The nuclear factor-κB (NF-κB) signaling pathway is one of the best understood immune-related pathways thanks to almost four decades of intense research. NF-κB signaling is activated by numerous ...discrete stimuli and is a master regulator of the inflammatory response to pathogens and cancerous cells, as well as a key regulator of autoimmune diseases. In this regard, the role of NF-κB signaling in immunity is not unlike that of the macrophage. The dynamics by which NF-κB proteins shuttle between the cytoplasm and the nucleus to initiate transcription have been studied rigorously in fibroblasts and other non-hematopoietic cells, but many questions remain as to how current models of NF-κB signaling and dynamics can be translated to innate immune cells such as macrophages. In this review, we will present recent research on the dynamics of NF-κB signaling and focus especially on how these dynamics vary in different cell types, while discussing why these characteristics may be important. We will end by looking ahead to how new techniques and technologies should allow us to analyze these signaling processes with greater clarity, bringing us closer to a more complete understanding of inflammatory transcription factor dynamics and how different cellular contexts might allow for appropriate control of innate immune responses.
Although memory impairment is the main symptom of Alzheimer's disease (AD), language impairment can be an important marker. Relatively few studies of language in AD quantify the impairments in ...connected speech using computational techniques.
We aim to demonstrate state-of-the-art accuracy in automatically identifying Alzheimer's disease from short narrative samples elicited with a picture description task, and to uncover the salient linguistic factors with a statistical factor analysis.
Data are derived from the DementiaBank corpus, from which 167 patients diagnosed with "possible" or "probable" AD provide 240 narrative samples, and 97 controls provide an additional 233. We compute a number of linguistic variables from the transcripts, and acoustic variables from the associated audio files, and use these variables to train a machine learning classifier to distinguish between participants with AD and healthy controls. To examine the degree of heterogeneity of linguistic impairments in AD, we follow an exploratory factor analysis on these measures of speech and language with an oblique promax rotation, and provide interpretation for the resulting factors.
We obtain state-of-the-art classification accuracies of over 81% in distinguishing individuals with AD from those without based on short samples of their language on a picture description task. Four clear factors emerge: semantic impairment, acoustic abnormality, syntactic impairment, and information impairment.
Modern machine learning and linguistic analysis will be increasingly useful in assessment and clustering of suspected AD.
The scattering trans-Neptunian Objects (TNOs) can be measured to smaller sizes than any other distant small-body population. We use the largest sample yet obtained, 68 discoveries, primarily by the ...Outer Solar System Origins Survey (OSSOS), to constrain the slope of its luminosity distribution, with sensitivity to much fainter absolute H-magnitudes than previous work. Using the analysis technique in Shankman et al., we confirm that a single slope for the H-distribution is not an accurate representation of the scattering TNOs and Centaurs, and that a break in the distribution is required, in support of previous conclusions. A bright-end slope of b = 0.9 transitioning to a faint-end slope f of 0.4-0.5 with a differential number contrast c from 1 (a knee) to 10 (a divot) provides an acceptable match to our data. We find that break magnitudes Hb of 7.7 and 8.3, values both previously suggested for dynamically hot Kuiper Belt populations, are equally non-rejectable for a range of f and c in our statistical analysis. Our preferred divot H-distribution transitions to f = 0.5 with a divot of contrast c = 3 at Hb = 8.3, while our preferred knee H-distribution transitions to f = 0.4 at Hb = 7.7. The intrinsic population of scattering TNOs required to match the OSSOS detections is 3 × 106 for Hr < 12, and 9 × 104 for Hr < 8.66 (D 100 km), with Centaurs having an intrinsic population two orders of magnitude smaller.
Spliceosome mutations are common in myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), but the oncogenic changes due to these mutations have not been identified. Here a global ...analysis of exon usage in AML samples revealed distinct molecular subsets containing alternative spliced isoforms of inflammatory and immune genes. Interleukin-1 receptor-associated kinase 4 (IRAK4) was the dominant alternatively spliced isoform in MDS and AML and is characterized by a longer isoform that retains exon 4, which encodes IRAK4-long (IRAK4-L), a protein that assembles with the myddosome, results in maximal activation of nuclear factor kappa-light-chain-enhancer of B cells (NF-κB) and is essential for leukaemic cell function. Expression of IRAK4-L is mediated by mutant U2 small nuclear RNA auxiliary factor 1 (U2AF1) and is associated with oncogenic signalling in MDS and AML. Inhibition of IRAK4-L abrogates leukaemic growth, particularly in AML cells with higher expression of the IRAK4-L isoform. Collectively, mutations in U2AF1 induce expression of therapeutically targetable 'active' IRAK4 isoforms and provide a genetic link to activation of chronic innate immune signalling in MDS and AML.
The affinities of extinct organisms are often difficult to resolve using morphological data alone. Chemical analysis of carbonaceous specimens can complement traditional approaches, but the search ...for taxon-specific signals in ancient, thermally altered organic matter is challenging and controversial, partly because suitable positive controls are lacking. Here, we show that non-destructive Fourier Transform Infrared Spectroscopy (FTIR) resolves in-situ molecular fingerprints in the famous 407 Ma Rhynie chert fossil assemblage of Aberdeenshire, Scotland, an important early terrestrial Lagerstätte. Remarkably, unsupervised clustering methods (principal components analysis and K-mean) separate the fossil spectra naturally into eukaryotes and prokaryotes (cyanobacteria). Additional multivariate statistics and machine-learning approaches also differentiate prokaryotes from eukaryotes, and discriminate eukaryotic tissue types, despite the overwhelming influence of silica. We find that these methods can clarify the affinities of morphologically ambiguous taxa; in the Rhynie chert for example, we show that the problematic "nematophytes" have a plant-like composition. Overall, we demonstrate that the famously exquisite preservation of cells, tissues and organisms in the Rhynie chert accompanies similarly impressive preservation of molecular information. These results provide a compelling positive control that validates the use of infrared spectroscopy to investigate the affinity of organic fossils in chert.
Tracking repeat migratory journeys of individual animals is required to assess phenotypic plasticity of individual migration behaviour in space and time. We used light-level geolocators to track the ...long-distance journeys of migratory songbirds (wood thrush, Hylocichla mustelina), and, for the first time, repeat journeys of individuals. We compare between- and within-individual variation in migration to examine flexibility of timing and route in spring and autumn. Date of departure from wintering sites in Central America, along with sex and age factors, explained most of the variation (71%) in arrival date at North American breeding sites. Spring migration showed high within-individual repeatability in timing, but not in route. In particular, spring departure dates of individuals were highly repeatable, with a mean difference between years of just 3 days. Autumn migration timing and routes were not repeatable. Our results provide novel evidence of low phenotypic plasticity in timing of spring migration, which may limit the ability of individuals to adjust migration schedules in response to climate change.
Many eukaryotic genes are expressed in randomly initiated bursts that are punctuated by periods of quiescence. Here, we show that the intermittent access of the promoters to transcription factors ...through relatively impervious chromatin contributes to this "noisy" transcription. We tethered a nuclease-deficient Cas9 fused to a histone acetyl transferase at the promoters of two endogenous genes in HeLa cells. An assay for transposase-accessible chromatin using sequencing showed that the activity of the histone acetyl transferase altered the chromatin architecture locally without introducing global changes in the nucleus and rendered the targeted promoters constitutively accessible. We measured the gene expression variability from the gene loci by performing single-molecule fluorescence in situ hybridization against mature messenger RNAs (mRNAs) and by imaging nascent mRNA molecules present at active gene loci in single cells. Because of the increased accessibility of the promoter to transcription factors, the transcription from two genes became less noisy, even when the average levels of expression did not change. In addition to providing evidence for chromatin accessibility as a determinant of the noise in gene expression, our study offers a mechanism for controlling gene expression noise which is otherwise unavoidable.
We present the first results of the Hubble Wide Field Camera 3 Test of Surfaces in the Outer Solar System. The purpose of this survey was to measure the surface properties of a large number of Kuiper ...Belt objects and attempt to infer compositional and dynamical correlations. We find that the Centaurs and the low-perihelion scattered disk and resonant objects exhibit virtually identical bifurcated optical color distributions and make up two well-defined groups of objects. Both groups have highly correlated optical and NIR colors that are well described by a pair of two-component mixture models that have different red components but share a common neutral component. The small, H sub(606) > ~ 5.6 high-perihelion excited objects are entirely consistent with being drawn from the two branches of the mixing model, suggesting that the color bifurcation of the Centaurs is apparent in all small excited objects. On the other hand, objects larger than H sub(606) ~ 5.6 are not consistent with the mixing model, suggesting some evolutionary process avoided by the smaller objects. The existence of a bifurcation amongst all excited populations argues that the two separate classes of object existed in the primordial disk before the excited Kuiper Belt was populated. The cold classical objects exhibit a different type of surface that has colors that are consistent with being drawn from the red branch of the mixing model, but with much higher albedos.
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