Systematic review of light exposure impact on human circadian rhythm

Light is necessary for life, and artificial light improves visual performance and safety, but there is an increasing concern of the potential health and environmental impacts of light. Findings from a number of studies suggest that mistimed light exposure disrupts the circadian rhythm in humans, potentially causing further health impacts. However, a variety of methods has been applied in individual experimental studies of light-induced circadian impacts, including definition of light exposure and outcomes. Thus, a systematic review is needed to synthesize the results. In addition, a review of the scientific evidence on the impacts of light on circadian rhythm is needed for developing an evaluation method of light pollution, i.e., the negative impacts of artificial light, in life cycle assessment (LCA). The current LCA practice does not have a method to evaluate the light pollution, neither in terms of human health nor the ecological impacts. The systematic literature survey was conducted by searching for two concepts: light and circadian rhythm. The circadian rhythm was searched with additional terms of melatonin and rapid-eye-movement (REM) sleep. The literature search resulted to 128 articles which were subjected to a data collection and analysis. Melatonin secretion was studied in 122 articles and REM sleep in 13 articles. The reports on melatonin secretion were divided into studies with specific light exposure (101 reports), usually in a controlled laboratory environment, and studies of prevailing light conditions typical at home or work environments (21 studies). Studies were generally conducted on adults in their twenties or thirties, but only very few studies experimented on children and elderly adults. Surprisingly many studies were conducted with a small sample size: 39 out of 128 studies were conducted with 10 or less subjects. The quality criteria of studies for more profound synthesis were a minimum sample size of 20 subjects and providing details of the light exposure (spectrum or wavelength; illuminance, irradiance or photon density). This resulted to 13 qualified studies on melatonin and 2 studies on REM sleep. Further analysis of these 15 reports indicated that a two-hour exposure to blue light (460 nm) in the evening suppresses melatonin, the maximum melatonin-suppressing effect being achieved at the shortest wavelengths (424 nm, violet). The melatonin concentration recovered rather rapidly, within 15 min from cessation of the exposure, suggesting a short-term or simultaneous impact of light exposure on the melatonin secretion. Melatonin secretion and suppression were reduced with age, but the light-induced circadian phase advance was not impaired with age. Light exposure in the evening, at night and in the morning affected the circadian phase of melatonin levels. In addition, even the longest wavelengths (631 nm, red) and intermittent light exposures induced circadian resetting responses, and exposure to low light levels (5–10 lux) at night when sleeping with eyes closed induced a circadian response. The review enables further development of an evaluation method of light pollution in LCA regarding the light-induced impacts on human circadian system.     

Identification of liver‐derived bone morphogenetic protein (BMP)‐9 as a potential new candidate for treatment of colorectal cancer

Colorectal cancer (CRC) is a high‐incidence malignancy worldwide which still needs better therapy options. Therefore, the aim of the present study was to investigate the responses of normal or malignant human intestinal epithelium to bone morphogenetic protein (BMP)‐9 and to find out whether the application of BMP‐9 to patients with CRC or the enhancement of its synthesis in the liver could be useful strategies for new therapy approaches. In silico analyses of CRC patient cohorts (TCGA database) revealed that high expression of the BMP‐target gene ID1, especially in combination with low expression of the BMP‐inhibitor noggin, is significantly associated with better patient survival. Organoid lines were generated from human biopsies of colon cancer (T‐Orgs) and corresponding non‐malignant areas (N‐Orgs) of three patients. The N‐Orgs represented tumours belonging to three different consensus molecular subtypes (CMS) of CRC. Overall, BMP‐9 stimulation of organoids promoted an enrichment of tumour‐suppressive gene expression signatures, whereas the stimulation with noggin had the opposite effects. Furthermore, treatment of organoids with BMP‐9 induced ID1 expression (independently of high noggin levels), while treatment with noggin reduced ID1.In summary, our data identify the ratio between ID1 and noggin as a new prognostic value for CRC patient outcome. We further show that by inducing ID1, BMP‐9 enhances this ratio, even in the presence of noggin. Thus, BMP‐9 is identified as a novel target for the development of improved anti‐cancer therapies of patients with CRC.     

Phosphorus Flux Through a Littoral Ecosystem: The Importance of Cladoceran Zooplankton and Young Fish

Foodchain relationships in water within a helophytic vegetation stand were experimentally investigated using the radioactive isotope ³³P as a tracer. The results proved the importance of cladoceran zooplankton (mainly Bosmina longispina LEYDIG) in the control of phytoplankton and the importance of young fish in the control of Bosmina abundance in the littoral water.     

Relative importance of habitat connectivity in shaping the genetic profiles of two southern African elephant‐shrews

Aim When interpreting genetic patterns across a landscape it is surprisingly difficult to disentangle the effects of landscape connectivity from those of species biology. Here, the spatial distributions of genetic variation of two sympatric elephant‐shrew species, the western rock elephant‐shrew (Elephantulus rupestris) and the round‐eared elephant‐shrew (Macroscelides proboscideus), are determined and compared. We selected these species because they have similar biologies but differ markedly in habitat use, the rationale being that differences in their genetic structure should be a result largely of landscape variables directly or indirectly affecting dispersal rather than of the biology of the species. Location South Africa and Namibia. Methods Mitochondrial sequence data (control region and cytochrome b) were used to describe the phylogeographic structure of these elephant‐shrew species across their distribution. To determine whether genetic variation is significantly structured, spatial analyses of molecular variation were performed. Isolation‐by‐distance versus alternative patterns of genetic structure was investigated using a Mantel test. Results Our analyses indicated an overall structured genetic profile for E. rupestris, a species closely associated with rocky outcrops. This was in contrast to a pattern mostly of isolation‐by‐distance across the distribution of M. proboscideus, a species found on gravel plains. Main conclusions Specific landscape features will differentially affect gene flow (both historical and current), and therefore also the spatial genetic structure, of species with markedly different habitat requirements. The genetic profiles for the two species included here support predictions based on the connectivity of their respective occupied habitats. The results also support the more general prediction that species with a naturally clustered distribution (such as E. rupestris) should have a more structured genetic pattern than those having a more continuous distribution (M. proboscideus).     

Constitutive signaling of the human cytomegalovirus-encoded chemokine receptor US28

Previously it was shown that the HHV-8-encoded chemokine receptor ORF74 shows considerable agonist-independent, constitutive activity giving rise to oncogenic transformation (Arvanitakis, L., Geras-Raaka, E., Varma, A., Gershengorn, M. C., and Cesarman, E. (1997) Nature 385, 347-350). In this study we report that a second viral-encoded chemokine receptor, the human cytomegalovirus-encoded US28, also efficiently signals in an agonist-independent manner. Transient expression of US28 in COS-7 cells leads to the constitutive activation of phospholipase C and NF-kappaB signaling via G(q/11) protein-dependent pathways. Whereas phospholipase C activation is mediated via Galpha(q/11) subunits, the activation of NF-kappaB strongly depends on betagamma subunits with a preference for the beta(2)gamma(1) dimer. The CC chemokines RANTES (regulated on activation, normal T cell expressed and secreted) and MCP-1 (monocyte chemotactic protein-1) act as neutral antagonists at US28, whereas the CX(3)C chemokine fractalkine acts as a partial inverse agonist with IC(50) values of 1-5 nm. Our data suggest that a high level of constitutive activity might be a more general characteristic of viral G protein-coupled receptors and that human cytomegalovirus might exploit this G protein-coupled receptor property to modulate the homeostasis of infected cells via the early gene product US28.     

The S-layer protein of Lactobacillus acidophilus ATCC 4356: identification and characterisation of domains responsible for S-protein assembly and cell wall binding

Lactobacillus acidophilus, like many other bacteria, harbors a surface layer consisting of a protein (S(A)-protein) of 43 kDa. S(A)-protein could be readily extracted and crystallized in vitro into large crystalline patches on lipid monolayers with a net negative charge but not on lipids with a net neutral charge. Reconstruction of the S-layer from crystals grown on dioleoylphosphatidylserine indicated an oblique lattice with unit cell dimensions (a=118 A; b=53 A, and gamma=102 degrees ) resembling those determined for the S-layer of Lactobacillus helveticus ATCC 12046. Sequence comparison of S(A)-protein with S-proteins from L. helveticus, Lactobacillus crispatus and the S-proteins encoded by the silent S-protein genes from L. acidophilus and L. crispatus suggested the presence of two domains, one comprising the N-terminal two-thirds (SAN), and another made up of the C-terminal one-third (SAC) of S(A)-protein. The sequence of the N-terminal domains is variable, while that of the C-terminal domain is highly conserved in the S-proteins of these organisms and contains a tandem repeat. Proteolytic digestion of S(A)-protein showed that SAN was protease-resistant, suggesting a compact structure. SAC was rapidly degraded by proteases and therefore probably has a more accessible structure. DNA sequences encoding SAN or Green Fluorescent Protein fused to SAC (GFP-SAC) were efficiently expressed in Escherichia coli. Purified SAN could crystallize into mono and multi-layered crystals with the same lattice parameters as those found for authentic S(A)-protein. A calculated S(A)-protein minus SAN density-difference map revealed the probable location, in projection, of the SAC domain, which is missing from the truncated SAN peptide. The GFP-SAC fusion product was shown to bind to the surface of L. acidophilus, L. helveticus and L. crispatus cells from which the S-layer had been removed, but not to non-stripped cells or to Lactobacillus casei.     

Heparan sulfate-modified CD44 promotes hepatocyte growth factor/scatter factor-induced signal transduction through the receptor tyrosine kinase c-Met

CD44 has been implicated in tumor progression and metastasis, but the mechanism(s) involved is as yet poorly understood. Recent studies have shown that CD44 isoforms containing the alternatively spliced exon v3 carry heparan sulfate side chains and are able to bind heparin-binding growth factors. In the present study, we have explored the possibility of a physical and functional interaction between CD44 and hepatocyte growth factor/scatter factor (HGF/SF), the ligand of the receptor tyrosine kinase c-Met. The HGF/SF-c-Met pathway mediates cell growth and motility and has been implicated in tumor invasion and metastasis. We demonstrate that a CD44v3 splice variant efficiently binds HGF/SF via its heparan sulfate side chain. To address the functional relevance of this interaction, Namalwa Burkitt's lymphoma cells were stably co-transfected with c-Met and either CD44v3 or the isoform CD44s, which lacks heparan sulfate. We show that, as compared with CD44s, CD44v3 promotes: (i) HGF/SF-induced phosphorylation of c-Met, (ii) phosphorylation of several downstream proteins, and (iii) activation of the MAP kinases ERK1 and -2. By heparitinase treatment and the use of a mutant HGF/SF with greatly decreased affinity for heparan sulfate, we show that the enhancement of c-Met signal transduction induced by CD44v3 was critically dependent on heparan sulfate moieties. Our results identify heparan sulfate-modified CD44 (CD44-HS) as a functional co-receptor for HGF/SF which promotes signaling through the receptor tyrosine kinase c-Met, presumably by concentrating and presenting HGF/SF. As both CD44-HS and c-Met are overexpressed on several types of tumors, we propose that the observed functional collaboration might be instrumental in promoting tumor growth and metastasis.