As genes that confer increased risk for autism spectrum disorder (ASD) are identified, a crucial next step is to determine how these risk factors impact brain structure and function and contribute to ...disorder heterogeneity. With three converging lines of evidence, we show that a common, functional ASD risk variant in the Met Receptor Tyrosine Kinase (MET) gene is a potent modulator of key social brain circuitry in children and adolescents with and without ASD. MET risk genotype predicted atypical fMRI activation and deactivation patterns to social stimuli (i.e., emotional faces), as well as reduced functional and structural connectivity in temporo-parietal regions known to have high MET expression, particularly within the default mode network. Notably, these effects were more pronounced in individuals with ASD. These findings highlight how genetic stratification may reduce heterogeneity and help elucidate the biological basis of complex neuropsychiatric disorders such as ASD.
► The ASD-related risk MET promoter variant alters functional activity and connectivity ► The MET risk allele also disrupts the integrity of major white matter tracts ► Effects are more pronounced in MET-expressing regions and across individuals with ASD ► Findings provide mechanistic insights into gene-brain-behavior relationships in ASD
Rudie et al. show how an autism risk factor in the MET gene impacts multiple aspects of brain circuitry in children with and without autism. The study provides new insight into the neurobiological basis of the disorder.
Sensory over-responsivity (SOR), defined as a negative response to or avoidance of sensory stimuli, is both highly prevalent and extremely impairing in youth with autism spectrum disorders (ASD), yet ...little is known about the neurological bases of SOR. This study aimed to examine the functional neural correlates of SOR by comparing brain responses to sensory stimuli in youth with and without ASD.
A total of 25 high-functioning youth with ASD and 25 age- and IQ-equivalent typically developing (TD) youth were presented with mildly aversive auditory and visual stimuli during a functional magnetic resonance imaging (fMRI) scan. Parents provided ratings of children's SOR and anxiety symptom severity.
Compared to TD participants, ASD participants displayed greater activation in primary sensory cortical areas as well as amygdala, hippocampus, and orbital-frontal cortex. In both groups, the level of activity in these areas was positively correlated with level of SOR severity as rated by parents, over and above behavioral ratings of anxiety.
This study demonstrates that youth with ASD show neural hyper-responsivity to sensory stimuli, and that behavioral symptoms of SOR may be related to both heightened responsivity in primary sensory regions as well as areas related to emotion processing and regulation.
Biomass burning is a common agricultural practice, because it allows elimination of postharvesting residues; nevertheless, it involves an inefficient combustion process that generates atmospheric ...pollutants emission, which has implications on health and climate change. This work focuses on the estimation of emission factors (EFs) of PM
2.5
, PM
10
, organic carbon (OC), elemental carbon (EC), carbon monoxide (CO), carbon dioxide (CO
2
), and methane (CH
4
) of residues from burning alfalfa, barley, beans, cotton, maize, rice, sorghum, and wheat in Mexico. Chemical characteristics of the residues were determined to establish their relationship with EFs, as well as with the modified combustion efficiency (MCE). Essays were carried out in an open combustion chamber with isokinetic sampling, following modified EPA 201-A method. EFs did not present statistical differences among different varieties of the same crop, but were statistically different among different crops, showing that generic values of EFs for all the agricultural residues can introduce significant uncertainties when used for climatic and atmospheric pollutant inventories. EFs of PM
2.5
ranged from 1.19 to 11.30 g kg
−1
, and of PM
10
from 1.77 to 21.56 g kg
−1
. EFs of EC correlated with lignin content, whereas EFs of OC correlated inversely with carbon content. EFs of EC and OC in PM
2.5
ranged from 0.15 to 0.41 g kg
−1
and from 0.33 to 5.29 g kg
−1
, respectively, and in PM
10
, from 0.17 to 0.43 g kg
−1
and from 0.54 to 11.06 g kg
−1
. CO
2
represented the largest gaseous emissions volume with 1053.35-1850.82 g kg
−1
, whereas the lowest was CH
4
with 1.61-5.59 g kg
−1
. CO ranged from 28.85 to 155.71 g kg
−1
, correlating inversely with carbon content and MCE. EFs were used to calculate emissions from eight agricultural residues burning in the country during 2016, to know the potential mitigation of climatic and atmospheric pollutants, provided this practice was banned.
Implications: The emission factors of particles, short-lived climatic pollutants, and atmospheric pollutants from the crop residues burning of eight agricultural wastes crops, determined in this study using a standardized method, provides better knowledge of the emissions of those species in Latin America and other developing countries, and can be used as inputs in air quality models and climatic studies. The EFs will allow the development of more accurate inventories of aerosols and gaseous pollutants, which will lead to the design of effective mitigation strategies and planning processes for sustainable agriculture.
•fMRI was used to examine the brain mechanisms through which tactile stimuli disrupt processing of social cues in youth with ASD.•Tactile stimuli caused up-regulation of auditory language areas in TD ...youth but decreases in these areas in ASD youth.•Directing attention to social cues mitigated the effect of the sensory distracter so that activation was sustained in auditory-language areas.•Attentional direction to social cues was associated with increases in medial prefrontal cortex for ASD youth.•Severity of sensory over-responsivity modulated the effect of the distracter and attentional direction on brain processing of social cues.
Sensory over-responsivity (SOR) is a common condition in autism spectrum disorders (ASD) that is associated with greater social impairment. However, the mechanisms through which sensory stimuli may affect social functioning are not well understood. This study used fMRI to examine brain activity while interpreting communicative intent in 15 high-functioning youth with ASD and 16 age- and IQ-matched typically-developing (TD) controls. Participants completed the task with and without a tactile sensory distracter, and with and without instructions directing their attention to relevant social cues. When completing the task in the presence of the sensory distracter, TD youth showed increased activity in auditory language and frontal regions whereas ASD youth showed decreased activation in these areas. Instructions mitigated this effect such that ASD youth did not decrease activation during tactile stimulation; instead, the ASD group showed increased medial prefrontal activity. SOR severity modulated the effect of the tactile stimulus on social processing. Results demonstrate for the first time a neural mechanism through which sensory stimuli cause disruption of social cognition, and that attentional modulation can restore neural processing of social cues through prefrontal regulation. Findings have implications for novel, integrative interventions that incorporate attentional directives to target both sensory and social symptoms.
Neuroimaging investigations of autism spectrum disorders (ASDs) have advanced our understanding of atypical brain function and structure, and have recently converged on a model of altered ...network-level connectivity. Traditional task-based functional magnetic resonance imaging (MRI) and volume-based structural MRI studies have identified widespread atypicalities in brain regions involved in social behavior and other core ASD-related behavioral deficits. More recent advances in MR-neuroimaging methods allow for quantification of brain connectivity using diffusion tensor imaging, functional connectivity, and graph theoretic methods. These newer techniques have moved the field toward a systems-level understanding of ASD etiology, integrating functional and structural measures across distal brain regions. Neuroimaging findings in ASD as a whole have been mixed and at times contradictory, likely due to the vast genetic and phenotypic heterogeneity characteristic of the disorder. Future longitudinal studies of brain development will be crucial to yield insights into mechanisms of disease etiology in ASD sub-populations. Advances in neuroimaging methods and large-scale collaborations will also allow for an integrated approach linking neuroimaging, genetics, and phenotypic data.
During the course of the 2015–2017 outbreak of Zika virus (ZIKV) in the Americas, the emerging virus was recognized as a congenital infection that could damage the developing brain. As the Latin ...American ZIKV outbreak advanced, the scientific and public health community questioned if this newly recognized neurotropic flavivirus could affect the developing brain of infants and young children infected after birth. We report here the study design, methods and the challenges and lessons learned from the rapid operationalization of a prospective natural history cohort study aimed at evaluating the potential neurological and neurodevelopmental effects of postnatal ZIKV infection in infants and young children, which had become epidemic in Central America. This study enrolled a cohort of 500 mothers and their infants, along with nearly 400 children 1.5–3.5 years of age who were born during the initial phase of the ZIKV epidemic in a rural area of Guatemala. Our solutions and lessons learned while tackling real-life challenges may serve as a guide to other researchers carrying out studies of emerging infectious diseases of public health priority in resource-constrained settings.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Despite substantial clinical benefit of targeted and immune checkpoint blockade-based therapies in melanoma, resistance inevitably develops. We show cytoskeletal remodeling and changes in expression ...and activity of ROCK-myosin II pathway during acquisition of resistance to MAPK inhibitors. MAPK regulates myosin II activity, but after initial therapy response, drug-resistant clones restore myosin II activity to increase survival. High ROCK-myosin II activity correlates with aggressiveness, identifying targeted therapy- and immunotherapy-resistant melanomas. Survival of resistant cells is myosin II dependent, regardless of the therapy. ROCK-myosin II ablation specifically kills resistant cells via intrinsic lethal reactive oxygen species and unresolved DNA damage and limits extrinsic myeloid and lymphoid immunosuppression. Efficacy of targeted therapies and immunotherapies can be improved by combination with ROCK inhibitors.
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•Therapy-resistant melanoma cells restore myosin II activity to increase survival•High myosin II activity identifies targeted and immunotherapy-resistant melanomas•ROCK-myosin II inhibition increases ROS-DNA damage and decreases PD-L1 and Tregs•ROCK inhibition enhances efficacy of MAPK inhibitors and immunotherapies
Orgaz et al. show that myosin II activity increases during melanoma adaptation to MAPK pathway inhibition. ROCK-myosin II signaling supports survival of resistant melanoma cells and promotes immunosuppression. ROCK inhibitors improve the efficacy of MAPK inhibitors and immunotherapies in melanoma models.
Although performance-based assessment of early childhood development is preferred, there are a number of limitations to this methodology in low resource settings (LRSs). Hence, clinicians and ...researchers often rely on caregiver report screening tools. The Ages and Stages Questionnaire 3 (ASQ) is one of the most widely used caregiver report measures globally. Adequate psychometric properties have been demonstrated in high income settings, especially when used in older children, high- risk children, or those with severe neurodevelopmental delays. However, its utility is more variable within very young children and for use in LRSs.
The reliability and validity of the ASQ was determined for children ages 0–5 years living in rural Guatemala. Internal consistency and test-retest reliability were assessed, as well as concurrent and predictive validity. Sensitivity, specificity, positive and negative predictive values related to performance-based developmental assessment (Mullen Scales of Early Learning; MSEL) and growth status (i.e. stunting) were also calculated.
Internal consistency reliability for the ASQ was adequate, except when results were limited by small sample size. Test-retest reliability ranged from low to moderate (r = 0.08–0.43; p < 0.05–0.01). However, there was significant variability in mean scores over time across ASQ domain scores. In terms of validity, the ASQ did not discriminate adequately between children who performed within or below age-expectations on performance-based developmental testing or those with and without stunting.
The ASQ did not demonstrate adequate psychometric properties in rural Guatemala, consistent with concerns documented in other LRSs. These results indicate that existing caregiver report screening measures of early childhood development should be utilized with caution in LRSs, and alternative methods for assessment or in the development and utilization of caregiver report measures should be considered.
•There are barriers to testing of developmental skills in Low Resource Settings and obstacles result in reliance on caregiver report screening measures.•Ages and Stages Questionnaire-3 is a widely utilized caregiver report screening measure.•Studies reports concerns about ASQ use other cultures or non-English speaking populations•In rural Guatemala, weak psychometric properties of the ASQ identified.•Results highlight challenges of reliance on caregiver report and use of screening measures.
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