RESUMO
Coordinated movement requires the nervous system to continuously compensate for changes in mechanical load across different conditions. For voluntary movements like reaching, the motor cortex is a critical hub that generates commands to move the limbs and counteract loads. How does cortex contribute to load compensation when rhythmic movements are sequenced by a spinal pattern generator? Here, we address this question by manipulating the mass of the forelimb in unrestrained mice during locomotion. While load produces changes in motor output that are robust to inactivation of motor cortex, it also induces a profound shift in cortical dynamics. This shift is minimally affected by cerebellar perturbation and significantly larger than the load response in the spinal motoneuron population. This latent representation may enable motor cortex to generate appropriate commands when a voluntary movement must be integrated with an ongoing, spinally-generated rhythm.
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Locomoção , Córtex Motor , Neurônios Motores , Animais , Córtex Motor/fisiologia , Camundongos , Neurônios Motores/fisiologia , Locomoção/fisiologia , Membro Anterior/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Movimento/fisiologia , Medula Espinal/fisiologia , Feminino , Cerebelo/fisiologiaRESUMO
Diffuse large B-cell lymphoma (DLBCL) is a common, genomically heterogenous disease that presents a clinical challenge despite the success of frontline regimens and second-line chimeric antigen receptor T-cell (CAR-T) therapy. Recently, genomic alterations and tumor microenvironment features associated with poor CAR-T response have been identified, namely those to the TP53 tumor suppressor gene. This retrospective analysis aimed to integrate various data to identify genomic partnerships capable of providing further clarity and actionable treatment targets within this population. Publicly available data were analyzed for differential expression based on TP53 and 24-month event-free survival (EFS24) status, revealing enrichments of the BRD4 bromodomain oncogene (p < 0.0001, p = 0.001). High-BRD4 and TP53 alterations were significantly associated with lower CDKN1A (p21) and TNFRSF10B (TRAIL-R2), a key tumor suppressor and CAR-T modulator, respectively. Significant loss of CD8 T-cell presence within low-TNFRSF0B (p = 0.0042) and altered-TP53 (p = 0.0424) patients showcased relevant outcome-associated tumor microenvironment features. Furthermore, reduced expression of CDKN1A was associated with low TNFRSF10B (FDR < 0.0001) and increased BRD4 interactant genes (FDR < 0.0001). Promisingly, in vitro MDM2 inhibition with Idasnutlin and TP53 reactivation via Eprenetapopt was able to renew TNFRSF10B protein expression. Additionally, applying the BRD4-degrading PROTAC ARV-825 and the CDK4/6 inhibitor Abemaciclib as single-agents and in synergistic combination significantly reduced TP53-altered DLBCL cell line viability. Our analysis presents key associations within a genomic network of actionable targets capable of providing clarity within the evolving precision CAR-T treatment landscape.
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Linfoma Difuso de Grandes Células B , Receptores de Antígenos Quiméricos , Humanos , Proteínas Nucleares , Estudos Retrospectivos , Proteína Supressora de Tumor p53/genética , Fatores de Transcrição/genética , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Microambiente Tumoral/genética , Proteínas que Contêm Bromodomínio , Proteínas de Ciclo Celular/genética , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/uso terapêutico , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/uso terapêuticoRESUMO
Coordinated movement requires the nervous system to continuously compensate for changes in mechanical load across different contexts. For voluntary movements like reaching, the motor cortex is a critical hub that generates commands to move the limbs and counteract loads. How does cortex contribute to load compensation when rhythmic movements are clocked by a spinal pattern generator? Here, we address this question by manipulating the mass of the forelimb in unrestrained mice during locomotion. While load produces changes in motor output that are robust to inactivation of motor cortex, it also induces a profound shift in cortical dynamics, which is minimally affected by cerebellar perturbation and significantly larger than the response in the spinal motoneuron population. This latent representation may enable motor cortex to generate appropriate commands when a voluntary movement must be integrated with an ongoing, spinally-generated rhythm.
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Aromatic chromophores possessing intramolecular hydrogen-bonds that can undergo excited-state intramolecular proton transfer (ESIPT) are critical tools for chemosensing/biosensing applications because they create large Stokes-shifted fluorescence with no overlap with the absorption spectrum to limit back-ground interferences. Classic ESIPT-active fluorophores, such as the 2-(2'-hydroxyphenyl) benzazole (HBX) series (X = NH, O, S), favor a ground-state (GS) enol (E) form that undergoes ESIPT to afford an excited-state (ES) keto (K) tautomer that generates red-shifted fluorescence. Herein, we have attached the HBX moiety to 6-methoxy-indanone (6MI) to create isomeric (ortho and para) ESIPT-active chalcone dyes and have characterized their photophysical properties in polar protic solvents (MeOH and glycerol (Gly)/MeOH mixtures) and a nonpolar aprotic (1,4-dioxane) solvent for comparison. The chalcones favor a GS E structure, which undergoes ESIPT in MeOH, Gly/MeOH mixtures, and dioxane to exclusively afford K emission with large Stokes shifts. The o-isomers possess expanded π-conjugation compared to their p-isomer counterparts, which diminishes their tendency to generate twisted intramolecular charge transfer (TICT) states. Consequently, the o-isomers have greater quantum yields and lack molecular rotor (MR) character with little K emission response to increased solvent viscosity. However, they possess strong positive solvatochromism, displaying significant blue wavelength shifts coupled with turn-on K emission in moving from polar protic MeOH to nonpolar dioxane. In contrast, the p-isomers display MR character with turn-on K emission in 75:25 Gly/MeOH compared to their emission in MeOH (up to 14-fold) due to a strong tendency for TICT. Mechanistic insight into the observed isomer-specific photophysical properties of the ESIPT-active chalcones was obtained through density functional theory (DFT) calculations. Implications for DNA biosensing applications are discussed.
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Maternal consumption of a Western-style diet (mWD) during pregnancy alters fatty acid metabolism and reduces insulin sensitivity in fetal skeletal muscle. The long-term impact of these fetal adaptations and the pathways underlying disordered lipid metabolism are incompletely understood. Therefore, we tested whether a mWD chronically fed to lean, insulin-sensitive adult Japanese macaques throughout pregnancy and lactation would impact skeletal muscle oxidative capacity and lipid metabolism in adolescent offspring fed a postweaning (pw) Western-style diet (WD) or control diet (CD). Although body weight was not different, retroperitoneal fat mass and subscapular skinfold thickness were significantly higher in pwWD offspring consistent with elevated fasting insulin and glucose. Maximal complex I (CI)-dependent respiration in muscle was lower in mWD offspring in the presence of fatty acids, suggesting that mWD impacts muscle integration of lipid with nonlipid oxidation. Abundance of all five oxidative phosphorylation complexes and VDAC, but not ETF/ETFDH, were reduced with mWD, partially explaining the lower respiratory capacity with lipids. Muscle triglycerides increased with pwWD; however, the fold increase in lipid saturation, 1,2-diacylglycerides, and C18 ceramide compared between pwCD and pwWD was greatest in mWD offspring. Reductions in CI abundance and VDAC correlated with reduced markers of oxidative stress, suggesting that these reductions may be an early-life adaptation to mWD to mitigate excess reactive oxygen species. Altogether, mWD, independent of maternal obesity or insulin resistance, results in sustained metabolic reprogramming in offspring muscle despite a healthy diet intervention. ARTICLE HIGHLIGHTS: In lean, active adolescent offspring, a postweaning Western-style diet (pwWD) leads to shifts in body fat distribution that are associated with poorer insulin sensitivity. Fatty acid-linked oxidative metabolism was reduced in skeletal muscles from offspring exposed to maternal Western-style diet (mWD) even when weaned to a healthy control diet for years. Reduced oxidative phosphorylation complex I-V and VDAC1 abundance partially explain decreased skeletal muscle respiration in mWD offspring. Prior exposure to mWD results in greater fold increase with pwWD in saturated lipids and bioactive lipid molecules (i.e. ceramide and sphingomyelin) associated with insulin resistance.
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Resistência à Insulina , Humanos , Animais , Gravidez , Feminino , Adolescente , Resistência à Insulina/fisiologia , Macaca fuscata/metabolismo , Metabolismo dos Lipídeos , Músculo Esquelético/metabolismo , Insulina/metabolismo , Dieta Ocidental/efeitos adversos , Ácidos Graxos/metabolismo , Ceramidas/metabolismo , Dieta HiperlipídicaRESUMO
Non-follicular low-grade B-cell lymphomas (LGBCL) are biologically diverse entities that share clinical and histologic features that make definitive pathologic categorization challenging. While most patients with LGBCL have an indolent course, some experience aggressive disease, highlighting additional heterogeneity across these subtypes. To investigate the potential for shared biology across subtypes, we performed RNA sequencing and applied machine learning approaches that identified five clusters of patients that grouped independently of subtype. One cluster was characterized by inferior outcome, upregulation of cell cycle genes, and increased tumor immune cell content. Integration of whole exome sequencing identified novel LGBCL mutations and enrichment of TNFAIP3 and BCL2 alterations in the poor survival cluster. Building on this, we further refined a transcriptomic signature associated with early clinical failure in two independent cohorts. Taken together, this study identifies unique clusters of LGBCL defined by novel gene expression signatures and immune profiles associated with outcome across diagnostic subtypes.
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Linfoma de Células B , Humanos , Linfoma de Células B/patologia , Perfilação da Expressão Gênica , TranscriptomaRESUMO
Geographic atrophy (GA) is a vision-threatening manifestation of age-related macular degeneration (AMD), one of the leading causes of blindness globally. Objective, rapid, reliable, and scalable quantification of GA from optical coherence tomography (OCT) retinal scans is necessary for disease monitoring, prognostic research, and clinical endpoints for therapy development. Such automatically quantified biomarkers on OCT are likely to further elucidate structure-function correlation in GA and thus the pathophysiological mechanisms of disease development and progression. In this work, we aimed to predict visual function with machine-learning applied to automatically acquired quantitative imaging biomarkers in GA. A post-hoc analysis of data from a clinical trial and routine clinical care was conducted. A deep-learning automated segmentation model was applied on OCT scans from 476 eyes (325 patients) with GA. A separate machine learning prediction model (Random Forest) used the resultant quantitative OCT (qOCT) biomarkers to predict cross-sectional visual acuity under standard (VA) and low luminance (LLVA). The primary outcome was regression coefficient (r2) and mean absolute error (MAE) for cross-sectional VA and LLVA in Early Treatment Diabetic Retinopathy Study (ETDRS) letters. OCT parameters were predictive of VA (r2 0.40 MAE 11.7 ETDRS letters) and LLVA (r2 0.25 MAE 12.1). Normalised random forest feature importance, as a measure of the predictive value of the three constituent features of GA; retinal pigment epithelium (RPE)-loss, photoreceptor degeneration (PDR), hypertransmission and their locations, was reported both on voxel-level heatmaps and ETDRS-grid subfields. The foveal region (46.5%) and RPE-loss (31.1%) had greatest predictive importance for VA. For LLVA, however, non-foveal regions (74.5%) and PDR (38.9%) were most important. In conclusion, automated qOCT biomarkers demonstrate predictive significance for VA and LLVA in GA. LLVA is itself predictive of GA progression, implying that the predictive qOCT biomarkers provided by our model are also prognostic.
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Atrofia Geográfica , Biomarcadores , Estudos Transversais , Atrofia Geográfica/diagnóstico por imagem , Humanos , Aprendizado de Máquina , Tomografia de Coerência Óptica/métodosRESUMO
During aging, microglia produce inflammatory factors, show reduced tissue surveillance, altered interactions with synapses, and prolonged responses to CNS insults, positioning these cells to have profound impact on the function of nearby neurons. We and others recently showed that microglial attributes differ significantly across brain regions in young adult mice. However, the degree to which microglial properties vary during aging is largely unexplored. Here, we analyze and manipulate microglial aging within the basal ganglia, brain circuits that exhibit prominent regional microglial heterogeneity and where neurons are vulnerable to functional decline and neurodegenerative disease. In male and female mice, we demonstrate that VTA and SNc microglia exhibit unique and premature responses to aging, compared with cortex and NAc microglia. This is associated with localized VTA/SNc neuroinflammation that may compromise synaptic function as early as middle age. Surprisingly, systemic inflammation, local neuron death, and astrocyte aging do not appear to underlie these early aging responses of VTA and SNc microglia. Instead, we found that microglial lysosome status was tightly linked to early aging of VTA microglia. Microglial ablation/repopulation normalized VTA microglial lysosome swelling and suppressed increases in VTA microglial density during aging. In contrast, CX3CR1 receptor KO exacerbated VTA microglial lysosome rearrangements and VTA microglial proliferation during aging. Our findings reveal a previously unappreciated regional variation in onset and magnitude of microglial proliferation and inflammatory factor production during aging and highlight critical links between microglial lysosome status and local microglial responses to aging.SIGNIFICANCE STATEMENT Microglia are CNS cells that are equipped to regulate neuronal health and function throughout the lifespan. We reveal that microglia in select brain regions begin to proliferate and produce inflammatory factors in late middle age, months before microglia in other brain regions. These findings demonstrate that CNS neuroinflammation during aging is not uniform. Moreover, they raise the possibility that local microglial responses to aging play a critical role in determining which populations of neurons are most vulnerable to functional decline and neurodegenerative disease.
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Microglia , Doenças Neurodegenerativas , Animais , Feminino , Masculino , Camundongos , Doenças Neuroinflamatórias , Neurônios/fisiologia , SinapsesRESUMO
The global terrestrial carbon sink is increasing1-3, offsetting roughly a third of anthropogenic CO2 released into the atmosphere each decade1, and thus serving to slow4 the growth of atmospheric CO2. It has been suggested that a CO2-induced long-term increase in global photosynthesis, a process known as CO2 fertilization, is responsible for a large proportion of the current terrestrial carbon sink4-7. The estimated magnitude of the historic increase in photosynthesis as result of increasing atmospheric CO2 concentrations, however, differs by an order of magnitude between long-term proxies and terrestrial biosphere models7-13. Here we quantify the historic effect of CO2 on global photosynthesis by identifying an emergent constraint14-16 that combines terrestrial biosphere models with global carbon budget estimates. Our analysis suggests that CO2 fertilization increased global annual photosynthesis by 11.85 ± 1.4%, or 13.98 ± 1.63 petagrams carbon (mean ± 95% confidence interval) between 1981 and 2020. Our results help resolve conflicting estimates of the historic sensitivity of global photosynthesis to CO2, and highlight the large impact anthropogenic emissions have had on ecosystems worldwide.
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Atmosfera/química , Dióxido de Carbono/metabolismo , Mapeamento Geográfico , Internacionalidade , Fotossíntese , Sequestro de Carbono , Respiração Celular , Ecossistema , Atividades Humanas , Aprendizado de Máquina , Plantas/metabolismo , Tecnologia de Sensoriamento Remoto , Imagens de Satélites , Análise Espaço-TemporalRESUMO
Mutation in proteins containing polyglutamine (polyQ) tracts has been shown to underlie a number of severe human neurodegenerative disorders such as Huntington's Disease and Spinocerebellar Ataxia. In this study, we identify and describe FAM171B as a novel polyQ protein containing fourteen consecutive glutamine residues in its National Center for Biotechnology Information (NCBI) referenced sequence. Utilizing western blotting, in situ hybridization, and immunohistochemistry, we demonstrate that FAM171B is widely expressed in mouse brain with pronounced localization in the hippocampus, cerebellum, and cerebral cortex. Furthermore, immunofluorescence experiments reveal that FAM171B predominantly localizes to vesicle-like structures in the cytoplasm of neurons. Finally, bioinformatic analysis suggests that FAM171B is robustly expressed in human brain, and (similar to other polyQ disease genes) its polyQ tract is polymorphic within the general human population. Thus, as a polyQ protein that is expressed in brain, FAM171B should be considered a candidate gene for an as yet molecularly uncharacterized neurodegenerative disease.
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Encéfalo/metabolismo , Biologia Computacional/métodos , Perfilação da Expressão Gênica/métodos , Proteínas de Membrana/biossíntese , Análise de Sequência de RNA/métodos , Animais , Expressão Gênica , Células HEK293 , Humanos , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Terrestrial ecosystems remove about 30 per cent of the carbon dioxide (CO2) emitted by human activities each year1, yet the persistence of this carbon sink depends partly on how plant biomass and soil organic carbon (SOC) stocks respond to future increases in atmospheric CO2 (refs. 2,3). Although plant biomass often increases in elevated CO2 (eCO2) experiments4-6, SOC has been observed to increase, remain unchanged or even decline7. The mechanisms that drive this variation across experiments remain poorly understood, creating uncertainty in climate projections8,9. Here we synthesized data from 108 eCO2 experiments and found that the effect of eCO2 on SOC stocks is best explained by a negative relationship with plant biomass: when plant biomass is strongly stimulated by eCO2, SOC storage declines; conversely, when biomass is weakly stimulated, SOC storage increases. This trade-off appears to be related to plant nutrient acquisition, in which plants increase their biomass by mining the soil for nutrients, which decreases SOC storage. We found that, overall, SOC stocks increase with eCO2 in grasslands (8 ± 2 per cent) but not in forests (0 ± 2 per cent), even though plant biomass in grasslands increase less (9 ± 3 per cent) than in forests (23 ± 2 per cent). Ecosystem models do not reproduce this trade-off, which implies that projections of SOC may need to be revised.
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Dióxido de Carbono/metabolismo , Sequestro de Carbono , Plantas/metabolismo , Solo/química , Biomassa , Pradaria , Modelos BiológicosRESUMO
Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma, and front line therapies have not improved overall outcomes since the advent of immunochemotherapy. By pairing DNA and gene expression data with clinical response data, we identified a high-risk subset of non-GCB DLBCL patients characterized by genomic alterations and expression signatures capable of sustaining an inflammatory environment. These mutational alterations (PIM1, SPEN, and MYD88 [L265P]) and expression signatures (NF-κB, IRF4, and JAK-STAT engagement) were associated with proliferative signaling, and were found to be enriched in patients treated with RCHOP that experienced unfavorable outcomes. However, patients with these high-risk mutations had more favorable outcomes when the immunomodulatory agent lenalidomide was added to RCHOP (R2CHOP). We are the first to report the genomic validation of a high-risk phenotype with a preferential response towards R2CHOP therapy in non-GCB DLBCL patients. These conclusions could be translated to a clinical setting to identify the ~38% of non-GCB patients that could be considered high-risk, and would benefit from alternative therapies to standard RCHOP based on personalized genomic data.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Seguimentos , Humanos , Lenalidomida/administração & dosagem , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prognóstico , Estudos Retrospectivos , Rituximab/administração & dosagem , Taxa de Sobrevida , Vincristina/administração & dosagem , Adulto JovemRESUMO
Across temperate North America, interannual variability (IAV) in gross primary production (GPP) and net ecosystem exchange (NEE) and their relationship with environmental drivers are poorly understood. Here, we examine IAV in GPP and NEE and their relationship to environmental drivers using two state-of-the-science flux products: NEE constrained by surface and space-based atmospheric CO2 measurements over 2010-2015 and satellite up-scaled GPP from FluxSat over 2001-2017. We show that the arid western half of temperate North America provides a larger contribution to IAV in GPP (104% of east) and NEE (127% of east) than the eastern half, in spite of smaller magnitude of annual mean GPP and NEE. This occurs because anomalies in western ecosystems are temporally coherent across the growing season leading to an amplification of GPP and NEE. In contrast, IAV in GPP and NEE in eastern ecosystems is dominated by seasonal compensation effects, associated with opposite responses to temperature anomalies in spring and summer. Terrestrial biosphere models in the MsTMIP ensemble generally capture these differences between eastern and western temperate North America, although there is considerable spread between models.
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Double/triple hit lymphoma (DH/TH), known as high-grade B-cell lymphoma (HGBL), is an aggressive diffuse large B cell lymphoma (DLBCL), defined as having concurrent MYC, BCL2, and/or BCL6 gene rearrangements. While gene rearrangements represent significant genetic events in cancer, copy number alterations (CNAs) also play an important role, and their contributions to rearrangements have yet to be fully elucidated. Using FISH and high-resolution CNA data, we defined the landscape of concurrent gene rearrangements and copy gains in MYC, BCL2, and BCL6, in a cohort of 479 newly diagnosed DLBCL. We also show that concurrent translocations and copy number alterations, in combinations similar to DH/TH, identify a unique subset of DLBCL, alternative DH/TH, that have survival outcomes similar to DH/TH DLBCL patients.
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Dosagem de Genes , Linfoma Difuso de Grandes Células B/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-myc/genética , Feminino , Humanos , Linfoma Difuso de Grandes Células B/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismoRESUMO
Pushrim-activated power-assisted wheels (PAPAWs) are assistive technologies that provide on-demand torque assistance to wheelchair users. Although the available power can reduce the physical load of wheelchair propulsion, it may also cause maneuverability and controllability issues. Commercially-available PAPAW controllers are insensitive to environmental changes, leading to inefficient and/or unsafe wheelchair movements. In this regard, adaptive velocity/torque control strategies could be employed to improve safety and stability. To investigate this objective, we propose a context-aware sensory framework to recognize terrain conditions. In this paper, we present a learning-based terrain classification framework for PAPAWs. Study participants performed various maneuvers consisting of common daily-life wheelchair propulsion routines on different indoor and outdoor terrains. Relevant features from wheelchair frame-mounted gyroscope and accelerometer measurements were extracted and used to train and test the proposed classifiers. Our findings revealed that a one-stage multi-label classification framework has a higher accuracy performance compared to a two-stage classification pipeline with an indoor-outdoor classification in the first stage. We also found that, on average, outdoor terrains can be classified with higher accuracy (90%) compared to indoor terrains (65%). This framework can be used for real-time terrain classification applications and provide the required information for an adaptive velocity/torque controller design.
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Pessoas com Deficiência , Cadeiras de Rodas , Humanos , AprendizagemRESUMO
BACKGROUND: The Allen Institute recently built a set of high-throughput experimental pipelines to collect comprehensive in vivo surveys of physiological activity in the visual cortex of awake, head-fixed mice. Developing these large-scale, industrial-like pipelines posed many scientific, operational, and engineering challenges. NEW METHOD: Our strategies for creating a cross-platform reference space to which all pipeline datasets were mapped required development of 1) a robust headframe, 2) a reproducible clamping system, and 3) data-collection systems that are built, and maintained, around precise alignment with a reference artifact. RESULTS: When paired with our pipeline clamping system, our headframe exceeded deflection and reproducibility requirements. By leveraging our headframe and clamping system we were able to create a cross-platform reference space to which multi-modal imaging datasets could be mapped. COMPARISON WITH EXISTING METHODS: Together, the Allen Brain Observatory headframe, surgical tooling, clamping system, and system registration strategy create a unique system for collecting large amounts of standardized in vivo datasets over long periods of time. Moreover, the integrated approach to cross-platform registration allows for multi-modal datasets to be collected within a shared reference space. CONCLUSIONS: Here we report the engineering strategies that we implemented when creating the Allen Brain Observatory physiology pipelines. All of the documentation related to headframe, surgical tooling, and clamp design has been made freely available and can be readily manufactured or procured. The engineering strategy, or components of the strategy, described in this report can be tailored and applied by external researchers to improve data standardization and stability.
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Encéfalo , Cabeça , Animais , Encéfalo/diagnóstico por imagem , Técnicas Histológicas , Camundongos , Reprodutibilidade dos Testes , VigíliaRESUMO
Microglia play critical roles during CNS development and undergo dramatic changes in tissue distribution, morphology, and gene expression as they transition from embryonic to neonatal to adult microglial phenotypes. Despite the magnitude of these phenotypic shifts, little is known about the time course and dynamics of these transitions and whether they vary across brain regions. Here, we define the time course of microglial maturation in key regions of the basal ganglia in mice, where significant regional differences in microglial phenotype are present in adults. We found that microglial density peaks in the ventral tegmental area (VTA) and nucleus accumbens (NAc) during the third postnatal week, driven by a burst of microglial proliferation. Microglial abundance is then refined to adult levels through a combination of tissue expansion and microglial programmed cell death. This overproduction and refinement of microglia was significantly more pronounced in the NAc than in the VTA and was accompanied by a sharp peak in NAc microglial lysosome abundance in the third postnatal week. Collectively, these data identify a key developmental window when elevated microglial density in discrete basal ganglia nuclei may support circuit refinement and could increase susceptibility to inflammatory insults.
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Microglia , Área Tegmentar Ventral , Animais , Gânglios da Base , Encéfalo , Camundongos , Núcleo AccumbensRESUMO
Global ecosystem function is highly dependent on climate and atmospheric composition, yet ecosystem responses to environmental changes remain uncertain. Cold, high-latitude ecosystems in particular have experienced rapid warming1, with poorly understood consequences2-4. Here, we use a satellite observed proxy for vegetation cover - the fraction of absorbed photosynthetically active radiation5 - to identify a decline in the temperature limitation of vegetation in global ecosystems between 1982 and 2012. We quantify the spatial functional response of maximum annual vegetation cover to temperature and show that the observed temporal decline in temperature limitation is consistent with expectations based on observed recent warming. An ensemble of Earth system models from the Coupled Model Intercomparison Project (CMIP5) mischaracterized the functional response to temperature, leading to a large overestimation of vegetation cover in cold regions. We identify a 16.4% decline in the area of vegetated land that is limited by temperature over the past three decades, and suggest an expected large decline in temperature limitation under future warming scenarios. This rapid observed and expected decline in temperature limitation highlights the need for an improved understanding of other limitations to vegetation growth in cold regions3,4,6, such as soil characteristics, species migration, recruitment, establishment, competition, and community dynamics.
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A bioactive glass series (0.42SiO2 -0.10Na2 O-0.08CaO-(0.40 - x)ZnO-(x)Ga2 O3 ) was synthesized, and it is efficacy against the Gram (-ve) bacteria Escherichia coli (E. coli), the Gram (+ve) bacteria Staphylococcus aureus (S. aureus), and the fungus Candida albicans (C. albicans), were characterized through liquid broth analysis. The glass series was also seeded in CMC-Dex hydrogels at three different loadings (0.05, 0.10, and 0.25 m2 ), and the antibacterial and antifungal efficacies of the resulting composites were characterized using both liquid broth and agar diffusion analysis. Liquid broth analysis was conducted using liquid extracts, which for glass samples were obtained after incubation for up to 30 days in both ultrapure water and phosphate buffered saline (PBS), while glass-hydrogel extracts were obtained solely in PBS. Glass extracts (water) decreased C. albicans viability, while those obtained in PBS decreased the viability of both E. coli and C. albicans. Glass-hydrogel extracts exhibited slight inhibition of E. coli and C. albicans. However, none of the liquid extracts decreased S. aureus viability. Glass-hydrogel composites produced inhibition zones in all three microbial cultures, with the greatest efficacy against C. albicans. The results of this study suggest these materials have potential as bone void-filling materials which display antifungal, and possibly, antibacterial properties. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1102-1113, 2017.