To our Readers : A Study of Guilt Redemption in Newspaper Corrections

With journalism credibility at its lowest ebb, more newspapers are taking time to correct mistakes and apologize for errors. In this thesis, I use Kenneth Burke\u27s theories to analyze newspaper corrections through guilt-redemption, purification and image restoration strategies. This study looks at two types of redemptive rhetoric and image-restoration strategies: front-page apologies and daily corrections from four newspapers. The front-page apologies are from The News Examiner and the Cincinnati Enquirer. The daily corrections are from The New York Times and the Rochester Democrat and Chronicle. This thesis contends that newspapers should use mortification in corrections and apologies because it is the proper rejoinder in maintaining credibility with readers, even when victimage is the preferred strategy of guilt redemption

On Optimal Multiple Changepoint Algorithms for Large Data

There is an increasing need for algorithms that can accurately detect changepoints in long time-series, or equivalent, data. Many common approaches to detecting changepoints, for example based on penalised likelihood or minimum description length, can be formulated in terms of minimising a cost over segmentations. Dynamic programming methods exist to solve this minimisation problem exactly, but these tend to scale at least quadratically in the length of the time-series. Algorithms, such as Binary Segmentation, exist that have a computational cost that is close to linear in the length of the time-series, but these are not guaranteed to find the optimal segmentation. Recently pruning ideas have been suggested that can speed up the dynamic programming algorithms, whilst still being guaranteed to find true minimum of the cost function. Here we extend these pruning methods, and introduce two new algorithms for segmenting data, FPOP and SNIP. Empirical results show that FPOP is substantially faster than existing dynamic programming methods, and unlike the existing methods its computational efficiency is robust to the number of changepoints in the data. We evaluate the method at detecting Copy Number Variations and observe that FPOP has a computational cost that is competitive with that of Binary Segmentation.Comment: 20 page

Efficient analysis of complex changepoint problems

Many time series experience abrupt changes in structure. Detecting where these changes in structure, or changepoints, occur is required for effective modelling of the data. In this thesis we explore the common approaches used for detecting changepoints. We focus in particular on techniques which can be formulated in terms of minimising a cost over segmentations and solved exactly using a class of dynamic programming algorithms. Often implementations of these dynamic programming methods have a computational cost which scales poorly with the length of the time series. Recently pruning ideas have been suggested that can speed up the dynamic programming algorithms, whilst still being guaranteed to be optimal. In this thesis we extend these methods. First we develop two new algorithms for segmenting piecewise constant data: FPOP and SNIP. We evaluate them against other methods in the literature. We then move on to develop the method OPPL for detecting changes in data subject to fitting a continuous piecewise linear model. We evaluate it against similar methods. We finally extend the OPPL method to deal with penalties that depend on the segment length

Detecting changes in slope with an L0 penalty

While there are many approaches to detecting changes in mean for a univariate time series, the problem of detecting multiple changes in slope has comparatively been ignored. Part of the reason for this is that detecting changes in slope is much more challenging: simple binary segmentation procedures do not work for this problem, while existing dynamic programming methods that work for the change in mean problem cannot be used for detecting changes in slope. We present a novel dynamic programming approach, CPOP, for finding the “best” continuous piecewise linear fit to data under a criterion that measures fit to data using the residual sum of squares, but penalizes complexity based on an L 0 penalty on changes in slope. We prove that detecting changes in this manner can lead to consistent estimation of the number of changepoints, and show empirically that using an L 0 penalty is more reliable at estimating changepoint locations than using an L 1 penalty. Empirically CPOP has good computational properties, and can analyze a time series with 10,000 observations and 100 changes in a few minutes. Our method is used to analyze data on the motion of bacteria, and provides better and more parsimonious fits than two competing approaches. Supplementary material for this article is available online

Chronic inflammatory arthritis drives systemic changes in circadian energy metabolism

SignificanceRheumatoid arthritis (RA) is a debilitating chronic inflammatory disease in which symptoms exhibit a strong time-of-day rhythmicity. RA is commonly associated with metabolic disturbance and increased incidence of diabetes and cardiovascular disease, yet the mechanisms underlying this metabolic dysregulation remain unclear. Here, we demonstrate that rhythmic inflammation drives reorganization of metabolic programs in distal liver and muscle tissues. Chronic inflammation leads to mitochondrial dysfunction and dysregulation of fatty acid metabolism, including accumulation of inflammation-associated ceramide species in a time-of-day-dependent manner. These findings reveal multiple points for therapeutic intervention centered on the circadian clock, metabolic dysregulation, and inflammatory signaling

Involvement of the skin during bluetongue virus infection and replication in the ruminant host

Bluetongue virus (BTV) is a double stranded (ds) RNA virus (genus Orbivirus; family Reoviridae), which is considered capable of infecting all species of domestic and wild ruminants, although clinical signs are seen mostly in sheep. BTV is arthropod-borne (“arbovirus”) and able to productively infect and replicate in many different cell types of both insects and mammalian hosts. Although the organ and cellular tropism of BTV in ruminants has been the subject of several studies, many aspects of its pathogenesis are still poorly understood, partly because of inherent problems in distinguishing between “virus replication” and “virus presence”.BTV replication and organ tropism were studied in a wide range of infected sheep tissues, by immuno-fluorescence-labeling of non-structural or structural proteins (NS2 or VP7 and core proteins, respectively) using confocal microscopy to distinguish between virus presence and replication. These results are compared to gross and microscopic pathological findings in selected organs from infected sheep. Replication was demonstrated in two major cell types: vascular endothelial cells, and agranular leukocytes which morphologically resemble lymphocytes, monocytes/macrophages and/or dendritic cells. Two organs (the skin and tonsils) were shown to support relatively high levels of BTV replication, although they have not previously been proposed as important replication sites during BTV infection. The high level of BTV replication in the skin is thought to be of major significance for the pathogenesis and transmission of BTV (via biting insects) and a refinement of our current model of BTV pathogenesis is discussed

The clock gene <i>Bmal1</i> inhibits macrophage motility, phagocytosis, and impairs defense against pneumonia

The circadian clock regulates many aspects of immunity. Bacterial infections are affected by time of day, but the mechanisms involved remain undefined. Here we show that loss of the core clock protein BMAL1 in macrophages confers protection against pneumococcal pneumonia. Infected mice show both reduced weight loss and lower bacterial burden in circulating blood. In vivo studies of macrophage phagocytosis reveal increased bacterial ingestion following Bmal1 deletion, which was also seen in vitro. BMAL1−/− macrophages exhibited marked differences in actin cytoskeletal organization, a phosphoproteome enriched for cytoskeletal changes, with reduced phosphocofilin and increased active RhoA. Further analysis of the BMAL1−/− macrophages identified altered cell morphology and increased motility. Mechanistically, BMAL1 regulated a network of cell movement genes, 148 of which were within 100 kb of high-confidence BMAL1 binding sites. Links to RhoA function were identified, with 29 genes impacting RhoA expression or activation. RhoA inhibition restored the phagocytic phenotype to that seen in control macrophages. In summary, we identify a surprising gain of antibacterial function due to loss of BMAL1 in macrophages, associated with a RhoA-dependent cytoskeletal change, an increase in cell motility, and gain of phagocytic function

Cardiac mitochondrial function depends on BUD23 mediated ribosome programming.

Efficient mitochondrial function is required in tissues with high energy demand such as the heart, and mitochondrial dysfunction is associated with cardiovascular disease. Expression of mitochondrial proteins is tightly regulated in response to internal and external stimuli. Here we identify a novel mechanism regulating mitochondrial content and function, through BUD23-dependent ribosome generation. BUD23 was required for ribosome maturation, normal 18S/28S stoichiometry and modulated the translation of mitochondrial transcripts in human A549 cells. Deletion of Bud23 in murine cardiomyocytes reduced mitochondrial content and function, leading to severe cardiomyopathy and death. We discovered that BUD23 selectively promotes ribosomal interaction with low GC-content 5'UTRs. Taken together we identify a critical role for BUD23 in bioenergetics gene expression, by promoting efficient translation of mRNA transcripts with low 5'UTR GC content. BUD23 emerges as essential to mouse development, and to postnatal cardiac function

Circadian rhythm of exhaled biomarkers in health and asthma

Circadian rhythms control many biological processes in the body in both health and disease. Greater understanding of diurnal variability in disease related biomarkers is crucial for their application in clinical practice and biomarkers of circadian rhythm are required to facilitate further research into disturbed chronicity. To determine if fractional exhaled nitric oxide and breath volatile biomarkers vary rhythmically during the day in healthy and asthmatic individuals. Ten individuals with moderate, atopic asthma (on regular inhaled corticosteroids) and 10 healthy volunteers (all non-smokers) completed an overnight visit where their exhaled breath volatiles and forced exhaled nitric oxide levels were collected every 6 h. Breath volatiles were analysed using gas chromatography mass spectrometry, after trapping these volatiles on sorbent materials for thermal desorption. Nine breath volatiles (including acetone and isoprene) exhibit diurnal variation across all individuals. Furthermore the circadian pattern of several VOCs is altered in individuals with asthma and fractional exhaled nitric oxide is rhythmic in asthma but not in healthy controls. Markers of circadian rhythm can be identified in breath and may offer insight into circadian profiling to help treat disease. Additionally this work suggests that time of day must be controlled when designing future biomarker discovery studies. Further work is required with larger cohorts to validate and extend these findings

REVERBa couples the circadian clock to hepatic glucocorticoid action.

The glucocorticoid receptor (GR) is a major drug target in inflammatory disease. However, chronic glucocorticoid (GC) treatment leads to disordered energy metabolism, including increased weight gain, adiposity, and hepatosteatosis - all programs modulated by the circadian clock. We demonstrated that while antiinflammatory GC actions were maintained irrespective of dosing time, the liver was significantly more GC sensitive during the day. Temporal segregation of GC action was underpinned by a physical interaction of GR with the circadian transcription factor REVERBa and co-binding with liver-specific hepatocyte nuclear transcription factors (HNFs) on chromatin. REVERBa promoted efficient GR recruitment to chromatin during the day, acting in part by maintaining histone acetylation, with REVERBa-dependent GC responses providing segregation of carbohydrate and lipid metabolism. Importantly, deletion of Reverba inverted circadian liver GC sensitivity and protected mice from hepatosteatosis induced by chronic GC administration. Our results reveal a mechanism by which the circadian clock acts through REVERBa in liver on elements bound by HNF4A/HNF6 to direct GR action on energy metabolism