Analysis of mortality metrics associated with a comprehensive range of disorders in Denmark, 2000 to 2018: A population-based cohort study

BackgroundThe provision of different types of mortality metrics (e.g., mortality rate ratios [MRRs] and life expectancy) allows the research community to access a more informative set of health metrics. The aim of this study was to provide a panel of mortality metrics associated with a comprehensive range of disorders and to design a web page to visualize all results.Methods and findingsIn a population-based cohort of all 7,378,598 persons living in Denmark at some point between 2000 and 2018, we identified individuals diagnosed at hospitals with 1,803 specific categories of disorders through the International Classification of Diseases-10th Revision (ICD-10) in the National Patient Register. Information on date and cause of death was obtained from the Registry of Causes of Death. For each of the disorders, a panel of epidemiological and mortality metrics was estimated, including incidence rates, age-of-onset distributions, MRRs, and differences in life expectancy (estimated as life years lost [LYLs]). Additionally, we examined models that adjusted for measures of air pollution to explore potential associations with MRRs. We focus on 39 general medical conditions to simplify the presentation of results, which cover 10 broad categories: circulatory, endocrine, pulmonary, gastrointestinal, urogenital, musculoskeletal, hematologic, mental, and neurologic conditions and cancer. A total of 3,676,694 males and 3,701,904 females were followed up for 101.7 million person-years. During the 19-year follow-up period, 1,034,273 persons (14.0%) died. For 37 of the 39 selected medical conditions, mortality rates were larger and life expectancy shorter compared to the Danish general population. For these 37 disorders, MRRs ranged from 1.09 (95% confidence interval [CI]: 1.09 to 1.10) for vision problems to 7.85 (7.77 to 7.93) for chronic liver disease, while LYLs ranged from 0.31 (0.14 to 0.47) years (approximately 16 weeks) for allergy to 17.05 (16.95 to 17.15) years for chronic liver disease. Adjustment for air pollution had very little impact on the estimates; however, a limitation of the study is the possibility that the association between the different disorders and mortality could be explained by other underlying factors associated with both the disorder and mortality.ConclusionsIn this study, we show estimates of incidence, age of onset, age of death, and mortality metrics (both MRRs and LYLs) for a comprehensive range of disorders. The interactive data visualization site (https://nbepi.com/atlas) allows more fine-grained analysis of the link between a range of disorders and key mortality estimates.

In a population-based study, Oleguer Plana-Ripoll and colleagues report on and develop an online resource to study mortality metrics and life expectancy associated with different health conditions among individuals living in Denmark.     

Temporal Variation in the Importance of a Dominant Consumer to Stream Nutrient Cycling

Animal excretion can be a significant nutrient flux within ecosystems, where it supports primary production and facilitates microbial decomposition of organic matter. The effects of excretory products on nutrient cycling have been documented for various species and ecosystems, but temporal variation in these processes is poorly understood. We examined variation in excretion rates of a dominant grazing snail, Elimia clavaeformis, and its contribution to nutrient cycling, over the course of 14 months in a well-studied, low-nutrient stream (Walker Branch, east Tennessee, USA). Biomass-specific excretion rates of ammonium varied over twofold during the study, coinciding with seasonal changes in food availability (measured as gross primary production) and water temperature (multiple linear regression, R ² = 0.57, P = 0.053). The contribution of ammonium excretion to nutrient cycling varied with seasonal changes in both biological (that is, nutrient uptake rate) and physical (that is, stream flow) variables. On average, ammonium excretion accounted for 58% of stream water ammonium concentrations, 26% of whole-stream nitrogen demand, and 66% of autotrophic nitrogen uptake. Phosphorus excretion by Elimia was contrastingly low throughout the year, supplying only 1% of total dissolved phosphorus concentrations. The high average N:P ratio (89:1) of snail excretion likely exacerbated phosphorus limitation in Walker Branch. To fully characterize animal excretion rates and effects on ecosystem processes, multiple measurements through time are necessary, especially in ecosystems that experience strong seasonality.     

Structure of the haemagglutinin-neuraminidase from human parainfluenza virus type III

The three-dimensional structure of the haemagglutinin-neuraminidase (HN) from a human parainfluenza virus is described at ca 2.0 A resolution, both in native form and in complex with three substrate analogues. In support of earlier work on the structure of the homologous protein from the avian pathogen Newcastle disease virus (NDV), we observe a dimer of beta-propellers and find no evidence for spatially separated sites performing the receptor-binding and neuraminidase functions of the protein. As with the NDV HN, the active site of the HN of parainfluenza viruses is structurally flexible, suggesting that it may be able to switch between a receptor-binding state and a catalytic state. However, in contrast to the NDV structures, we observe no ligand-induced structural changes that extend beyond the active site and modify the dimer interface.     

A carboxy-terminal trimerization domain stabilizes conformational epitopes on the stalk domain of soluble recombinant hemagglutinin substrates

Recently, a new class of broadly neutralizing anti-influenza virus antibodies that target the stalk domain of the viral hemagglutinin was discovered. As such, induction, isolation, characterization, and quantification of these novel antibodies has become an area of intense research and great interest. Since most of these antibodies bind to conformational epitopes, the structural integrity of hemagglutinin substrates for the detection and quantification of these antibodies is of high importance. Here we evaluate the binding of these antibodies to soluble, secreted hemagglutinins with or without a carboxy-terminal trimerization domain based on the natural trimerization domain of T4 phage fibritin. The lack of such a domain completely abolishes binding to group 1 hemagglutinins and also affects binding to group 2 hemagglutinins. Additionally, the presence of a trimerization domain positively influences soluble hemagglutinin stability during expression and purification. Our findings suggest that a carboxy-terminal trimerization domain is a necessary requirement for the structural integrity of stalk epitopes on recombinant soluble influenza virus hemagglutinin.     

Tree water dynamics in a drying and warming world

Disentangling the relative impacts of precipitation reduction and vapour pressure deficit (VPD) on plant water dynamics and determining whether acclimation may influence these patterns in the future is an important challenge. Here, we report sap flux density (F_D), stomatal conductance (G_s), hydraulic conductivity (K_L) and xylem anatomy in piñon pine (Pinus edulis) and juniper (Juniperus monosperma) trees subjected to five years of precipitation reduction, atmospheric warming (elevated VPD) and their combined effects. No acclimation occurred under precipitation reduction: lower G_s and F_D were found for both species compared to ambient conditions. Warming reduced the sensibility of stomata to VPD for both species but resulted in the maintenance of G_s and F_D to ambient levels only for piñon. For juniper, reduced soil moisture under warming negated benefits of stomatal adjustments and resulted in reduced F_D, G_s and K_L. Although reduced stomatal sensitivity to VPD also occurred under combined stresses, reductions in G_s, F_D and K_L took place to similar levels as under single stresses for both species. Our results show that stomatal conductance adjustments to high VPD could minimize but not entirely prevent additive effects of warming and drying on water use and carbon acquisition of trees in semi‐arid regions.     

Capturing protein communities by structural proteomics in a thermophilic eukaryote

The arrangement of proteins into complexes is a key organizational principle for many cellular functions. Although the topology of many complexes has been systematically analyzed in isolation, their molecular sociology in situ remains elusive. Here, we show that crude cellular extracts of a eukaryotic thermophile, Chaetomium thermophilum, retain basic principles of cellular organization. Using a structural proteomics approach, we simultaneously characterized the abundance, interactions, and structure of a third of the C. thermophilum proteome within these extracts. We identified 27 distinct protein communities that include 108 interconnected complexes, which dynamically associate with each other and functionally benefit from being in close proximity in the cell. Furthermore, we investigated the structure of fatty acid synthase within these extracts by cryoEM and this revealed multiple, flexible states of the enzyme in adaptation to its association with other complexes, thus exemplifying the need for in situ studies. As the components of the captured protein communities are known—at both the protein and complex levels—this study constitutes another step forward toward a molecular understanding of subcellular organization.     

Creating two-dimensional patterned substrates for protein and cell confinement

Microcontact printing provides a rapid, highly reproducible method for the creation of well-defined patterned substrates.(1) While microcontact printing can be employed to directly print a large number of molecules, including proteins,(2) DNA,(3) and silanes,(4) the formation of self-assembled monolayers (SAMs) from long chain alkane thiols on gold provides a simple way to confine proteins and cells to specific patterns containing adhesive and resistant regions. This confinement can be used to control cell morphology and is useful for examining a variety of questions in protein and cell biology. Here, we describe a general method for the creation of well-defined protein patterns for cellular studies.(5) This process involves three steps: the production of a patterned master using photolithography, the creation of a PDMS stamp, and microcontact printing of a gold-coated substrate. Once patterned, these cell culture substrates are capable of confining proteins and/or cells (primary cells or cell lines) to the pattern. The use of self-assembled monolayer chemistry allows for precise control over the patterned protein/cell adhesive regions and non-adhesive regions; this cannot be achieved using direct protein stamping. Hexadecanethiol, the long chain alkane thiol used in the microcontact printing step, produces a hydrophobic surface that readily adsorbs protein from solution. The glycol-terminated thiol, used for backfilling the non-printed regions of the substrate, creates a monolayer that is resistant to protein adsorption and therefore cell growth.(6) These thiol monomers produce highly structured monolayers that precisely define regions of the substrate that can support protein adsorption and cell growth. As a result, these substrates are useful for a wide variety of applications from the study of intercellular behavior(7) to the creation of microelectronics.(8) While other types of monolayer chemistry have been used for cell culture studies, including work from our group using trichlorosilanes to create patterns directly on glass substrates,(9) patterned monolayers formed from alkane thiols on gold are straight-forward to prepare. Moreover, the monomers used for monolayer preparation are commercially available, stable, and do not require storage or handling under inert atmosphere. Patterned substrates prepared from alkane thiols can also be recycled and reused several times, maintaining cell confinement.(10).     

Dynamic proteomics in individual human cells uncovers widespread cell-cycle dependence of nuclear proteins

We examined cell cycle-dependent changes in the proteome of human cells by systematically measuring protein dynamics in individual living cells. We used time-lapse microscopy to measure the dynamics of a random subset of 20 nuclear proteins, each tagged with yellow fluorescent protein (YFP) at its endogenous chromosomal location. We synchronized the cells in silico by aligning protein dynamics in each cell between consecutive divisions. We observed widespread (40%) cell-cycle dependence of nuclear protein levels and detected previously unknown cell cycle-dependent localization changes. This approach to dynamic proteomics can aid in discovery and accurate quantification of the extensive regulation of protein concentration and localization in individual living cells.     

Cell surface galactosyltransferase as a recognition molecule during development

Recent results from our laboratory suggest that a variety of cellular interactions during development are mediated, in part, by the binding of a cell surface enzyme, galactosyltransferase (GalTase), to its specific lactosaminoglycan (LAG) substrate on adjacent cell surfaces and in the extracellular matrix. Our present interest in surface GalTase developed from earlier biochemical studies of a series of morphogenetic mutations in the mouse which map to the T/t-complex. These studies identified a specific defect in the regulation of surface GalTase activity on morphogenetically abnormal cells, while eight other enzymes showed normal activity. This led us to consider the unique function of surface GalTase in those cell interactions that are influenced by mutations of the T/t-complex. By using a multidisciplinary approach, which included genetic, biochemical and immunological probes, we have found that GalTase functions as a surface receptor during fertilization, early embryonic cell adhesions, and embryonic cell migration on basal lamina matrices. Recently, we have examined the expression of surface GalTase during spermatogenesis, as well as the fate of sperm GalTase following the acrosome reaction. This paper summarizes the results of these studies, as well as others, which suggest that GalTase functions as a surface receptor during those cell interactions regulated by the T/t-complex alleles.