There is currently a renaissance of interest in the many functions of cerebrospinal fluid (CSF). Altered flow of CSF, for example, has been shown to impair the clearance of pathogenic inflammatory ...proteins involved in neurodegenerative diseases, such as amyloid-β. In addition, the role of CSF in the newly discovered lymphatic system of the brain has become a prominently researched area in clinical neuroscience, as CSF serves as a conduit between the central nervous system and immune system.
This article will review the importance of CSF in regulating normal brain development and function, from the prenatal period throughout the lifespan, and highlight recent research that CSF abnormalities in autism spectrum disorder (ASD) are present in infancy, are detectable by conventional structural MRI, and could serve as an early indicator of altered neurodevelopment.
The identification of early CSF abnormalities in children with ASD, along with emerging knowledge of the underlying pathogenic mechanisms, has the potential to serve as early stratification biomarkers that separate children with ASD into biological subtypes that share a common pathophysiology. Such subtypes could help parse the phenotypic heterogeneity of ASD and map on to targeted, biologically based treatments.
Ceramides contribute to the lipotoxicity that underlies diabetes, hepatic steatosis, and heart disease. By genetically engineering mice, we deleted the enzyme dihydroceramide desaturase 1 (DES1), ...which normally inserts a conserved double bond into the backbone of ceramides and other predominant sphingolipids. Ablation of DES1 from whole animals or tissue-specific deletion in the liver and/or adipose tissue resolved hepatic steatosis and insulin resistance in mice caused by leptin deficiency or obesogenic diets. Mechanistic studies revealed ceramide actions that promoted lipid uptake and storage and impaired glucose utilization, none of which could be recapitulated by (dihydro)ceramides that lacked the critical double bond. These studies suggest that inhibition of DES1 may provide a means of treating hepatic steatosis and metabolic disorders.
The human visual system has undergone evolutionary changes to develop sophisticated mechanisms that enable stable color perception under varying illumination. These mechanisms are known as chromatic ...adaptation, a fundamental aspect of color vision. Chromatic adaptation can be divided into two categories: sensory adaptation, which involves automatic adjustments in the visual system, such as retinal gain control, in response to changes in the stimulus, and cognitive adaptation, which depends on the observer's knowledge of the scene and context. The geometric mean has been suggested to be the fundamental mathematical relationship that governs peripheral sensory adaptation. This paper proposes the WGM model, an advanced chromatic adaptation model based on a weighted geometric mean approach that can anticipate incomplete adaptation as it moves along the Planckian or Daylight locus. Compared with two other chromatic adaptation models (CAT16 and vK20), the WGM model is tested with different corresponding color data sets and found to be a significantly improvement while also predicting degree of adaptation (sensory and cognitive adaptation) in a physiologically plausible manner.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Rock mechanics studies and dynamic earthquake simulations show that patterns of seismicity evolve with time through (1) accumulation phase, (2) localization phase, and (3) rupture phase. We observe a ...similar pattern of changes in seismicity during the past century across California and Nevada. To quantify these changes, we correlate GPS strain rates with seismicity. Earthquakes of M > 6.5 are collocated with regions of highest strain rates. By contrast, smaller magnitude earthquakes of M ≥ 4 show clear spatiotemporal changes. From 1933 to the late 1980s, earthquakes of M ≥ 4 were more diffused and broadly distributed in both high and low strain rate regions (accumulation phase). From the late 1980s to 2016, earthquakes were more concentrated within the high strain rate areas focused on the major fault strands (localization phase). In the same time period, the rate of M > 6.5 events also increased significantly in the high strain rate areas. The strong correlation between current strain rate and the later period of seismicity indicates that seismicity is closely related to the strain rate. The spatial patterns suggest that before the late 1980s, the strain rate field was also broadly distributed because of the stress shadows from previous large earthquakes. As the deformation field evolved out of the shadow in the late 1980s, strain has refocused on the major fault systems and we are entering a period of increased risk for large earthquakes in California.
Key Points
Earthquakes of M > 6.5 occurred in regions of highest strain rate over the past century. Its rate has increased significantly since late 1980s
From 1933 to the late 1980s, earthquakes of M ≥ 4 were more diffused and broadly distributed in both high and low strain rate regions
From the late 1980s to 2016, earthquakes were more concentrated within the high strain rate areas focused on the major fault strands
Autism spectrum disorder (ASD) is a heterogeneous condition that affects 1 in 68 children. Diagnosis is based on the presence of characteristic behavioral impairments that emerge in the second year ...of life and thus is not typically made until 3 to 4 years of age. Recent studies of early brain and behavior development have provided important new insights into the nature of this condition. Autism-specific brain imaging features have been identified as early as 6 months of age, and age-specific brain and behavior changes have been demonstrated across the first 2 years of life, highlighting the developmental nature of ASD. New findings demonstrate that early brain imaging in the first year of life holds great promise for presymptomatic prediction of ASD. There is a general understanding in medicine that earlier treatment has better outcomes than later treatment, and in autism, there is an emerging consensus that earlier intervention results in more successful outcomes for the child. Examining early brain and behavior trajectories also has the potential to parse the etiologic heterogeneity in ASD, a well-recognized impediment to developing targeted, mechanistic treatments. This review highlights the current state of the science in the pursuit of early brain and behavioral markers of autism during infancy and examines the potential implications of these findings for treatment of this condition.
Cancer-associated mutations in genes encoding RNA splicing factors (SFs) commonly occur in leukemias, as well as in a variety of solid tumors, and confer dependence on wild-type splicing. These ...observations have led to clinical efforts to directly inhibit the spliceosome in patients with refractory leukemias. Here, we identify that inhibiting symmetric or asymmetric dimethylation of arginine, mediated by PRMT5 and type I protein arginine methyltransferases (PRMTs), respectively, reduces splicing fidelity and results in preferential killing of SF-mutant leukemias over wild-type counterparts. These data identify genetic subsets of cancer most likely to respond to PRMT inhibition, synergistic effects of combined PRMT5 and type I PRMT inhibition, and a mechanistic basis for the therapeutic efficacy of PRMT inhibition in cancer.
Display omitted
•Inhibition of SDMA or ADMA preferentially kills splicing factor (SF)-mutant cells•Combined inhibition of PRMT5 and type I PRMTs has synergistic effects•RNA-binding proteins are the most enriched cellular substrates of PRMTs•Inhibition of RNA splicing underlies the cytotoxic effects of PRMT inhibition
Fong et al. show that spliceosomal mutant leukemias are preferentially sensitive to inhibition of protein arginine methyltransferases (PRMTs), that RNA-binding proteins are enriched among substrates of PRMT5 and type I PRMTs, and that combined PRMT5 and type I PRMT inhibition synergistically kill these leukemia cells.
Current theories of the glymphatic system (GS) hypothesize that it relies on cerebrospinal fluid (CSF) circulation to disseminate growth factors and remove metabolic waste from the brain with ...increased CSF production and circulation during sleep; thereby, linking sleep disturbance with elements of CSF circulation and GS exchange. However, our growing knowledge of the relations between sleep, CSF, and the GS are plagued by variability in sleep and CSF measures across a wide array of pathologies. Hence, this review aims to summarize the dynamic relationships between sleep, CSF-, and GS-related features in samples of typically developing individuals and those with autoimmune/inflammatory, neurodegenerative, neurodevelopmental, sleep-related, neurotraumatic, neuropsychiatric, and skull atypicalities. One hundred and ninety articles (total n = 19,129 participants) were identified and reviewed for pathology, CSF circulation and related metrics, GS function, and sleep. Numerous associations were documented between sleep problems and CSF metabolite concentrations (e.g., amyloid-beta, orexin, tau proteins) and increased CSF volumes or pressure. However, these relations were not universal, with marked differences across pathologies. It is clear that elements of CSF circulation/composition and GS exchange represent pathways influenced by sleep; however, carefully designed studies and advances in GS measurement are needed to delineate the nuanced relationships.
The objective of this study was to determine whether functional connectivity of the amygdala is altered in preschool-age children with autism spectrum disorder (ASD) and to assess the clinical ...relevance of observed alterations in amygdala connectivity.
A resting-state functional connectivity magnetic resonance imaging study of the amygdala (and a parallel study of primary visual cortex) was conducted in 72 boys (mean age 3.5 years; n = 43 with ASD; n = 29 age-matched controls).
The ASD group showed significantly weaker connectivity between the amygdala and several brain regions involved in social communication and repetitive behaviors, including bilateral medial prefrontal cortex, temporal lobes, and striatum (p < .05, corrected). Weaker connectivity between the amygdala and frontal and temporal lobes was significantly correlated with increased autism severity in the ASD group (p < .05). In a parallel analysis examining the functional connectivity of primary visual cortex, the ASD group showed significantly weaker connectivity between visual cortex and sensorimotor regions (p < .05, corrected). Weaker connectivity between visual cortex and sensorimotor regions was not correlated with core autism symptoms, but instead was correlated with increased sensory hypersensitivity in the visual/auditory domain (p < .05).
These findings indicate that preschool-age children with ASD have disrupted functional connectivity between the amygdala and regions of the brain important for social communication and language, which might be clinically relevant because weaker connectivity was associated with increased autism severity. Moreover, although amygdala connectivity was associated with behavioral domains that are diagnostic of ASD, altered connectivity of primary visual cortex was related to sensory hypersensitivity.
The use of liquid biopsies for cancer detection and management is rapidly gaining prominence
. Current methods for the detection of circulating tumour DNA involve sequencing somatic mutations using ...cell-free DNA, but the sensitivity of these methods may be low among patients with early-stage cancer given the limited number of recurrent mutations
. By contrast, large-scale epigenetic alterations-which are tissue- and cancer-type specific-are not similarly constrained
and therefore potentially have greater ability to detect and classify cancers in patients with early-stage disease. Here we develop a sensitive, immunoprecipitation-based protocol to analyse the methylome of small quantities of circulating cell-free DNA, and demonstrate the ability to detect large-scale DNA methylation changes that are enriched for tumour-specific patterns. We also demonstrate robust performance in cancer detection and classification across an extensive collection of plasma samples from several tumour types. This work sets the stage to establish biomarkers for the minimally invasive detection, interception and classification of early-stage cancers based on plasma cell-free DNA methylation patterns.
PDF
