sound absorption

Author Posting. © Acoustical Society of America, 2009. This article is posted here by permission of Acoustical Society of America for personal use, not for redistribution. The definitive version was published in Journal of the Acoustical Society of America 125 (2009): 1971-1981, doi:10.1121/1.3089591.The practical usefulness of long-range acoustic measurements of ocean acidity-linked sound absorption is analyzed. There are two applications: Determining spatially-averaged pH via absorption measurement and verifying absorption effects in an area of known pH. The method is a differential-attenuation technique, with the difference taken across frequency. Measurement performance versus mean frequency and range is examined. It is found that frequencies below 500 Hz are optimal. These are lower than the frequency where the measurement would be most sensitive in the absence of noise and signal fluctuation (scintillation). However, attenuation serves to reduce signal-to-noise ratio with increasing distance and frequency, improving performance potential at lower frequencies. Use of low frequency allows longer paths to be used, with potentially better spatial averaging. Averaging intervals required for detection of fluctuations or trends with the required precision are computed

High-frequency acoustic scattering from turbulent oceanic microstructure : the importance of density fluctuations

Author Posting. © Acoustical Society of America, 2003. This article is posted here by permission of Acoustical Society of America for personal use, not for redistribution. The definitive version was published in Journal of the Acoustical Society of America 114 (2003): 2685-2697, doi:10.1121/1.1614258.Acoustic scattering techniques provide a unique and powerful tool to remotely investigate the physical properties of the ocean interior over large spatial and temporal scales. With high-frequency acoustic scattering it is possible to probe physical processes that occur at the microstructure scale, spanning submillimeter to centimeter scale processes. An acoustic scattering model for turbulent oceanic microstructure is presented in which the current theory, which only accounts for fluctuations in the sound speed, has been extended to include fluctuations in the density as well. The inclusion of density fluctuations results in an expression for the scattering cross section per unit volume, σv, that is explicitly dependent on the scattering angle. By relating the variability in the density and sound speed to random fluctuations in oceanic temperature and salinity, σv has been expressed in terms of the temperature and salinity wave number spectra, and the temperature-salinity co-spectrum. A Batchelor spectrum for temperature and salinity, which depends on parameters such as the dissipation rates of turbulent kinetic energy and temperature variance, has been used to evaluate σv. Two models for the temperature-salinity co-spectrum have also been used. The predictions indicate that fluctuations in the density could be as important in determining backscattering as fluctuations in the sound speed. Using data obtained in the ocean with a high resolution vertical microstructure profiler, it is predicted that scattering from oceanic microstructure can be as strong as scattering from zooplankton.This work was supported in part by ONR, NSF, and the Woods Hole Oceanographic Institution

Mutation in the Gene Encoding Ubiquitin Ligase LRSAM1 in Patients with Charcot-Marie-Tooth Disease

Charcot-Marie-Tooth disease (CMT) represents a family of related sensorimotor neuropathies. We studied a large family from a rural eastern Canadian community, with multiple individuals suffering from a condition clinically most similar to autosomal recessive axonal CMT, or AR-CMT2. Homozygosity mapping with high-density SNP genotyping of six affected individuals from the family excluded 23 known genes for various subtypes of CMT and instead identified a single homozygous region on chromosome 9, at 122,423,730–129,841,977 Mbp, shared identical by state in all six affected individuals. A homozygous pathogenic variant was identified in the gene encoding leucine rich repeat and sterile alpha motif 1 (LRSAM1) by direct DNA sequencing of genes within the region in affected DNA samples. The single nucleotide change mutates an intronic consensus acceptor splicing site from AG to AA. Direct analysis of RNA from patient blood demonstrated aberrant splicing of the affected exon, causing an obligatory frameshift and premature truncation of the protein. Western blotting of immortalized cells from a homozygous patient showed complete absence of detectable protein, consistent with the splice site defect. LRSAM1 plays a role in membrane vesicle fusion during viral maturation and for proper adhesion of neuronal cells in culture. Other ubiquitin ligases play documented roles in neurodegenerative diseases. LRSAM1 is a strong candidate for the causal gene for the genetic disorder in our kindred

Clinical Outcomes and Patient-Matched Molecular Composition of Relapsed Medulloblastoma

PURPOSE We sought to investigate clinical outcomes of relapsed medulloblastoma and to compare molecular features between patient-matched diagnostic and relapsed tumors. METHODS Children and infants enrolled on either SJMB03 (NCT00085202) or SJYC07 (NCT00602667) trials who experienced medulloblastoma relapse were analyzed for clinical outcomes, including anatomic and temporal patterns of relapse and postrelapse survival. A largely independent, paired molecular cohort was analyzed by DNA methylation array and next-generation sequencing. RESULTS A total of 72 of 329 (22%) SJMB03 and 52 of 79 (66%) SJYC07 patients experienced relapse with significant representation of Group 3 and wingless tumors. Although most patients exhibited some distal disease (79%), 38% of patients with sonic hedgehog tumors experienced isolated local relapse. Time to relapse and postrelapse survival varied by molecular subgroup with longer latencies for patients with Group 4 tumors. Postrelapse radiation therapy among previously nonirradiated SJYC07 patients was associated with long-term survival. Reirradiation was only temporizing for SJMB03 patients. Among 127 patients with patient-matched tumor pairs, 9 (7%) experienced subsequent nonmedulloblastoma CNS malignancies. Subgroup (96%) and subtype (80%) stabilities were largely maintained among the remainder. Rare subgroup divergence was observed from Group 4 to Group 3 tumors, which is coincident with genetic alterations involving MYC, MYCN, and FBXW7. Subgroup-specific patterns of alteration were identified for driver genes and chromosome arms. CONCLUSION Clinical behavior of relapsed medulloblastoma must be contextualized in terms of up-front therapies and molecular classifications. Group 4 tumors exhibit slower biological progression. Utility of radiation at relapse is dependent on patient age and prior treatments. Degree and patterns of molecular conservation at relapse vary by subgroup. Relapse tissue enables verification of molecular targets and identification of occult secondary malignancies