microRNAs and death receptors

Death receptors induce apoptosis through either the Type I or II pathway. In Type I cells, the initiator caspase-8 directly activates effector caspases such as caspase-3, whereas in Type II cells, the death signal is amplified through mitochondria thereby activating effector caspases causing cell death. Recently, there have been advances in elucidating the early events in the CD95 signaling pathways and how post-translational modifications regulate CD95 signaling. This review will focus on recent insights into the mechanisms of the two different types of CD95 signaling pathways, and will introduce miRNAs as regulators of death receptor signaling.     

Microclimatic buffering by logging residues and forest edges reduces clear‐cutting impacts on forest bryophytes

Question: The practice of extracting logging residues after clear‐cutting for bioenergy purposes is spreading. Logging residues constitute a shelter in clear‐cut areas and therefore concerns have been expressed that their removal could make the ground and its vegetation more exposed to extreme microclimatic conditions. We asked whether logging residues and forest edges can protect ground‐dwelling forest bryophytes from fatal microclimate events following clear‐cutting. Location: Boreal forests of central Sweden. Methods: Using transplants of eight forest floor bryophyte species we experimentally analysed the sheltering effect (less solar radiation and less wind) of logging residues and forest edges in seven clear‐cut areas. Transplants were placed in two contrasting positions in each area; near a north‐facing forest edge and in the centre of the clear‐cut area. In each position, half of the transplants were covered by a layer of spruce branches and the other half was left uncovered. We estimated proportion of apparently living shoots (apparent vitality) and measured radial growth of transplants during one growing season. Results: Position in the clear‐cut area, but not cover of spruce branches, clearly influenced radial growth. Vitality scores were higher among transplants covered with branches and the lowest apparent vitality was observed in uncovered transplants in the middle of clear‐cut areas. The change in area of apparently living shoots during the course of the experiment (growth minus mortality) was unaffected by branch cover close to the edge but positively affected in the centre of the clear‐cut area. In general, the effect of branch cover on bryophytes was higher in the centre of clear‐cut areas. Here, climatic measurements showed that branch cover buffers during periods of extreme microclimates. Conclusions: Extraction of logging residues after clear‐felling may reduce the survival of some ground‐dwelling forest organisms. The additional sheltering provided by branches was unimportant close to forest edges. We suggest smaller clear‐cut areas, green‐tree retention and other ways to make logged areas shadier and less windy to mitigate the reduced shelter caused by harvest of logging residues.     

Induction of Attachment of the Mussel Perna perna by Natural Products from the Brown Seaweed Stypopodium zonale

Marine invertebrates settle, attach, and/or metamorphose in response to signals from several sources, including seaweeds. In response to the aquaculture challenge of producing constant numbers of juveniles from cultured species, natural inducers have been screened for their ability to improve those processes. However, few chemical inducers of attachment of invertebrates have been identified, and even less of these were secondary metabolites. The goal of this work was to isolate the natural products responsible for induction activity using bioassay-guided fractionation of the organic extract of the brown seaweed Stypopodium zonale and the attachment of juveniles of the common brown mussel, Perna perna, as a model. The meroditerpene epitaondiol, identified by comparison of spectral data with the literature, promoted as much as 4.7 times more mussel attachment compared to controls at the natural concentration found in this alga (0.041% of the crude extract or 0.012% of algal dry weight). This is the first report showing that a seaweed produces terpenoid compounds as cues for invertebrate attachment, and future studies evaluating this action on settlement of mussels in the field are expected to improve aquaculture technology by increasing mussel spat production.     

Principal stratification with predictors of compliance for randomized trials with 2 active treatments

In behavioral medicine trials, such as smoking cessation trials, 2 or more active treatments are often compared. Noncompliance by some subjects with their assigned treatment poses a challenge to the data analyst. The principal stratification framework permits inference about causal effects among subpopulations characterized by potential compliance. However, in the absence of prior information, there are 2 significant limitations: (1) the causal effects cannot be point identified for some strata and (2) individuals in the subpopulations (strata) cannot be identified. We propose to use additional information-compliance-predictive covariates-to help identify the causal effects and to help describe characteristics of the subpopulations. The probability of membership in each principal stratum is modeled as a function of these covariates. The model is constructed using marginal compliance models (which are identified) and a sensitivity parameter that captures the association between the 2 marginal distributions. We illustrate our methods in both a simulation study and an analysis of data from a smoking cessation trial.     

The emergence of leaders and followers in foraging pairs when the qualities of individuals differ

Background  

Foraging in groups offers animals a number of advantages, such as increasing their likelihood of finding food or detecting and avoiding predators. In order for a group to remain together, there has to be some degree of coordination of behaviour and movement between its members (which may in some cases be initiated by a decision-making leader, and in other cases may emerge as an underlying property of the group). For example, behavioural synchronisation is a phenomenon where animals within a group initiate and then continue to conduct identical behaviours, and has been characterised for a wide range of species. We examine how a pair of animals should behave using a state-dependent approach, and ask what conditions are likely to lead to behavioural synchronisation occurring, and whether one of the individuals is more likely to act as a leader.     

High Functional Diversity in Mycobacterium tuberculosis Driven by Genetic Drift and Human Demography

Mycobacterium tuberculosis infects one third of the human world population and kills someone every 15 seconds. For more than a century, scientists and clinicians have been distinguishing between the human- and animal-adapted members of the M. tuberculosis complex (MTBC). However, all human-adapted strains of MTBC have traditionally been considered to be essentially identical. We surveyed sequence diversity within a global collection of strains belonging to MTBC using seven megabase pairs of DNA sequence data. We show that the members of MTBC affecting humans are more genetically diverse than generally assumed, and that this diversity can be linked to human demographic and migratory events. We further demonstrate that these organisms are under extremely reduced purifying selection and that, as a result of increased genetic drift, much of this genetic diversity is likely to have functional consequences. Our findings suggest that the current increases in human population, urbanization, and global travel, combined with the population genetic characteristics of M. tuberculosis described here, could contribute to the emergence and spread of drug-resistant tuberculosis.     

Rationale for prostaglandin I2 in bone marrow oedema – from theory to application

Introduction

Bone marrow oedema (BME) and avascular osteonecrosis (AVN) are disorders of unclear origin. Although there are numerous operative and non-operative treatments for AVN, pain management in patients with AVN remains challenging. Prostaglandins play an important role in inflammatory responses and cell differentiation. It is thought that prostaglandin I₂ ([PGI₂] or synonoma prostacyclin) and its analogues promote bone regeneration on a cellular or systemic level. The purpose of this study was to assess the curative and symptomatic efficacy of the prostacyclin analogue iloprost in BME and AVN patients.

Method

We are reporting on 50 patients (117 bones) affected by BME/AVN who were treated with iloprost. Pain levels before, during and 3 and 6 months after iloprost application were evaluated by a visual analogue scale (VAS). The short form(SF)-36 health survey served to judge general health status before and after treatment. Harris Hip Score (HHS) and Knee Society Score (KSS) were performed as functional scores and MRI and X-rays before and 3 and 6 months after iloprost application served as objective parameters for morphological changes of the affected bones.

Results

We found a significant improvement in pain, functional and radiological outcome in BME and early AVN stages after iloprost application, whereas patients with advanced AVN stages did not benefit from iloprost infusions. Mean pain level decreased from 5.26 (day 0) to 1.63 (6 months) and both HHS and KSS increased during follow-up. Moreover, the SF-36 increased from 353.2 (day 0) to 560.5 points (6 months). We found a significant decrease in BME on MRI scans after iloprost application.

Conclusions

In addition to other drugs, iloprost may be an alternative substance which should be considered in the treatment of BME/AVN-associated pain.     

Antibody suspension bead arrays within serum proteomics

Antibody microarrays offer a powerful tool to screen for target proteins in complex samples. Here, we describe an approach for systematic analysis of serum, based on antibodies and using color-coded beads for the creation of antibody arrays in suspension. This method, adapted from planar antibody arrays, offers a fast, flexible, and multiplexed procedure to screen larger numbers of serum samples, and no purification steps are required to remove excess labeling substance. The assay system detected proteins down to lower picomolar levels with dynamic ranges over 3 orders of magnitude. The feasibility of this workflow was shown in a study with more than 200 clinical serum samples tested for 20 serum proteins.     

Distinction between human cytochrome P450 (CYP) isoforms and identification of new phosphorylation sites by mass spectrometry

In mammals, Cytochrome P450 (CYP) enzymes are bound to membranes of the endoplasmic reticulum and mitochondria, where they are responsible for the oxidative metabolism of many xenobiotics as well as organic endogenous compounds. In humans, 57 isoforms were identified which are classified based on sequence homology. In the present work, we demonstrate the performance of a mass spectrometry-based strategy to simultaneously detect and differentiate distinct human Cytochrome P450 (CYP) isoforms including the highly similar CYP3A4, CYP3A5, CYP3A7, as well as CYP2C8, CYP2C9, CYP2C18, CYP2C19, and CYP4F2, CYP4F3, CYP4F11, CYP4F12. Compared to commonly used immunodetection methods, mass spectrometry overcomes limitations such as low antibody specificity and offers high multiplexing possibilities. Furthermore, CYP phosphorylation, which may affect various biochemical and enzymatic properties of these enzymes, is still poorly analyzed, especially in human tissues. Using titanium dioxide resin combined with tandem mass spectrometry for phosphopeptide enrichment and sequencing, we discovered eight human P450 phosphorylation sites, seven of which were novel. The data from surgical human liver samples establish that the isoforms CYP1A2, CYP2A6, CYP2B6, CYP2E1, CYP2C8, CYP2D6, CYP3A4, CYP3A7, and CYP8B1 are phosphorylated in vivo. These results will aid in further investigation of the functional significance of protein phosphorylation for this important group of enzymes.