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Children with developmental language disorder (DLD) struggle to learn their native language for no apparent reason. While research on the neurobiological underpinnings of the disorder has focused on the role of corticostriatal systems, little is known about the role of the cerebellum in DLD. Corticocerebellar circuits might be involved in the disorder as they contribute to complex sensorimotor skill learning, including the acquisition of spoken language. Here, we used diffusion-weighted imaging data from 77 typically developing and 54 children with DLD and performed probabilistic tractography to identify the cerebellum's white matter tracts: the inferior, middle, and superior cerebellar peduncles. Children with DLD showed lower fractional anisotropy (FA) in the inferior cerebellar peduncles (ICP), fiber tracts that carry motor and sensory input via the inferior olive to the cerebellum. Lower FA in DLD was driven by lower axial diffusivity. Probing this further with more sophisticated modeling of diffusion data, we found higher orientation dispersion but no difference in neurite density in the ICP of children with DLD. Reduced FA is therefore unlikely to be reflecting microstructural differences in myelination, rather the organization of axons in these pathways is disrupted. ICP microstructure was not associated with language or motor coordination performance in our sample. We also found no differences in the middle and superior peduncles, the main pathways connecting the cerebellum with the cortex. To conclude, it is not corticocerebellar but atypical olivocerebellar white matter connections that characterize DLD and suggest the involvement of the olivocerebellar system in speech and language acquisition and development.
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Hormonal imbalance during pregnancy is a risk factor for neuropsychiatric impairment in the offspring. It has been suggested that hypothyroidism leads to dysfunction of cortical GABAergic interneurons and inhibitory system development that in turn underlies impairment of the central nervous system. Here we investigated how gestational hypothyroidism affected offspring GABAergic system development as well as redox regulation parameters, because of previous links identified between the two. Experimental Gestational Hypothyroidism (EGH) was induced in CD-1 mice with 0.02% methimazole (MMI) in drinking water from embryonic day 9 (E9) until tissue collection at embryonic day 14 (E14) or E18. We examined GABAergic cell distribution and inhibitory system development gene expression as well as redox relevant gene expression and direct measures across all embryos regardless of sex. Intrauterine restriction of maternal thyroid hormones significantly impacted both of these outcomes in brain, as well as altering redox regulation in the placenta. GAD67+ neuronal migration was reduced, accompanied by a disruption in gene expression influencing GABAergic cell migration and cortical inhibitory neural system development. EGH also altered embryonic brain gene expression of Gpx1, Nfe2l2, Cat levels in the dorsal E14 brains. Additionally, EGH resulted in elevated TBARS, Gpx1 and Nfe2l2 in the ventral E18 brains. Furthermore, EGH downregulated placental Gpx1 gene expression at E14 and increased protein oxidation at E18. These findings support the hypothesis that sufficient maternal thyroid hormone supply to the fetus influences central nervous system development, including processes of GABAergic system development and redox equilibrium.
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Encéfalo , Neurônios GABAérgicos , Glutationa Peroxidase GPX1 , Glutationa Peroxidase , Hipotireoidismo , Estresse Oxidativo , Animais , Feminino , Gravidez , Hipotireoidismo/metabolismo , Camundongos , Encéfalo/metabolismo , Encéfalo/embriologia , Neurônios GABAérgicos/metabolismo , Glutationa Peroxidase/metabolismo , Glutationa Peroxidase/genética , Metimazol , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Movimento Celular , Glutamato Descarboxilase/metabolismo , Glutamato Descarboxilase/genética , Masculino , Placenta/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Hormônios Tireóideos/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismoRESUMO
Approximately 7% of children have developmental language disorder (DLD), a neurodevelopmental condition associated with persistent language learning difficulties without a known cause. Our understanding of the neurobiological basis of DLD is limited. Here, we used FreeSurfer to investigate cortical surface area and thickness in a large cohort of 156 children and adolescents aged 10-16 years with a range of language abilities, including 54 with DLD, 28 with a history of speech-language difficulties who did not meet criteria for DLD, and 74 age-matched controls with typical language development (TD). We also examined cortical asymmetries in DLD using an automated surface-based technique. Relative to the TD group, those with DLD showed smaller surface area bilaterally in the inferior frontal gyrus extending to the anterior insula, in the posterior temporal and ventral occipito-temporal cortex, and in portions of the anterior cingulate and superior frontal cortex. Analysis of the whole cohort using a language proficiency factor revealed that language ability correlated positively with surface area in similar regions. There were no differences in cortical thickness, nor in asymmetry of these cortical metrics between TD and DLD. This study highlights the importance of distinguishing between surface area and cortical thickness in investigating the brain basis of neurodevelopmental disorders and suggests the development of cortical surface area to be of importance to DLD. Future longitudinal studies are required to understand the developmental trajectory of these cortical differences in DLD and how they relate to language maturation.
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As access to long-acting injectable antiretroviral therapy (LAI ART) expands, understanding patient perceptions and experiences around LAI should inform equitable scale-up and effective implementation strategies. This study used qualitative research design relying on semi-structured interviews conducted among persons with HIV (PWH) who were either virally suppressed on oral treatment (n = 11) or had received at least one dose of injectables (n = 7). Approximately half of participants identified as male (10/18) and most identified as African American (17/18). Among participants on oral ART, many described the prospect of injectable treatment as likely convenient and discreet, relieving the stress of remembering to take daily pill. Nearly all had heard of LAI ART prior to the interview, often from television or internet commercials. Most were excited about less frequent dosing, though expressed concern about the logistics involved in coming to clinic every two months. Many expressed uncertainties regarding the relative effectiveness of LAI ART compared with oral therapy and were wary of potential pain related to injections. In contrast, all persons on LAI ART described injection-site soreness as manageable. In addition to acknowledging the convenience of every-two-month injections, some persons receiving LAI ART expressed relief by lifting the emotional stress of taking a daily-pill that reminded them of their HIV positive status. Emerging clinical trial data supports the individual and public health benefits of LAI ART, regardless of prior viral-suppression; our work adds to a growing body of literature demonstrating the potential psychological benefits associated with this novel treatment modality for PWH regardless of recent viral-suppression.
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Fármacos Anti-HIV , Infecções por HIV , Entrevistas como Assunto , Pesquisa Qualitativa , Humanos , Masculino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/psicologia , Adulto , Pessoa de Meia-Idade , Feminino , North Carolina , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/uso terapêutico , Injeções , Preparações de Ação Retardada , Acessibilidade aos Serviços de Saúde , Adesão à Medicação/psicologia , Adesão à Medicação/estatística & dados numéricos , Conhecimentos, Atitudes e Prática em SaúdeRESUMO
Iodine oxoacids are recognised for their significant contribution to the formation of new particles in marine and polar atmospheres. Nevertheless, to incorporate the iodine oxoacid nucleation mechanism into global simulations, it is essential to comprehend how this mechanism varies under various atmospheric conditions. In this study, we combined measurements from the CLOUD (Cosmic Leaving OUtdoor Droplets) chamber at CERN and simulations with a kinetic model to investigate the impact of temperature, ionisation, and humidity on iodine oxoacid nucleation. Our findings reveal that ion-induced particle formation rates remain largely unaffected by changes in temperature. However, neutral particle formation rates experience a significant increase when the temperature drops from +10 °C to -10 °C. Running the kinetic model with varying ionisation rates demonstrates that the particle formation rate only increases with a higher ionisation rate when the iodic acid concentration exceeds 1.5 × 107 cm-3, a concentration rarely reached in pristine marine atmospheres. Consequently, our simulations suggest that, despite higher ionisation rates, the charged cluster nucleation pathway of iodic acid is unlikely to be enhanced in the upper troposphere by higher ionisation rates. Instead, the neutral nucleation channel is likely to be the dominant channel in that region. Notably, the iodine oxoacid nucleation mechanism remains unaffected by changes in relative humidity from 2% to 80%. However, under unrealistically dry conditions (below 0.008% RH at +10 °C), iodine oxides (I2O4 and I2O5) significantly enhance formation rates. Therefore, we conclude that iodine oxoacid nucleation is the dominant nucleation mechanism for iodine nucleation in the marine and polar boundary layer atmosphere.
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BACKGROUND: Inter-individual variation in blood pressure (BP) arises in part from sequence variants within enhancers modulating the expression of causal genes. We propose that these genes, active in tissues relevant to BP physiology, can be identified from tissue-level epigenomic data and genotypes of BP-phenotyped individuals. METHODS: We used chromatin accessibility data from the heart, adrenal, kidney, and artery to identify cis-regulatory elements (CREs) in these tissues and estimate the impact of common human single-nucleotide variants within these CREs on gene expression, using machine learning methods. To identify causal genes, we performed a gene-wise association test. We conducted analyses in 2 separate large-scale cohorts: 77â 822 individuals from the Genetic Epidemiology Research on Adult Health and Aging and 315â 270 individuals from the UK Biobank. RESULTS: We identified 309, 259, 331, and 367 genes (false discovery rate <0.05) for diastolic BP and 191, 184, 204, and 204 genes for systolic BP in the artery, kidney, heart, and adrenal, respectively, in Genetic Epidemiology Research on Adult Health and Aging; 50% to 70% of these genes were replicated in the UK Biobank, significantly higher than the 12% to 15% expected by chance (P<0.0001). These results enabled tissue expression prediction of these 988 to 2875 putative BP genes in individuals of both cohorts to construct an expression polygenic score. This score explained ≈27% of the reported single-nucleotide variant heritability, substantially higher than expected from prior studies. CONCLUSIONS: Our work demonstrates the power of tissue-restricted comprehensive CRE analysis, followed by CRE-based expression prediction, for understanding BP regulation in relevant tissues and provides dual-modality supporting evidence, CRE and expression, for the causality genes.
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Pressão Sanguínea , Polimorfismo de Nucleotídeo Único , Humanos , Pressão Sanguínea/genética , Pressão Sanguínea/fisiologia , Masculino , Feminino , Elementos Facilitadores Genéticos/genética , Pessoa de Meia-Idade , Regulação da Expressão Gênica , Hipertensão/genética , Hipertensão/fisiopatologia , Idoso , Rim/metabolismo , Adulto , Glândulas Suprarrenais/metabolismo , Estudo de Associação Genômica Ampla/métodosRESUMO
Diffuse Midline Gliomas (DMGs) are universally fatal, primarily pediatric malignancies affecting the midline structures of the central nervous system. Despite decades of clinical trials, treatment remains limited to palliative radiation therapy. A major challenge is the coexistence of molecularly distinct malignant cell states with potentially orthogonal drug sensitivities. To address this challenge, we leveraged established network-based methodologies to elucidate Master Regulator (MR) proteins representing mechanistic, non-oncogene dependencies of seven coexisting subpopulations identified by single-cell analysis-whose enrichment in essential genes was validated by pooled CRISPR/Cas9 screens. Perturbational profiles of 372 clinically relevant drugs helped identify those able to invert the activity of subpopulation-specific MRs for follow-up in vivo validation. While individual drugs predicted to target individual subpopulations-including avapritinib, larotrectinib, and ruxolitinib-produced only modest tumor growth reduction in orthotopic models, systemic co-administration induced significant survival extension, making this approach a valuable contribution to the rational design of combination therapy.
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Telomeres are important to chromosomal stability, and changes in their length correlate with disease, potentially relevant to brain disorders. Assessing telomere length in human brain is invasive, but whether peripheral tissue telomere length correlates with that in brain is not known. Saliva, buccal, blood, and brain samples were collected at time points before, during, and after subjects undergoing neurosurgery (n = 35) for intractable epilepsy. DNA was isolated from samples and average telomere length assessed by qPCR. Correlations of telomere length between tissue samples were calculated across subjects. When data were stratified by sex, saliva telomere length correlated with brain telomere length in males only. Buccal telomere length correlated with brain telomere length when males and females were combined. These findings indicate that in living subjects, telomere length in peripheral tissues variably correlates with that in brain and may be dependent on sex. Peripheral tissue telomere length may provide insight into brain telomere length, relevant to assessment of brain disorder pathophysiology.
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Ultrafine particles (UFP, those with diameters ≤ 100 nm), have been reported to potentially penetrate deeply into the respiratory system, translocate through the alveoli, and affect various organs, potentially correlating with increased mortality. The aim of this study is to assess long-term trends (5-11 years) in mostly urban UFP concentrations based on measurements of particle number size distributions (PNSD). Additionally, concentrations of other pollutants and meteorological variables were evaluated to support the interpretations. PNSD datasets from 12 urban background (UB), 5 traffic (TR), 3 suburban background (SUB) and 1 regional background (RB) sites in 15 European cities and 1 in the USA were evaluated. The non-parametric Theil-Sen's method was used to detect monotonic trends. Meta-analyses were carried out to assess the overall trends and those for different environments. The results showed significant decreases in NO, NO2, BC, CO, and particle concentrations in the Aitken (25-100 nm) and the Accumulation (100-800 nm) modes, suggesting a positive impact of the implementation of EURO 5/V and 6/VI vehicle standards on European air quality. The growing use of Diesel Particle Filters (DPFs) might also have clearly reduced exhaust emissions of BC, PM, and the Aitken and Accumulation mode particles. However, as reported by prior studies, there remains an issue of poor control of Nucleation mode particles (smaller than 25 nm), which are not fully reduced with current DPFs, without emission controls for semi-volatile organic compounds, and might have different origins than road traffic. Thus, contrasting trends for Nucleation mode particles were obtained across the cities studied. This mode also affected the UFP and total PNC trends because of the high proportion of Nucleation mode particles in both concentration ranges. It was also found that the urban temperature increasing trends might have also influenced those of PNC, Nucleation and Aitken modes.
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Poluentes Atmosféricos , Poluição do Ar , Poluentes Atmosféricos/análise , Poluição do Ar/análise , Cidades , Monitoramento Ambiental/métodos , Europa (Continente) , Tamanho da Partícula , Material Particulado/análise , Emissões de Veículos/análiseRESUMO
PURPOSE: Diffuse midline glioma (DMG) is a fatal tumor traditionally treated with radiation therapy (RT) and previously characterized as having a noninflammatory tumor immune microenvironment (TIME). FLASH is a novel RT technique using ultra-high dose rate that is associated with decreased toxicity and effective tumor control. However, the effect of FLASH and conventional (CONV) RT on the DMG TIME has not yet been explored. METHODS AND MATERIALS: Here, we performed single-cell RNA sequencing (scRNA-seq) and flow cytometry on immune cells isolated from an orthotopic syngeneic murine model of brainstem DMG after the use of FLASH (90 Gy/sec) or CONV (2 Gy/min) dose-rate RT and compared to unirradiated tumor (SHAM). RESULTS: At day 4 post-RT, FLASH exerted similar effects as CONV in the predominant microglial (MG) population, including the presence of two activated subtypes. However, at day 10 post-RT, we observed a significant increase in the type 1 interferon α/ß receptor (IFNAR+) in MG in CONV and SHAM compared to FLASH. In the non-resident myeloid clusters of macrophages (MACs) and dendritic cells (DCs), we found increased type 1 interferon (IFN1) pathway enrichment for CONV compared to FLASH and SHAM by scRNA-seq. We observed this trend by flow cytometry at day 4 post-RT in IFNAR+ MACs and DCs, which equalized by day 10 post-RT. DMG control and murine survival were equivalent between RT dose rates. CONCLUSIONS: Our work is the first to map CONV and FLASH immune alterations of the DMG TIME with single-cell resolution. Although DMG tumor control and survival were similar between CONV and FLASH, we found that changes in immune compartments differed over time. Importantly, although both RT modalities increased IFN1, we found that the timing of this response was cell-type and dose-rate dependent. These temporal differences, particularly in the context of tumor control, warrant further study.
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Glioma , Microglia , Animais , Glioma/radioterapia , Glioma/imunologia , Glioma/patologia , Camundongos , Microglia/efeitos da radiação , Microglia/imunologia , Microambiente Tumoral/imunologia , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Receptor de Interferon alfa e beta/genética , Camundongos Endogâmicos C57BL , Análise de Célula Única/métodos , Células Dendríticas/imunologia , Células Dendríticas/efeitos da radiação , Macrófagos/imunologiaRESUMO
Balovaptan is a brain-penetrating vasopressin receptor 1a antagonist previously investigated for the core symptoms of autism spectrum disorder (ASD). A population pharmacokinetic (PK) model of balovaptan was developed, initially to assist clinical dosing for adult and pediatric ASD studies and subsequently for new clinical indications including malignant cerebral edema (MCE) and post-traumatic stress disorder. The final model incorporates one-compartment disposition and describes time- and dose-dependent non-linear PK through empirical drug binding and a gut extraction component with turnover. An age effect on clearance observed in children was modeled by an asymptotic function that predicts adult-equivalent exposures at 40% of the adult dose for children aged 2-4 years, 70% for 5-9 years, and at the full adult dose for ≥ 10 years. The model was adapted for intravenous (IV) balovaptan dosing and combined with in vitro and ex vivo pharmacodynamic data to simulate brain receptor occupancy as a guide for dosing in a phase II trial of MCE prophylaxis after acute ischemic stroke. A sequence of three stepped-dose daily infusions of 50, 25 and 15 mg over 30 or 60 min was predicted to achieve a target occupancy of ≥ 80% in ≥ 95% of patients over a 3-day period. This model predicts both oral and IV balovaptan exposure across a wide age range and will be a valuable tool to analyze and predict its PK in new indications and target populations, including pediatric patients.
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Relação Dose-Resposta a Droga , Modelos Biológicos , Humanos , Criança , Pré-Escolar , Adulto , Antagonistas dos Receptores de Hormônios Antidiuréticos/farmacocinética , Antagonistas dos Receptores de Hormônios Antidiuréticos/administração & dosagem , Adolescente , Masculino , Feminino , Benzazepinas/farmacocinética , Benzazepinas/administração & dosagem , Adulto Jovem , Edema Encefálico/tratamento farmacológico , Pessoa de Meia-Idade , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacosRESUMO
Aerosols formed and grown by gas-to-particle processes are a major contributor to smog and haze in megacities, despite the competition between growth and loss rates. Rapid growth rates from ammonium nitrate formation have the potential to sustain particle number in typical urban polluted conditions. This process requires supersaturation of gas-phase ammonia and nitric acid with respect to ammonium nitrate saturation ratios. Urban environments are inhomogeneous. In the troposphere, vertical mixing is fast, and aerosols may experience rapidly changing temperatures. In areas close to sources of pollution, gas-phase concentrations can also be highly variable. In this work we present results from nucleation experiments at -10 °C and 5 °C in the CLOUD chamber at CERN. We verify, using a kinetic model, how long supersaturation is likely to be sustained under urban conditions with temperature and concentration inhomogeneities, and the impact it may have on the particle size distribution. We show that rapid and strong temperature changes of 1 °C min-1 are needed to cause rapid growth of nanoparticles through ammonium nitrate formation. Furthermore, inhomogeneous emissions of ammonia in cities may also cause rapid growth of particles.
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The rapid emergence of antimicrobial resistance is a global concern, and high levels of resistance have been detected in chicken populations worldwide. The purpose of this study was to determine the prevalence of antimicrobial resistance in Escherichia coli and Salmonella spp. isolated from healthy chickens in Timor-Leste. Through a cross-sectional study, cloacal swabs and boot swabs were collected from 25 live bird markets and two layer farms respectively. E. coli and Salmonella spp. from these samples were tested for susceptibility to six antimicrobials using a disk diffusion test, and a subset was tested for susceptibility to 27 antimicrobials using broth-based microdilution. E. coli and Salmonella spp. isolates showed the highest resistance towards either tetracycline or ampicillin on the disk diffusion test. E. coli from layer farms (odds ratio:5.2; 95%CI 2.0-13.1) and broilers (odds ratio:18.1; 95%CI 5.3-61.2) were more likely to be multi-drug resistant than those from local chickens. Based on the broth-based microdilution test, resistance to antimicrobials in the Timor-Leste Antimicrobial Guidelines for humans were low, except for resistance to ciprofloxacin in Salmonella spp. (47.1%). Colistin resistance in E. coli was 6.6%. Although this study shows that antimicrobial resistance in chickens was generally low in Timor-Leste, there should be ongoing monitoring in commercial chickens as industry growth might be accompanied with increased antimicrobial use.
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Highly oxygenated organic molecules (HOMs) are a major source of new particles that affect the Earth's climate. HOM production from the oxidation of volatile organic compounds (VOCs) occurs during both the day and night and can lead to new particle formation (NPF). However, NPF involving organic vapors has been reported much more often during the daytime than during nighttime. Here, we show that the nitrate radicals (NO3), which arise predominantly at night, inhibit NPF during the oxidation of monoterpenes based on three lines of observational evidence: NPF experiments in the CLOUD (Cosmics Leaving OUtdoor Droplets) chamber at CERN (European Organization for Nuclear Research), radical chemistry experiments using an oxidation flow reactor, and field observations in a wetland that occasionally exhibits nocturnal NPF. Nitrooxy-peroxy radicals formed from NO3 chemistry suppress the production of ultralow-volatility organic compounds (ULVOCs) responsible for biogenic NPF, which are covalently bound peroxy radical (RO2) dimer association products. The ULVOC yield of α-pinene in the presence of NO3 is one-fifth of that resulting from ozone chemistry alone. Even trace amounts of NO3 radicals, at sub-parts per trillion level, suppress the NPF rate by a factor of 4. Ambient observations further confirm that when NO3 chemistry is involved, monoterpene NPF is completely turned off. Our results explain the frequent absence of nocturnal biogenic NPF in monoterpene (α-pinene)-rich environments.
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Poluentes Atmosféricos , Monoterpenos Bicíclicos , Ozônio , Compostos Orgânicos Voláteis , Monoterpenos/química , Nitratos/química , Aerossóis/análise , Compostos Orgânicos Voláteis/químicaRESUMO
BACKGROUND: Pneumonia remains a common complication in trauma patients. Sirtuin 1 (SIRT1) is an anti-inflammatory NAD + -dependent deacetylase that has been shown to reduce the severity of ARDS in polymicrobial sepsis. The impact of SIRT1 in acute pneumonia, however, remains unknown. We hypothesized that SIRT1 deletion in pneumonia would worsen the inflammatory response and clinical severity, and that increased SIRT1 expression would be protective. METHODS: Ten- to 14-week-old male and female SIRT1 knockout (S1KO) mice, SIRT1 overexpressor (S1OE) mice, and their wildtype (WT) littermates underwent intra-tracheal inoculation with Pseudomonas aeruginosa . Rectal temperature was recorded, SIRT1 lung protein was quantified by western blotting, Sirt1 mRNA was measured by qPCR, and lung leukocyte subpopulations were analyzed by flow cytometry. Data were analyzed by one-way ANOVA using Prism software. RESULTS: Pneumonia created a functional SIRT1 knockdown in the lungs of WT mice by 4 hours, resulting in comparable SIRT1 levels and temperatures to the S1KO mice by 12 hours. Pneumonia also partially reduced SIRT1expression in S1OE mice, but S1OE mice still had improved thermoregulation 12 hours after pneumonia. In all groups, Sirt1 mRNA expression was not affected by infection. Sirtuin 1 deletion was associated with decreased neutrophil infiltration in the lung, as well as a shift toward a more immature neutrophil phenotype. SIRT1 deletion was also associated with decreased myeloperoxidase-positive neutrophils in the lungs following pneumonia, indicating decreased neutrophil activity. S1OE mice had no change in lung leukocyte subpopulations when compared to WT. CONCLUSION: Pneumonia creates a functional SIRT1 knockdown in mice. SIRT1 deletion altered the early inflammatory cell response to pneumonia, resulting in a neutrophil response that would be less favorable for bacterial clearance. Despite overexpression of SIRT1, S1OE mice also developed low SIRT1 levels and exhibited only minimal improvement. This suggests increasing SIRT1 transcription is not sufficient to overcome pneumonia-induced downregulation and has implications for future treatment options. Targeting SIRT1 through increasing protein stability may promote a more efficient inflammatory cell response to pneumonia, thereby preventing subsequent lung injury.
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Neutrófilos , Pneumonia , Humanos , Masculino , Camundongos , Feminino , Animais , Neutrófilos/metabolismo , Sirtuína 1/genética , Sirtuína 1/metabolismo , Regulação para Baixo , RNA Mensageiro/metabolismo , Camundongos Endogâmicos C57BL , Modelos Animais de DoençasRESUMO
Autism spectrum disorder (ASD) is an increasingly prevalent neurodevelopmental condition characterized by social and communication deficits as well as patterns of restricted, repetitive behavior. Abnormal brain development has long been postulated to underlie ASD, but longitudinal studies aimed at understanding the developmental course of the disorder have been limited. More recently, abnormal development of the striatum in ASD has become an area of interest in research, partially due to overlap of striatal functions and deficit areas in ASD, as well as the critical role of the striatum in early development, when ASD is first detected. Focusing on the dorsal striatum and the associated symptom domain of restricted, repetitive behavior, we review the current literature on dorsal striatal abnormalities in ASD, including studies on functional connectivity, morphometry, and cellular and molecular substrates. We highlight that observed striatal abnormalities in ASD are often dynamic across development, displaying disrupted developmental trajectories. Important findings include an abnormal trajectory of increasing corticostriatal functional connectivity with age and increased striatal growth during childhood in ASD. We end by discussing striatal findings from animal models of ASD. In sum, the studies reviewed here demonstrate a key role for developmental disruptions of the dorsal striatum in the pathogenesis of ASD. Directing attention toward these findings will improve our understanding of ASD and of how associated deficits may be better addressed.
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Transtorno do Espectro Autista , Animais , Humanos , Imageamento por Ressonância Magnética , Encéfalo , Mapeamento Encefálico , Corpo EstriadoRESUMO
The main nucleating vapor in the atmosphere is thought to be sulfuric acid (H2SO4), stabilized by ammonia (NH3). However, in marine and polar regions, NH3 is generally low, and H2SO4 is frequently found together with iodine oxoacids [HIOx, i.e., iodic acid (HIO3) and iodous acid (HIO2)]. In experiments performed with the CERN CLOUD (Cosmics Leaving OUtdoor Droplets) chamber, we investigated the interplay of H2SO4 and HIOx during atmospheric particle nucleation. We found that HIOx greatly enhances H2SO4(-NH3) nucleation through two different interactions. First, HIO3 strongly binds with H2SO4 in charged clusters so they drive particle nucleation synergistically. Second, HIO2 substitutes for NH3, forming strongly bound H2SO4-HIO2 acid-base pairs in molecular clusters. Global observations imply that HIOx is enhancing H2SO4(-NH3) nucleation rates 10- to 10,000-fold in marine and polar regions.
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INTRODUCTION: The Automated Quantification Algorithm (AQuA) is a rapid and efficient method for targeted NMR-based metabolomics, currently optimised for blood plasma. AQuA quantifies metabolites from 1D-1H NMR spectra based on the height of only one signal per metabolite, which minimises the computational time and workload of the method without compromising the quantification accuracy. OBJECTIVES: To develop a fast and computationally efficient extension of AQuA for quantification of selected metabolites in highly complex samples, with minimal prior sample preparation. In particular, the method should be capable of handling interferences caused by broad background signals. METHODS: An automatic baseline correction function was combined with AQuA into an automated workflow, the extended AQuA, for quantification of metabolites in plant root exudate NMR spectra that contained broad background signals and baseline distortions. The approach was evaluated using simulations as well as a spike-in experiment in which known metabolite amounts were added to a complex sample matrix. RESULTS: The extended AQuA enables accurate quantification of metabolites in 1D-1H NMR spectra with varying complexity. The method is very fast (< 1 s per spectrum) and can be fully automated. CONCLUSIONS: The extended AQuA is an automated quantification method intended for 1D-1H NMR spectra containing broad background signals and baseline distortions. Although the method was developed for plant root exudates, it should be readily applicable to any NMR spectra displaying similar issues as it is purely computational and applied to NMR spectra post-acquisition.
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Algoritmos , Metabolômica , Metabolômica/métodos , Espectroscopia de Prótons por Ressonância Magnética , Exsudatos e Transudatos , Raízes de PlantasRESUMO
Yarrowia lipolytica is an oleaginous yeast that produces high titers of fatty acid-derived biofuels and biochemicals. It can grow on hydrophobic carbon sources and lignocellulosic hydrolysates. The genome sequence of Y. lipolytica NRRL Y-64008 is reported to aid in its development as a biotechnological chassis for producing biofuels and bioproducts.