Wrist actimetry circadian rhythm as a robust predictor of colorectal cancer patients survival

The disruption of the circadian timing system (CTS), which rhythmically controls cellular metabolism and proliferation, accelerated experimental cancer progression. A measure of CTS function in cancer patients could thus provide novel prediction information for outcomes, and help to identify novel specific therapies. The rest-activity circadian rhythm is a reliable and non-invasive CTS biomarker, which was monitored using a wrist watch accelerometer for 2 days in 436 patients with metastatic colorectal cancer. The relative percentage of activity in-bed versus out-of-bed (I < O) constituted the tested CTS measure, whose prognostic value for overall survival (OS) and progression-free survival (PFS) was determined in a pooled analysis of three patient cohorts with different treatment exposures. Median OS was 21.6 months [17.8–25.5] for patients with I < O above the median value of 97.5% as compared to 11.9 months [10.4–13.3] for those with a lower I < O (Log-rank p < 0.001). Multivariate analyses retained continuous I < O as a joint predictor of both OS and PFS, with respective hazard ratios (HR) of 0.954 (p < 0.001) and 0.970 (p < 0.001) for each 1% increase in I < O. HRs had similar values in all the patient subgroups tested. The circadian physiology biomarker I < O constitutes a robust and independent quantitative predictor of cancer patient outcomes, that can be easily and cost-effectively measured during daily living. Interventional studies involving 24-h schedules of clock-targeted drugs, light intensity, exercise and/or meals are needed for testing the relevance of circadian synchronization for the survival of patients with disrupted rhythms

MACSIMS : multiple alignment of complete sequences information management system

BACKGROUND: In the post-genomic era, systems-level studies are being performed that seek to explain complex biological systems by integrating diverse resources from fields such as genomics, proteomics or transcriptomics. New information management systems are now needed for the collection, validation and analysis of the vast amount of heterogeneous data available. Multiple alignments of complete sequences provide an ideal environment for the integration of this information in the context of the protein family. RESULTS: MACSIMS is a multiple alignment-based information management program that combines the advantages of both knowledge-based and ab initio sequence analysis methods. Structural and functional information is retrieved automatically from the public databases. In the multiple alignment, homologous regions are identified and the retrieved data is evaluated and propagated from known to unknown sequences with these reliable regions. In a large-scale evaluation, the specificity of the propagated sequence features is estimated to be >99%, i.e. very few false positive predictions are made. MACSIMS is then used to characterise mutations in a test set of 100 proteins that are known to be involved in human genetic diseases. The number of sequence features associated with these proteins was increased by 60%, compared to the features available in the public databases. An XML format output file allows automatic parsing of the MACSIM results, while a graphical display using the JalView program allows manual analysis. CONCLUSION: MACSIMS is a new information management system that incorporates detailed analyses of protein families at the structural, functional and evolutionary levels. MACSIMS thus provides a unique environment that facilitates knowledge extraction and the presentation of the most pertinent information to the biologist. A web server and the source code are available at

The Inner-Shelf Dynamics Experiment

17 USC 105 interim-entered record; under review.The article of record as published may be found at http://dx.doi.org/10.1175/BAMS-D-19-0281.1The inner shelf, the transition zone between the surfzone and the midshelf, is a dynamically complex region with the evolution of circulation and stratification driven by multiple physical processes. Cross-shelf exchange through the inner shelf has important implications for coastal water quality, ecological connectivity, and lateral movement of sediment and heat. The Inner-Shelf Dynamics Experiment (ISDE) was an intensive, coordinated, multi-institution field experiment from September–October 2017, conducted from the midshelf, through the inner shelf, and into the surfzone near Point Sal, California. Satellite, airborne, shore- and ship-based remote sensing, in-water moorings and ship-based sampling, and numerical ocean circulation models forced by winds, waves, and tides were used to investigate the dynamics governing the circulation and transport in the inner shelf and the role of coastline variability on regional circulation dynamics. Here, the following physical processes are highlighted: internal wave dynamics from the midshelf to the inner shelf; flow separation and eddy shedding off Point Sal; offshore ejection of surfzone waters from rip currents; and wind-driven subtidal circulation dynamics. The extensive dataset from ISDE allows for unprecedented investigations into the role of physical processes in creating spatial heterogeneity, and nonlinear interactions between various inner-shelf physical processes. Overall, the highly spatially and temporally resolved oceanographic measurements and numerical simulations of ISDE provide a central framework for studies exploring this complex and fascinating region of the ocean.U.S. Office of Naval Research (ONR)ONR Departmental Research Initiative (DRI)Inner-Shelf Dynamics Experiment (ISDE

Daily rhythms of the sleep-wake cycle

The amount and timing of sleep and sleep architecture (sleep stages) are determined by several factors, important among which are the environment, circadian rhythms and time awake. Separating the roles played by these factors requires specific protocols, including the constant routine and altered sleep-wake schedules. Results from such protocols have led to the discovery of the factors that determine the amounts and distribution of slow wave and rapid eye movement sleep as well as to the development of models to determine the amount and timing of sleep. One successful model postulates two processes. The first is process S, which is due to sleep pressure (and increases with time awake) and is attributed to a 'sleep homeostat'. Process S reverses during slow wave sleep (when it is called process S'). The second is process C, which shows a daily rhythm that is parallel to the rhythm of core temperature. Processes S and C combine approximately additively to determine the times of sleep onset and waking. The model has proved useful in describing normal sleep in adults. Current work aims to identify the detailed nature of processes S and C. The model can also be applied to circumstances when the sleep-wake cycle is different from the norm in some way. These circumstances include: those who are poor sleepers or short sleepers; the role an individual's chronotype (a measure of how the timing of the individual's preferred sleep-wake cycle compares with the average for a population); and changes in the sleep-wake cycle with age, particularly in adolescence and aging, since individuals tend to prefer to go to sleep later during adolescence and earlier in old age. In all circumstances, the evidence that sleep times and architecture are altered and the possible causes of these changes (including altered S, S' and C processes) are examined

Capillary dynamics and the interstitial fluid lymphatic system

The capillaries are the ?business end? of the circulatory system, where materials exchange between the plasma and tissues. Water-soluble molecules can diffuse through pores in the capillaries, and a Gibbs?Donnan equilibrium exists between the plasma and interstitium. There are several types of capillaries, which vary in their anatomical integrity and permeability. There is also a bulk flow of fluids between the plasma and interstitium, described by the Starling forces. Originally, these forces were thought to cause fluids to leave the capillaries at the arteriolar end and return at the venular end; the role of the lymphatics was to provide an ?overflow? mechanism due to protein leakage out of the capillaries. More recent work indicates that this concept needs modification. Lymph flow and interstitial colloidal osmotic pressure are now known to be greater than first thought, and the interstitium has a slightly negative hydrostatic pressure. It is now believed that filtration takes place along most of the capillary, and the lymphatic system plays a more important role in maintaining plasma?interstitium equilibrium and preventing oedema. The system acts as a ?closed? one in that the changes in fluid formation (e.g. following haemorrhage or cardiac failure) are self-limiting. However, in some circulations (e.g. those to the kidneys, glands and the gut), net fluid production or absorption is required. This requirement is fulfilled by an independence from the Starling forces, the systems behaving as ?open? ones.The capillaries are the ?business end? of the circulatory system, where materials exchange between the plasma and tissues. Water-soluble molecules can diffuse through pores in the capillaries, and a Gibbs?Donnan equilibrium exists between the plasma and interstitium. There are several types of capillaries, which vary in their anatomical integrity and permeability. There is also a bulk flow of fluids between the plasma and interstitium, described by the Starling forces. Originally, these forces were thought to cause fluids to leave the capillaries at the arteriolar end and return at the venular end; the role of the lymphatics was to provide an ?overflow? mechanism due to protein leakage out of the capillaries. More recent work indicates that this concept needs modification. Lymph flow and interstitial colloidal osmotic pressure are now known to be greater than first thought, and the interstitium has a slightly negative hydrostatic pressure. It is now believed that filtration takes place along most of the capillary, and the lymphatic system plays a more important role in maintaining plasma?interstitium equilibrium and preventing oedema. The system acts as a ?closed? one in that the changes in fluid formation (e.g. following haemorrhage or cardiac failure) are self-limiting. However, in some circulations (e.g. those to the kidneys, glands and the gut), net fluid production or absorption is required. This requirement is fulfilled by an independence from the Starling forces, the systems behaving as ?open? ones