MR Elastography-Based Assessment of Matrix Remodeling at Lesion Sites Associated With Clinical Severity in a Model of Multiple Sclerosis

Magnetic resonance imaging (MRI) with gadolinium based contrast agents (GBCA) is routinely used in the clinic to visualize lesions in multiple sclerosis (MS). Although GBCA reveal endothelial permeability, they fail to expose other aspects of lesion formation such as the magnitude of inflammation or tissue changes occurring at sites of blood-brain barrier (BBB) disruption. Moreover, evidence pointing to potential side effects of GBCA has been increasing. Thus, there is an urgent need to develop GBCA-independent imaging tools to monitor pathology in MS. Using MR-elastography (MRE), we previously demonstrated in both MS and the animal model experimental autoimmune encephalomyelitis (EAE) that inflammation was associated with a reduction of brain stiffness. Now, using the relapsing-remitting EAE model, we show that the cerebellum-a region with predominant inflammation in this model-is especially prone to loss of stiffness. We also demonstrate that, contrary to GBCA-MRI, reduction of brain stiffness correlates with clinical disability and is associated with enhanced expression of the extracellular matrix protein fibronectin (FN). Further, we show that FN is largely expressed by activated astrocytes at acute lesions, and reflects the magnitude of tissue remodeling at sites of BBB breakdown. Therefore, MRE could emerge as a safe tool suitable to monitor disease activity in MS

MAVS Positively Regulates Mitochondrial Integrity and Metabolic Fitness in B Cells

Activated B cells experience metabolic changes that require mitochondrial remodeling, in a process incompletely defined. In this study, we report that mitochondrial antiviral signaling protein (MAVS) is involved in BCR-initiated cellular proliferation and prolonged survival. MAVS is well known as a mitochondrial-tethered signaling adaptor with a central role in viral RNA-sensing pathways that induce type I IFN. The role of MAVS downstream of BCR stimulation was recognized in absence of IFN, indicative of a path for MAVS activation that is independent of viral infection. Mitochondria of BCR-activated MAVS-deficient mouse B cells exhibited a damaged phenotype including disrupted mitochondrial morphology, excess mitophagy, and the temporal progressive blunting of mitochondrial oxidative capacity with mitochondrial hyperpolarization and cell death. Costimulation of MAVS-deficient B cells with anti-CD40, in addition to BCR stimulation, partially corrected the mitochondrial structural defects and functionality. Our data reveal a (to our knowledge) previously unrecognized role of MAVS in controlling the metabolic fitness of B cells, most noticeable in the absence of costimulatory help. ImmunoHorizons, 2023, 7: 587–599.This work was supported by the Intramural Research Program of the National Institutes of Health/National Institute of Allergy and Infectious Diseases (to S.B), and by the National Heart, Lung, and Blood Institute (to M.N.S). J.W. was partially sponsored by The People’s Hospital of Zhejiang Province, Hangzhou, China. J.T. was partially supported by Ministry of Science and Innovation of Spain Grants RYC2018-026050-I and PID2019-105665RA-I00

Phenothiazine-mediated rescue of cognition in tau transgenic mice requires neuroprotection and reduced soluble tau burden

Abstract Background It has traditionally been thought that the pathological accumulation of tau in Alzheimer's disease and other tauopathies facilitates neurodegeneration, which in turn leads to cognitive impairment. However, recent evidence suggests that tau tangles are not the entity responsible for memory loss, rather it is an intermediate tau species that disrupts neuronal function. Thus, efforts to discover therapeutics for tauopathies emphasize soluble tau reductions as well as neuroprotection. Results Here, we found that neuroprotection alone caused by methylene blue (MB), the parent compound of the anti-tau phenothiaziazine drug, Rember™, was insufficient to rescue cognition in a mouse model of the human tauopathy, progressive supranuclear palsy (PSP) and fronto-temporal dementia with parkinsonism linked to chromosome 17 (FTDP17): Only when levels of soluble tau protein were concomitantly reduced by a very high concentration of MB, was cognitive improvement observed. Thus, neurodegeneration can be decoupled from tau accumulation, but phenotypic improvement is only possible when soluble tau levels are also reduced. Conclusions Neuroprotection alone is not sufficient to rescue tau-induced memory loss in a transgenic mouse model. Development of neuroprotective agents is an area of intense investigation in the tauopathy drug discovery field. This may ultimately be an unsuccessful approach if soluble toxic tau intermediates are not also reduced. Thus, MB and related compounds, despite their pleiotropic nature, may be the proverbial "magic bullet" because they not only are neuroprotective, but are also able to facilitate soluble tau clearance. Moreover, this shows that neuroprotection is possible without reducing tau levels. This indicates that there is a definitive molecular link between tau and cell death cascades that can be disrupted.http://deepblue.lib.umich.edu/bitstream/2027.42/78314/1/1750-1326-5-45.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78314/2/1750-1326-5-45.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/78314/3/1750-1326-5-45-S1.PDFPeer Reviewe

Visualization of Inflammation in Experimental Colitis by Magnetic Resonance Imaging Using Very Small Superparamagnetic Iron Oxide Particles

Inflammatory bowel diseases (IBD) comprise mainly ulcerative colitis (UC) and Crohn´s disease (CD). Both forms present with a chronic inflammation of the (gastro) intestinal tract, which induces excessive changes in the composition of the associated extracellular matrix (ECM). In UC, the inflammation is limited to the colon, whereas it can occur throughout the entire gastrointestinal tract in CD. Tools for early diagnosis of IBD are still very limited and highly invasive and measures for standardized evaluation of structural changes are scarce. To investigate an efficient non-invasive way of diagnosing intestinal inflammation and early changes of the ECM, very small superparamagnetic iron oxide nanoparticles (VSOPs) in magnetic resonance imaging (MRI) were applied in two mouse models of experimental colitis: the dextran sulfate sodium (DSS)-induced colitis and the transfer model of colitis. For further validation of ECM changes and inflammation, tissue sections were analyzed by immunohistochemistry. For in depth ex-vivo investigation of VSOPs localization within the tissue, Europium-doped VSOPs served to visualize the contrast agent by imaging mass cytometry (IMC). VSOPs accumulation in the inflamed colon wall of DSS-induced colitis mice was visualized in T2* weighted MRI scans. Components of the ECM, especially the hyaluronic acid content, were found to influence VSOPs binding. Using IMC, co-localization of VSOPs with macrophages and endothelial cells in colon tissue was shown. In contrast to the DSS model, colonic inflammation could not be visualized with VSOP-enhanced MRI in transfer colitis. VSOPs present a potential contrast agent for contrast-enhanced MRI to detect intestinal inflammation in mice at an early stage and in a less invasive manner depending on hyaluronic acid content

A three gene DNA methylation biomarker accurately classifies early stage prostate cancer

Background: We identify and validate accurate diagnostic biomarkers for prostate cancer through a systematic evaluation of DNA methylation alterations. Materials and methods: We assembled three early prostate cancer cohorts (total patients = 699) from which we collected and processed over 1300 prostatectomy tissue samples for DNA extraction. Using real-time methylation-specific PCR, we measured normalized methylation levels at 15 frequently methylated loci. After partitioning sample sets into independent training and validation cohorts, classifiers were developed using logistic regression, analyzed, and validated. Results: In the training dataset, DNA methylation levels at 7 of 15 genomic loci (glutathione S-transferase Pi 1 [GSTP1], CCDC181, hyaluronan, and proteoglycan link protein 3 [HAPLN3], GSTM2, growth arrest-specific 6 [GAS6], RASSF1, and APC) showed large differences between cancer and benign samples. The best binary classifier was the GAS6/GSTP1/HAPLN3 logistic regression model, with an area under these curves of 0.97, which showed a sensitivity of 94%, and a specificity of 93% after external validation. Conclusion: We created and validated a multigene model for the classification of benign and malignant prostate tissue. With false positive and negative rates below 7%, this three-gene biomarker represents a promising basis for more accurate prostate cancer diagnosis

Phenotypic Plasticity of Leaf Shape along a Temperature Gradient in Acer rubrum

Both phenotypic plasticity and genetic determination can be important for understanding how plants respond to environmental change. However, little is known about the plastic response of leaf teeth and leaf dissection to temperature. This gap is critical because these leaf traits are commonly used to reconstruct paleoclimate from fossils, and such studies tacitly assume that traits measured from fossils reflect the environment at the time of their deposition, even during periods of rapid climate change. We measured leaf size and shape in Acer rubrum derived from four seed sources with a broad temperature range and grown for two years in two gardens with contrasting climates (Rhode Island and Florida). Leaves in the Rhode Island garden have more teeth and are more highly dissected than leaves in Florida from the same seed source. Plasticity in these variables accounts for at least 6–19 % of the total variance, while genetic differences among ecotypes probably account for at most 69–87 %. This study highlights the role of phenotypic plasticity in leaf-climate relationships. We suggest that variables related to tooth count and leaf dissection in A. rubrum can respond quickly to climate change, which increases confidence in paleoclimate methods that use these variables

A greve, o carnaval e os comícios: O mundo do trabalho portuário em Buenos Aires e a configuração de uma comunidade obreira, verão de 1904

Objetivo/contexto: El presente trabajo indaga sobre el proceso de configuración de una comunidad obrera en el puerto de Buenos Aires, resultado de la acción de los trabajadores y habitantes del barrio obrero a inicios del siglo XX. Originalidad: En el cruce de diversas historiografías (historia social, cultural y política), aquí se propone mirar de manera conjunta la dimensión laboral, la conflictividad obrera, el tiempo de la fiesta o carnaval y la participación electoral, para pensar, desde esta multiplicidad de eventos y experiencias, la aparición de una comunidad obrera radicalizada y con una particular identificación gestada en la movilización durante una época específica a comienzos del siglo XX. Metodología: A partir de una coyuntura significativa, como fueron los meses de fines de 1903 e inicios de 1904 en el barrio portuario, y basado en un variado conjunto de documentos (periódicos comerciales, barriales, gremiales, de las izquierdas, revistas de actualidad, informes policiales, fotografías, entre otros), el artículo reconstruye la experiencia obrera en los escenarios de la protesta, el carnaval y la votación para diputados celebrada durante ese verano. Al mismo tiempo, se ponderan aquí la dimensión territorial de la configuración comunitaria y los lugares centrales de la trama conformada por la protesta, la fiesta y las elecciones. Conclusiones: El análisis permite identificar que las sociabilidades obreras en el puerto consolidaron una comunidad, afincada en solidaridades familiares, corporativas, partidistas y vecinales obreras, en tiempos de movilización gremial, política y festiva, y de confrontación radicalizada con el Estado y las empresas.Objective/context: This paper inquires about the process of emergence of a working-class community in the port of Buenos Aires, resulting from actions by workers and inhabitants of the working-class neighborhood at the beginning of the 20th century. Originality: At the crossroads of diverse historiographies (social, cultural and political history), this paper proposes a joint regard at the labor dimension, worker disputes, carnival celebrations and electoral participation, and to use this multiplicity of events and experiences to think about the emergence of a radicalized worker community, with a particular identity gestated in the mobilization during a specific time at the beginning of the 20th century. Methodology: The months from late 1903 to early 1904 were an important juncture in the port district, and based on a diverse set of documents (commercial, neighborhood, trade and left-wing newspapers, news magazines, police reports, photographs, among others), this paper reconstructs the worker experience in three settings converging in the summer months: protest, carnival and legislative polls. At the same time, it ponders the territorial dimension of community configuration and the key places that formed the backdrop to a story of protest, celebration, and elections. Conclusions: This analysis shows us that worker sociabilities around the port consolidated a community based on family, corporate, partisan, neighborhood and worker solidarities, in times of labor, political and festive mobilization, and of radicalized confrontation with the State and with corporations.Objetivo/contexto: O presente trabalho indaga sobre o processo de configuração de uma comunidade obreira no porto de Buenos Aires, resultado da ação dos trabalhadores e habitantes do bairro obreiro no início do século XX. Originalidade: No cruzamento de diversas historiografias (história social, cultural e política), propõe-se aqui observar, de maneira conjunta, a dimensão laboral, a conflituosidade obreira, o tempo da festa ou carnaval e a participação eleitoral para pensar, a partir dessa multiplicidade de eventos e experiências, a aparição de uma comunidade obreira radicalizada e com uma identificação particular gestada na mobilização durante uma época específica no começo do século XX. Metodologia: A partir de uma conjuntura significativa, como foi o final de 1903 e início de 1904 no bairro portuário e baseado em um variado conjunto de documentos (jornais comerciais, de bairros, de grêmios, das esquerdas, revistas de atualidades, relatórios policiais, fotografias, entre outros), o artigo reconstrói a experiência obreira nos cenários do protesto, do carnaval e da votação para deputados celebrada nesse verão. Ao mesmo tempo, ponderam-se aqui a dimensão territorial da configuração comunitária e os lugares centrais da trama formada pelo protesto, pela festa e pelas eleições. Conclusões: A análise permite identificar que as sociabilidades obreiras no porto consolidaram uma comunidade, estabelecida em solidariedades familiares, corporativas, partidaristas e de vizinhanças obreiras, em tempos de mobilização gremial, política e festiva, e de confronto radicalizado com o Estado e com as empresas.Fil: Caruso, Laura Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de San Martin. Instituto de Altos Estudios Sociales. Centro de Estudios de Historia E Historia del Arte.; Argentin

Black carbon content in airway macrophages is associated with increased severe exacerbations and worse COPD morbidity in SPIROMICS

Background Airway macrophages (AM), crucial for the immune response in chronic obstructive pulmonary disease (COPD), are exposed to environmental particulate matter (PM), which they retain in their cytoplasm as black carbon (BC). However, whether AM BC accurately reflects environmental PM2.5 exposure, and can serve as a biomarker of COPD outcomes, is unknown. Methods We analyzed induced sputum from participants at 7 of 12 sites SPIROMICS sites for AM BC content, which we related to exposures and to lung function and respiratory outcomes. Models were adjusted for batch (first vs. second), age, race (white vs. non-white), income (<$35,000,$35,000~$74,999, ≥$75,000, decline to answer), BMI, and use of long-acting beta-agonist/long-acting muscarinic antagonists, with sensitivity analysis performed with inclusion of urinary cotinine and lung function as covariates. Results Of 324 participants, 143 were current smokers and 201 had spirometric-confirmed COPD. Modeled indoor fine (< 2.5 μm in aerodynamic diameter) particulate matter (PM2.5) and urinary cotinine were associated with higher AM BC. Other assessed indoor and ambient pollutant exposures were not associated with higher AM BC. Higher AM BC was associated with worse lung function and odds of severe exacerbation, as well as worse functional status, respiratory symptoms and quality of life. Conclusion Indoor PM2.5 and cigarette smoke exposure may lead to increased AM BC deposition. Black carbon content in AMs is associated with worse COPD morbidity in current and former smokers, which remained after sensitivity analysis adjusting for cigarette smoke burden. Airway macrophage BC, which may alter macrophage function, could serve as a predictor of experiencing worse respiratory symptoms and impaired lung function

TRY plant trait database – enhanced coverage and open access

Plant traits - the morphological, anatomical, physiological, biochemical and phenological characteristics of plants - determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait‐based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits - almost complete coverage for ‘plant growth form’. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait–environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives