Predicting gene expression in the human malaria parasite Plasmodium falciparum using histone modification, nucleosome positioning, and 3D localization features.

Empirical evidence suggests that the malaria parasite Plasmodium falciparum employs a broad range of mechanisms to regulate gene transcription throughout the organism's complex life cycle. To better understand this regulatory machinery, we assembled a rich collection of genomic and epigenomic data sets, including information about transcription factor (TF) binding motifs, patterns of covalent histone modifications, nucleosome occupancy, GC content, and global 3D genome architecture. We used these data to train machine learning models to discriminate between high-expression and low-expression genes, focusing on three distinct stages of the red blood cell phase of the Plasmodium life cycle. Our results highlight the importance of histone modifications and 3D chromatin architecture in Plasmodium transcriptional regulation and suggest that AP2 transcription factors may play a limited regulatory role, perhaps operating in conjunction with epigenetic factors

How do I sound to me? Perceived changes in communication in Parkinson's disease

Objective: To examine self and carer perceived changes in communication associated with Parkinson's disease and relate these to speech intelligibility, gender, age and other disease measures. Design: Cross-sectional survey of a hospital- and community-based sample of 176 people with Parkinson's disease and their carers using a questionnaire based on semantic differential techniques. Participants: One hundred and four people with Parkinson's disease with no history of communication difficulties prior to onset of their Parkinson's disease and 45 primary carers who returned completed questionnaires. Main outcome measures: Differences in ratings for `before' the onset of Parkinson's disease versus present status. Results: There was a strong perception of negative impact on communication between `before' and `now', irrespective of age and gender and largely independent of disease severity and duration, intelligibility and cognitive status. Activities of daily living (assessed by Unified Parkinson's Disease Rating Scale (UPDRS) II) and depression rating scale scores had the strongest association with change (adjusted R 2 0.27). There was a significant correlation between the rank order of perceived change in features examined in people with Parkinson's disease versus their carers, though in general carers rated change as having less impact. Conclusions: Parkinson's disease exercises a strong influence on communication even before apparent alterations to intelligibility or motor status

Randomised trial of glutamine, selenium, or both, to supplement parenteral nutrition for critically ill patients

Peer reviewedPublisher PD

Climate-induced changes in river flow regimes will alter future bird distributions

Anthropogenic forcing of the climate is causing an intensification of the global water cycle, leading to an increase in the frequency and magnitude of floods and droughts. River flow shapes the ecology of riverine ecosystems and climate-driven changes in river flows are predicted to have severe consequences for riverine species, across all levels of trophic organization. However, understanding species' responses to variation in flow is limited through a lack of quantitative modelling of hydroecological interactions. Here, we construct a Bioclimatic Envelope Model (BEM) ensemble based on a suite of plausible future flow scenarios to show how predicted alterations in flow regimes may alter the distribution of a predatory riverine species, the White-throated Dipper (Cinclus cinclus). Models predicted a gradual diminution of dipper probability of occurrence between present day and 2098. This decline was most rapid in western areas of Great Britain and was principally driven by a projected decrease in flow magnitude and variability around low flows. Climate-induced changes in river flow may, therefore, represent a previously unidentified mechanism by which climate change may mediate range shifts in birds and other riverine biota

The future of image-guided radiotherapy-is image everything?

MR-based image-guided (IG) radiotherapy via all-in-one MR treatment units (MR-linacs) is one of the hottest topics in contemporary radiotherapy research. From ingenious engineering solutions to complex physical problems, researchers have developed machines with the promise of superior image quality, and all the advantages this may confer. Benefits include better tumour visualisation, online adaptation and the potential for image biomarker-based personalised RT. However, it is important to remember that the technical challenges are real. In many instances, they are skillfully managed rather than abolished, a point illustrated by the wide variety of MR-linac designs. The proposed benefits also deserve careful inspection. Better visibility of the primary tumour on an IG scan cannot be bad, but does not automatically equate to better IG, which often depends on a more generalised match to daily anatomy. MR-linac will undoubtedly be a rich milieu to search for IMBs, but these will need to be carefully validated, and similar work with CT-based biomarkers using existing, cheaper, and more widely available hardware is currently ongoing. Online adaptation is an attractive concept, but practicalities are complex, and more work is required to understand which patients will benefit from plan adaptation, and when. Finally, the issue of cost cannot be overlooked, nor can the research community's responsibilities to global healthcare inequalities. MR-linac is an exciting and ingenious technology, which merits both investment and research. It may not, however, have the future to itself

Structure of the regulatory hyaluronan binding domain in the inflammatory leukocyte homing receptor CD44

Adhesive interactions involving CD44, the cell surface receptor for hyaluronan, underlie fundamental processes such as inflammatory leukocyte homing and tumor metastasis. Regulation of such events is critical and appears to be effected by changes in CD44 N-glycosylation that switch the receptor "on" or "off" under appropriate circumstances. How altered glycosylation influences binding of hyaluronan to the lectin-like Link module in CD44 is unclear, although evidence suggests additional flanking sequences peculiar to CD44 may be involved. Here we show using X-ray crystallography and NMR spectroscopy that these sequences form a lobular extension to the Link module, creating an enlarged HA binding domain and a formerly unidentified protein fold. Moreover, the disposition of key N-glycosylation sites reveals how specific sugar chains could alter both the affinity and avidity of CD44 HA binding. Our results provide the necessary structural framework for understanding the diverse functions of CD44 and developing novel therapeutic strategies

Early Contrast Enhancement: a novel Magnetic Resonance Imaging biomarker of pleural malignancy

Introduction: Pleural Malignancy (PM) is often occult on subjective radiological assessment. We sought to define a novel, semi-objective Magnetic Resonance Imaging (MRI) biomarker of PM, targeted to increased tumour microvessel density (MVD) and applicable to minimal pleural thickening. Materials and methods: 60 consecutive patients with suspected PM underwent contrast-enhanced 3-T MRI then pleural biopsy. In 58/60, parietal pleura signal intensity (SI) was measured in multiple regions of interest (ROI) at multiple time-points, generating ROI SI/time curves and Mean SI gradient (MSIG: SI increment/time). The diagnostic performance of Early Contrast Enhancement (ECE; which was defined as a SI peak in at least one ROI at or before 4.5 min) was compared with subjective MRI and Computed Tomography (CT) morphology results. MSIG was correlated against tumour MVD (based on Factor VIII immunostain) in 31 patients with Mesothelioma. Results: 71% (41/58) patients had PM. Pleural thickening was <10 mm in 49/58 (84%). ECE sensitivity was 83% (95% CI 61–94%), specificity 83% (95% CI 68–91%), positive predictive value 68% (95% CI 47–84%), negative predictive value 92% (78–97%). ECE performance was similar or superior to subjective CT and MRI. MSIG correlated with MVD (r = 0.4258, p = .02). Discussion: ECE is a semi-objective, perfusion-based biomarker of PM, measurable in minimal pleural thickening. Further studies are warranted

Effects of density, species interactions, and environmental stochasticity on the dynamics of British bird communities

Our knowledge of the factors affecting species abundances is mainly based on time-series analyses of a few well-studied species at single or few localities, but we know little about whether results from such analyses can be extrapolated to the community level. We apply a joint species distribution model to long-term time-series data on British bird communities to examine the relative contribution of intra- and interspecific density dependence at different spatial scales, as well as the influence of environmental stochasticity, to spatiotemporal interspecific variation in abundance. Intraspecific density dependence has the major structuring effect on these bird communities. In addition, environmental fluctuations affect spatiotemporal differences in abundance. In contrast, species interactions had a minor impact on variation in abundance. Thus, important drivers of single-species dynamics are also strongly affecting dynamics of communities in time and space.Peer reviewe

North Atlantic ecosystem sensitivity to Holocene shifts in Meridional Overturning Circulation

Rapid changes in North Atlantic climate over the last millennia were driven by coupled sea surface/atmospheric processes and rates of deep-water formation. Holocene climate changes, however, remain poorly documented due to a lack of high-resolution paleoclimate records, and their impacts on marine ecosystems remain unknown. We present a 4500 years absolute-dated sea surface radiocarbon record from northeast Atlantic cold-water corals. In contrast to the current view that surface ocean changes occurred on millennial-scale cycles, our record shows more abrupt changes in surface circulation. Changes were centered at 3.4, 2.7, 1.7 and 1.2 ky BP, and associated with atmospheric re-organization. Solar irradiance may have influenced these anomalies, but changes in North Atlantic deep-water convection are likely to have amplified these signals. Critically, we provide the first evidence that these perturbations in Atlantic Meridional Overturning Circulation led to the decline of cold-water coral ecosystems from 1.2 to ~ 0.1 ky BP