T-tubule disease: Relationship between t-tubule organization and regional contractile performance in human dilated cardiomyopathy.

Evidence from animal models suggest that t-tubule changes may play an important role in the contractile deficit associated with heart failure. However samples are usually taken at random with no regard as to regional variability present in failing hearts which leads to uncertainty in the relationship between contractile performance and possible t-tubule derangement. Regional contraction in human hearts was measured by tagged cine MRI and model fitting. At transplant, failing hearts were biopsy sampled in identified regions and immunocytochemistry was used to label t-tubules and sarcomeric z-lines. Computer image analysis was used to assess 5 different unbiased measures of t-tubule structure/organization. In regions of failing hearts that showed good contractile performance, t-tubule organization was similar to that seen in normal hearts, with worsening structure correlating with the loss of regional contractile performance. Statistical analysis showed that t-tubule direction was most highly correlated with local contractile performance, followed by the amplitude of the sarcomeric peak in the Fourier transform of the t-tubule image. Other area based measures were less well correlated. We conclude that regional contractile performance in failing human hearts is strongly correlated with the local t-tubule organization. Cluster tree analysis with a functional definition of failing contraction strength allowed a pathological definition of 't-tubule disease'. The regional variability in contractile performance and cellular structure is a confounding issue for analysis of samples taken from failing human hearts, although this may be overcome with regional analysis by using tagged cMRI and biopsy mapping.

Changing composition of SARS-CoV-2 lineages and rise of Delta variant in England.

BACKGROUND: Since its emergence in Autumn 2020, the SARS-CoV-2 Variant of Concern (VOC) B.1.1.7 (WHO label Alpha) rapidly became the dominant lineage across much of Europe. Simultaneously, several other VOCs were identified globally. Unlike B.1.1.7, some of these VOCs possess mutations thought to confer partial immune escape. Understanding when and how these additional VOCs pose a threat in settings where B.1.1.7 is currently dominant is vital. METHODS: We examine trends in the prevalence of non-B.1.1.7 lineages in London and other English regions using passive-case detection PCR data, cross-sectional community infection surveys, genomic surveillance, and wastewater monitoring. The study period spans from 31st January 2021 to 15th May 2021. FINDINGS: Across data sources, the percentage of non-B.1.1.7 variants has been increasing since late March 2021. This increase was initially driven by a variety of lineages with immune escape. From mid-April, B.1.617.2 (WHO label Delta) spread rapidly, becoming the dominant variant in England by late May. INTERPRETATION: The outcome of competition between variants depends on a wide range of factors such as intrinsic transmissibility, evasion of prior immunity, demographic specificities and interactions with non-pharmaceutical interventions. The presence and rise of non-B.1.1.7 variants in March likely was driven by importations and some community transmission. There was competition between non-B.1.17 variants which resulted in B.1.617.2 becoming dominant in April and May with considerable community transmission. Our results underscore that early detection of new variants requires a diverse array of data sources in community surveillance. Continued real-time information on the highly dynamic composition and trajectory of different SARS-CoV-2 lineages is essential to future control efforts. FUNDING: National Institute for Health Research, Medicines and Healthcare products Regulatory Agency, DeepMind, EPSRC, EA Funds programme, Open Philanthropy, Academy of Medical Sciences Bill,Melinda Gates Foundation, Imperial College Healthcare NHS Trust, The Novo Nordisk Foundation, MRC Centre for Global Infectious Disease Analysis, Community Jameel, Cancer Research UK, Imperial College COVID-19 Research Fund, Medical Research Council, Wellcome Sanger Institute.

COVID-19 cycles and rapidly evaluating lockdown strategies using spectral analysis.

Spectral analysis characterises oscillatory time series behaviours such as cycles, but accurate estimation requires reasonable numbers of observations. At the time of writing, COVID-19 time series for many countries are short: pre- and post-lockdown series are shorter still. Accurate estimation of potentially interesting cycles seems beyond reach with such short series. We solve the problem of obtaining accurate estimates from short series by using recent Bayesian spectral fusion methods. We show that transformed daily COVID-19 cases for many countries generally contain three cycles operating at wavelengths of around 2.7, 4.1 and 6.7 days (weekly) and that shorter wavelength cycles are suppressed after lockdown. The pre- and post-lockdown differences suggest that the weekly effect is at least partly due to non-epidemic factors. Unconstrained, new cases grow exponentially, but the internal cyclic structure causes periodic declines. This suggests that lockdown success might only be indicated by four or more daily falls. Spectral learning for epidemic time series contributes to the understanding of the epidemic process and can help evaluate interventions. Spectral fusion is a general technique that can fuse spectra recorded at different sampling rates, which can be applied to a wide range of time series from many disciplines.

A wavelet lifting approach to long-memory estimation.

Reliable estimation of long-range dependence parameters is vital in time series. For example, in environmental and climate science such estimation is often key to understanding climate dynamics, variability and often prediction. The challenge of data collection in such disciplines means that, in practice, the sampling pattern is either irregular or blighted by missing observations. Unfortunately, virtually all existing Hurst parameter estimation methods assume regularly sampled time series and require modification to cope with irregularity or missing data. However, such interventions come at the price of inducing higher estimator bias and variation, often worryingly ignored. This article proposes a new Hurst exponent estimation method which naturally copes with data sampling irregularity. The new method is based on a multiscale lifting transform exploiting its ability to produce wavelet-like coefficients on irregular data and, simultaneously, to effect a necessary powerful decorrelation of those coefficients. Simulations show that our method is accurate and effective, performing well against competitors even in regular data settings. Armed with this evidence our method sheds new light on long-memory intensity results in environmental and climate science applications, sometimes suggesting that different scientific conclusions may need to be drawn.

Impact of adenoviral transduction with SREBP1c or AMPK on pancreatic islet gene expression profile: analysis with oligonucleotide microarrays.

Accumulation of triglyceride in islets may contribute to the loss of glucose-stimulated insulin secretion (GSIS) in some forms of type 2 diabetes (Diraison et al., Biochem J 373:769-778, 2004). Here, we use adenoviral vectors and oligonucleotide microarrays to determine the effects of the forced expression of SREBP1c on the gene expression profile of rat islets. Sterol regulatory element binding protein-1c (SREBP1c) overexpression led to highly significant (P <0.1 with respect to null adenovirus) changes in the expression of 1,238 genes or expressed sequence tags, of which 1,180 (95.3%) were upregulated. By contrast, overexpression of constitutively active AMP-activated protein kinase (AMPK), expected to promote lipolysis, altered the expression of 752 genes, of which 702 (93%) were upregulated. To identify specific targets for SREBP1c or AMPK, we eliminated messages that were 1) affected in the same direction by the expression of either protein, 2) changed by less than twofold, or 3) failed a positive false discovery test; 206 SREBP1c-regulated genes (195; 95% upregulated) and 48 AMPK-regulated genes (33; 69% upregulated) remained. As expected, SREBP1c-induced genes included those involved in cholesterol (6), fatty acid (3), and eicosanoid synthesis. Interestingly, somatostatin receptor (sstr1) expression was increased by SREBP1c, whereas AMPK induced the expression of peptide YY, the early endocrine pancreas marker.