Pleiotropic effects of statins: do they matter?

Treatment with the 3-hydroxy-3-methylglutaryl coenyzme A reductase inhibitors (or statins) reduces the risk for cardiovascular events across a broad spectrum of patient profiles, as evidenced by both primary prevention and secondary prevention trials. Improved survival by way of reduced deaths from coronary heart disease was also reported with these agents, which are primarily indicated for substantial reduction in LDL-cholesterol levels. However, the statins are extremely complex drugs and exhibit a wide variety of vascular effects that may or may not be dependent on their lipid-modifying properties. These so-called pleiotropic effects include alterations of endothelial function, inflammation, coagulation, and plaque stability. The relative contribution of the nonlipid effects of statin therapy to the well-documented clinical benefits is currently under intense investigation.     

Pipefishes and seahorses: Are they all sex role reversed?

The male pregnancy of pipefishes and seahorses has led to the inference that females compete most intensely for access to mates, because males limit female reproduction. However, recent work has shown that in different species either sex may be the predominant competitor for mates. In this family, there is an apparent association between the mating pattern and the sex roles: polygamous species show reversed sex roles whereas monogamous species exhibit 'conventional' sex roles. These studies emphasize that sex role reversal is not synonymous with male parental care.     

Opioid and melanocortin receptors: do they have overlapping pharmacophores?

We have identified compound 1 as a novel ligand for opioid and melanocortin (MC) receptors, which is derived from the overlapping of a well known structure for the delta opioid receptor, 2,6-dimethyltyrosine (Dmt)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic), and a small molecule for the MC receptor, Tic-DPhe(p-Cl)-piperidin-4-yl-N-phenyl-propionamide. Ligand 1 showed that there is an overlapping pharmacophore between opioid and MC receptors through the Tic residue. The ligand displayed high biological activities at the delta opioid receptor (Ki = 0.38 nM in binding assay, EC(50) = 0.48 nM in GTP-gamma-S binding assay, IC(50) = 74 nM in MVD) as an agonist instead of an antagonist and showed selective binding affinity (IC(50) = 2.3 muM) at the MC-3 receptor rather than at the MC-5 receptor. A study of the structure-activity relationships demonstrated that the residues in positions 2, 3, and the C-terminus act as a pharmacophore for the MC receptors, and the residues in positions 1 and 2 act as a pharmacophore for the opioid receptors. Thus, this structural construct can be used to prepare chimeric structures with adjacent or overlapping pharmacophores for opioid and MC receptors.     

Oxysterols in human circulation: which role do they have?

Oxysterols are oxygenated derivatives of cholesterol that are intermediates in cholesterol excretion pathways. They may also be regarded as transport forms of cholesterol and introduction of an additional hydroxyl group facilitates flux of cholesterol across cell membranes and the blood-brain barrier. According to current concepts, oxysterols are also mediating a number of cholesterol-induced metabolic effects. The recent discovery of nuclear receptors with an affinity for oxysterols has given support to this concept. Nuclear receptors such as liver X receptor alpha do have a role in cholesterol homeostasis, but there is still only indirect evidence that oxysterols are the physiological ligands. In this overview we report some recent advancements in our knowledge about the origin and metabolic fate of the quantitatively most important oxysterols occurring in the circulation. In addition, we discuss the possibility that some of these oxysterols may activate liver X receptors and regulate cholesterol homeostasis.     

Are there edge effects on forest fungi and if so do they matter?

Fungi are vital within forest ecosystems through their mycorrhizal relationships with trees, and as the main agents of wood decomposition and thus carbon and nutrient cycling. Globally, forests are becoming increasingly fragmented, creating forest patches that are isolated, reduced in area, and exposed at edges. Edges are often ecologically distinct from the forest interior due to their exposure to the matrix habitat. This exposure can result in altered microclimatic conditions and flows of biotic and abiotic materials such as spores or inorganic nitrogen, respectively.Although fungi are known to be affected by microclimate and nitrogen deposition, knowledge of forest edge effects on fungi is extremely limited; however, a consideration of the factors known to regulate fungal activity in combination with known biotic and abiotic edge effects implies that forest edges are likely to strongly influence fungi. These include responses of fungi to the altered microclimate and nitrogen levels at forest edges, at both the individual and community level; interactions with plants and animals that have been influenced by edges; above–belowground feedback between mycorrhizal fungi and host trees. The small body of existing research focuses on fruit body presence and distribution; fungal biomass and community composition in soil have been touched upon. Positive, negative and neutral edge responses have been found, the majority of studies finding a significant effect on some of the parameters measured. Generally, abundance of fruit bodies and biomass in the soil is lower at the forest edge.Understanding how fungi respond to edges is essential to a more complete knowledge of carbon and nitrogen cycling in forest edges, influence of mycorrhizal species on vegetation, and conservation of rare fungi. As edges become increasingly dominant landscape features it is vital to investigate processes within them, to understand ecosystem function at a landscape scale.     

Biomarkers in outpatient heart failure management; Are they correlated to and do they influence clinical judgment?

Aims

Heart failure (HF) management is complicated by difficulties in clinical assessment. Biomarkers may help guide HF management, but the correspondence between clinical evaluation and biomarker serum levels has hardly been studied. We investigated the correlation between biomarkers and clinical signs and symptoms, the influence of patient characteristics and comorbidities on New York Heart Association (NYHA) classification and the effect of using biomarkers on clinical evaluation.

Methods and results

This post-hoc analysis comprised 622 patients (77 ± 8 years, 76 % NYHA class ≥3, 80 % LVEF ≤45 %) participating in TIME-CHF, randomising patients to either NT-proBNP-guided or symptom-guided therapy. Biomarker measurements and clinical evaluation were performed at baseline and after 1, 3, 6, 12 and 18 months. NT-proBNP, GDF-15, hs-TnT and to a lesser extent hs-CRP and cystatin-C were weakly correlated to NYHA, oedema, jugular vein distension and orthopnoea (ρ-range: 0.12–0.33; p < 0.01). NT-proBNP correlated more strongly to NYHA class in the NT-proBNP-guided group compared with the symptom-guided group. NYHA class was significantly influenced by age, body mass index, anaemia, and the presence of two or more comorbidities.

Conclusion

In HF, biomarkers correlate only weakly with clinical signs and symptoms. NYHA classification is influenced by several comorbidities and patient characteristics. Clinical judgement seems to be influenced by a clinician’s awareness of NT-proBNP concentrations.

Electronic supplementary material

The online version of this article (doi:10.1007/s12471-013-0503-y) contains supplementary material, which is available to authorized users.     

Bacterial flagella: Do they rotate or do they propagate waves of bending?

Conclusion Whether the flagellum is rigid or nearly so or whether there are moving helical lines of contraction (Astbury et al. 1955,Lowy andSpencer 1968), incompatible sets of bonds at different radii (Klug 1967), subunits which alter their configurational states (Asakura 1966, 1970) or slip between subunits carried by edge dislocations (Harris andScriven 1971, 1973), the prevention of apparent rotation of the flagellum will result in actual rotation of the body. The differences between the two classes of mechanisms have a scale beyond the power of resolution of the light microscope. Because of this it is most unlikely that direct observation of a moving bacterium will provide evidence favouring any one of the mechanisms. The mechanism of movement of bacterial flagella remains unknown.     

Body odour preferences in men and women: do they aim for specific MHC combinations or simply heterozygosity?

The major histocompatibility complex (MHC) is an immunologically important group of genes that appears to be under natural as well as sexual selection. Several hypotheses suggest that certain MHC-allele combinations (usually heterozygous ones) are superior under selective pressure by pathogens. This could influence mate choice in a way that preferences function to create MHC-heterozygous offspring, or that they function to create specific allele combinations that are beneficial under the current environmental conditions through their complementary or epistatic effects. To test these hypotheses, we asked 121 men and women to score the odours of six T-shirts, worn by two women and four men. Their scorings of pleasantness correlated negatively with the degree of MHC similarity between smeller and T-shirt-wearer in men and women who were not using the contraceptive pill (but not in Pill-users). Depending on the T-shirt-wearer, the amount of variance in the scorings of odour pleasantness that was explained by the degree of MHC similarity (r2) varied between nearly 0 and 23%. There was no apparent effect of gender in this correlation: the highest r2 was actually reached with one of the male odours sniffed by male smellers. Men and women who were reminded of their own mate/ex-mate when sniffing a T-shirt had significantly fewer MHC-alleles in common with this T-shirt-wearer than expected by chance. This suggests that the MHC or linked genes influence human mate choice. We found no significant effect when we tested for an influence of the MHC on odour preferences after the degree of similarity between T-shirt-wearer and smeller was statistically controlled for. This suggests that in our study populations the MHC influences body odour preferences mainly, if not exclusively, by the degree of similarity or dissimilarity. The observed preferences would increase heterozygosity in the progeny. They do not seem to aim for more specific MHC combinations.     

Can forest management have season-dependent effects on bird diversity?

Forest management modified the original structure of most European forests, and in the most extreme cases, genuinely natural and semi-natural forests were turned into plantations through clear felling and replanting, often using non-native species. We compared the bird community structure of native oak woods of northern Italy with that of their anthropogenic counter-parts: black locust and sweet chestnut woods. The three stand types were compared in terms of vegetation structure, bird species richness, diversity and abundance of foraging guilds. We analysed both the overwintering and the breeding community, to assess whether management had specific seasonal effects on bird diversity. Forestry-imposed disturbances affected bird diversity more consistently in winter than in breeding time: bird species richness and diversity were significantly greater in oak and chestnut stands, which were the preferred habitat for bark foragers and foliage gleaners. In the breeding period, bird diversity of black locust woodlands increased, and inter-stand differences were not significant. At this time of year, understorey gleaners were more abundant in black locust stands (where shrubs were denser). In winter, species richness, diversity and the abundance of several guilds were positively correlated with stand age, whereas in the breeding period canopy gleaners preferred younger woodlots. Despite the lack of inter-stand differences in breeding bird diversity, young-managed woods benefited generalist birds that need no particular conservation efforts. Conversely, priority species for forest conservation such as specialised bark foragers positively selected native and mature stands throughout the year. We suggest that detailed year-round studies on diversity and community composition could sharpen the precision with which it is possible to prescribe conservation measures in forested areas.     

Mechanosensitive channels: what can they do and how do they do it?

While mechanobiological processes employ diverse mechanisms, at their heart are force-induced perturbations in the structure and dynamics of molecules capable of triggering subsequent events. Among the best characterized force-sensing systems are bacterial mechanosensitive channels. These channels reflect an intimate coupling of protein conformation with the mechanics of the surrounding membrane; the membrane serves as an adaptable sensor that responds to an input of applied force and converts it into an output signal, interpreted for the cell by mechanosensitive channels. The cell can exploit this information in a number of ways: ensuring cellular viability in the presence of osmotic stress and perhaps also serving as a signal transducer for membrane tension or other functions. This review focuses on the bacterial mechanosensitive channels of large (MscL) and small (MscS) conductance and their eukaryotic homologs, with an emphasis on the outstanding issues surrounding the function and mechanism of this fascinating class of molecules.     

‘Are fish what they eat’ all year round?

Isotope turnover in muscle of ectotherms depends primarily on growth rather than on metabolic replacement. Ectotherms, such as fish, have a discontinuous pattern of growth over the year, so the isotopic signature of muscle (δ¹³C and δ¹⁵N) may only reflect food consumed during periods of growth. In contrast, the liver is a regulatory tissue, with a continuous protein turnover. Therefore, the isotopic composition of liver should respond year round to changes in the isotopic signature of food sources. Therefore, we predicted that (1) Whitefish in Lake Geneva would have larger seasonal variation in the isotopic variation of the liver compared to that of the muscle tissue, and (2) the isotope composition of fish muscle would reflect a long-term image of the isotope composition of the food consumed only throughout the growth period. To test these expectations, we compared the isotope compositions of Whitefish muscle, liver and food in a 20-month study. We found that the seasonal amplitude of isotope variation was two to three times higher in liver compared to muscle tissue. During the autumn and winter, when growth was limited, only the isotopic signature of liver responded to changes in the isotope composition of the food sources. The δ¹³C and δ¹⁵N of muscle tissue only reflected the food consumed during the spring and summer growth period.     

Fungi,a neglected component of acidophilic biofilms: do they have a potential for biotechnology?

Extremophiles - Fungi from extreme environments, including acidophilic ones, belong to biotechnologically most attractive organisms. They can serve as a source of enzymes and metabolites with...     

Inflammation,Depression and Dementia: Are they Connected?

Chronic inflammation is now considered to be central to the pathogenesis not only of such medical disorders as cardiovascular disease, multiple sclerosis, diabetes and cancer but also of major depression. If chronic inflammatory changes are a common feature of depression, this could predispose depressed patients to neurodegenerative changes in later life. Indeed there is now clinical evidence that depression is a common antecedent of Alzheimer’s disease and may be an early manifestation of dementia before the cognitive declines becomes apparent. This review summarises the evidence that links chronic low grade inflammation with changes in brain structure that could precipitate neurodegenerative changes associated with Alzheimer’s disease and other dementias. For example, neuronal loss is a common feature of major depression and dementia. It is hypothesised that the progress from depression to dementia could result from the activation of macrophages in the blood, and microglia in the brain, that release pro-inflammatory cytokines. Such cytokines stimulate a cascade of inflammatory changes (such as an increase in prostaglandin E2, nitric oxide in addition to more pro-inflammatory cytokines) and a hypersecretion of cortisol. The latter steroid inhibits protein synthesis thereby reducing the synthesis of neurotrophic factors and preventing reairto damages neuronal networks. In addition, neurotoxic end products of the tryptophan-kynurenine pathway, such as quinolinic acid, accumulate in astrocytes and neurons in both depression and dementia. Thus increased neurodegeneration, reduced neuroprotection and neuronal repair are common pathological features of major depression and dementia. Such changes may help to explain why major depression is a frequent prelude to dementia in later life. Special issue dedicated to Dr. Moussa Youdim.     

Pathogenic archaea: do they exist?

Archaea are microorganisms that are distinct from bacteria and eukaryotes. They are prevalent in extreme environments, and yet found in most ecosystems. They are a natural component of the microbiota of most, if not all, humans and other animals. Despite their ubiquity and close association with humans, animals and plants, no pathogenic archaea have been identified. Because no archaeal pathogens have yet been identified, there is a general assumption that archaeal pathogens do not exist. This review examines whether this is a good assumption by investigating the potential for archaea to be or become pathogens. This is achieved by addressing: the diversity of archaea versus known pathogens, opportunities for archaea to demonstrate pathogenicity and be detected as pathogens, reports linking archaea with disease, and immune responses to archaea. In addition, molecular and genomic data are examined for the presence of systems utilised in pathogenesis. The view of this report is that, although archaea can presently be described as non-pathogenic, they have the potential to be (discovered as) pathogens. The present optimistic view that there are no archaeal pathogens is tainted by a severe lack of relevant knowledge, which may have important consequences in the future.     

Cytosolic glycosidases: do they exist?

The substrate specificity of the alpha-D-mannosidases of rat liver lysosome and cytosol was examined using oligosaccharides of the oligomannosidic type. The hydrolysis products were characterized by 400 MHz 1H-NMR spectroscopy. Both catabolic pathways occur in ordered ways, but are quite different. In fact, the lysosomal pathway is a two-step process: the first step involves a Zn(2+)-independent alpha-1,2-mannosidase activity, whereas the second involves a Zn(2+)-dependent alpha-1,3- and alpha-1,6-mannosidase activity. The final product is the disaccharide Man(beta 1-4)GlcNAc. In contrast, the cytosolic pathway leads, in one step, to a unique hexasaccharide (Man5GlcNAc) which has the same structure as the polyprenolic intermediate synthesized on the cytosolic face of the rough endoplasmic reticulum during the biosynthesis of N-glycosylprotein glycans: Man(alpha 1-2)-Man(alpha 1-2)Man(alpha 1-3)[Man(alpha 1-6)] Man(beta 1-4)GlcNAc(beta 1-4)-GlcNAc(alpha)P-P-Dol. In addition, the enzymatic parameters of lysosome, endoplasmic reticulum and cytosol alpha-D-mannosidases are quite different. These results lead to the conclusion that the cytosol contains specific alpha-D-mannosidases which do not originate from lysosomes nor from endoplasmic reticulum. The discovery of cytosolic endo-N-acetyl-beta-D-glucosaminidase active on 'immature complex glycans' (glycopeptides of the oligomannosidic type and of the desialylated N-acetyllactosaminic type) as well as on the glycosyl-dolichol pyrophosphate intermediates allows us to hypothesize that these enzymes belong to a control system of N-glycosylprotein biosynthesis, their role being to destroy unfinished glycans. The fate of the formed oligosaccharide structures is discussed: are they destroyed by cytosolic or lysosomal exoglycosidases, or do they carry an 'oligosaccharin-like activity'?     

Stress physiology in marine mammals: how well do they fit the terrestrial model?

Stressors are commonly accepted as the causal factors, either internal or external, that evoke physiological responses to mediate the impact of the stressor. The majority of research on the physiological stress response, and costs incurred to an animal, has focused on terrestrial species. This review presents current knowledge on the physiology of the stress response in a lesser studied group of mammals, the marine mammals. Marine mammals are an artificial or pseudo grouping from a taxonomical perspective, as this group represents several distinct and diverse orders of mammals. However, they all are fully or semi-aquatic animals and have experienced selective pressures that have shaped their physiology in a manner that differs from terrestrial relatives. What these differences are and how they relate to the stress response is an efflorescent topic of study. The identification of the many facets of the stress response is critical to marine mammal management and conservation efforts. Anthropogenic stressors in marine ecosystems, including ocean noise, pollution, and fisheries interactions, are increasing and the dramatic responses of some marine mammals to these stressors have elevated concerns over the impact of human-related activities on a diverse group of animals that are difficult to monitor. This review covers the physiology of the stress response in marine mammals and places it in context of what is known from research on terrestrial mammals, particularly with respect to mediator activity that diverges from generalized terrestrial models. Challenges in conducting research on stress physiology in marine mammals are discussed and ways to overcome these challenges in the future are suggested.     

Where have all the flowers gone? Are our woodland flowers disappearing?

The owner of a wood in Norfolk once told me that he thought that the lily of the valley has declined over the last 20 years. In Wytham Woods near Oxford the dense bramble patches I studied in the 1970s didn't seem so thick ten years later. Were these slips of the memory or did Pete Seeger have a point with his 1961 song - Where have all the flowers gone?