STAT3 Activation in Skeletal Muscle Links Muscle Wasting and the Acute Phase Response in Cancer Cachexia

Cachexia, or weight loss despite adequate nutrition, significantly impairs quality of life and response to therapy in cancer patients. In cancer patients, skeletal muscle wasting, weight loss and mortality are all positively associated with increased serum cytokines, particularly Interleukin-6 (IL-6), and the presence of the acute phase response. Acute phase proteins, including fibrinogen and serum amyloid A (SAA) are synthesized by hepatocytes in response to IL-6 as part of the innate immune response. To gain insight into the relationships among these observations, we studied mice with moderate and severe Colon-26 (C26)-carcinoma cachexia.Moderate and severe C26 cachexia was associated with high serum IL-6 and IL-6 family cytokines and highly similar patterns of skeletal muscle gene expression. The top canonical pathways up-regulated in both were the complement/coagulation cascade, proteasome, MAPK signaling, and the IL-6 and STAT3 pathways. Cachexia was associated with increased muscle pY705-STAT3 and increased STAT3 localization in myonuclei. STAT3 target genes, including SOCS3 mRNA and acute phase response proteins, were highly induced in cachectic muscle. IL-6 treatment and STAT3 activation both also induced fibrinogen in cultured C2C12 myotubes. Quantitation of muscle versus liver fibrinogen and SAA protein levels indicates that muscle contributes a large fraction of serum acute phase proteins in cancer.These results suggest that the STAT3 transcriptome is a major mechanism for wasting in cancer. Through IL-6/STAT3 activation, skeletal muscle is induced to synthesize acute phase proteins, thus establishing a molecular link between the observations of high IL-6, increased acute phase response proteins and muscle wasting in cancer. These results suggest a mechanism by which STAT3 might causally influence muscle wasting by altering the profile of genes expressed and translated in muscle such that amino acids liberated by increased proteolysis in cachexia are synthesized into acute phase proteins and exported into the blood

Problems of multi-species organisms: endosymbionts to holobionts

The organism is one of the fundamental concepts of biology and has been at the center of many discussions about biological individuality, yet what exactly it is can be confusing. The definition that we find generally useful is that an organism is a unit in which all the subunits have evolved to be highly cooperative, with very little conflict. We focus on how often organisms evolve from two or more formerly independent organisms. Two canonical transitions of this type—replicators clustered in cells and endosymbiotic organelles within host cells—demonstrate the reality of this kind of evolutionary transition and suggest conditions that can favor it. These conditions include co-transmission of the partners across generations and rules that strongly regulate and limit conflict, such as a fair meiosis. Recently, much attention has been given to associations of animals with microbes involved in their nutrition. These range from tight endosymbiotic associations like those between aphids and Buchnera bacteria, to the complex communities in animal intestines. Here, starting with a reflection about identity through time (which we call “Theseus’s fish”), we consider the distinctions between these kinds of animal–bacteria interactions and describe the criteria by which a few can be considered jointly organismal but most cannot

Kin discrimination and possible cryptic species in the social amoeba Polysphondylium violaceum

Abstract Background The genetic diversity of many protists is unknown. The differences that result from this diversity can be important in interactions among individuals. The social amoeba Polysphondylium violaceum, which is a member of the Dictyostelia, has a social stage where individual amoebae aggregate together to form a multicellular fruiting body with dead stalk cells and live spores. Individuals can either cooperate with amoebae from the same clone, or sort to form clonal fruiting bodies. In this study we look at genetic diversity in P. violaceum and at how this diversity impacts social behavior. Results The phylogeny of the ribosomal DNA sequence (17S to 5.8S region) shows that P. violaceum is made up of at least two groups. Mating compatibility is more common between clones from the same phylogenetic group, though matings between clones from different phylogenetic groups sometimes occurred. P. violaceum clones are more likely to form clonal fruiting bodies when they are mixed with clones from a different group than when they are mixed with a clone of the same group. Conclusion Both the phylogenetic and mating analyses suggest the possibility of cryptic species in P. violaceum. The level of divergence found within P. violaceum is comparable to the divergence between sibling species in other dictyostelids. Both major groups A/B and C/D/E/F show kin discrimination, which elevates relatedness within fruiting bodies but not to the level of clonality. The diminished cooperation in mixes between groups suggests that the level of genetic variation between individuals influences the extent of their cooperation

The regulation of IL-10 expression

Interleukin (IL)-10 is an important immunoregulatory cytokine and an understanding of how IL-10 expression is controlled is critical in the design of immune intervention strategies. IL-10 is produced by almost all cell types within the innate (including macrophages, monocytes, dendritic cells (DCs), mast cells, neutrophils, eosinophils and natural killer cells) and adaptive (including CD4(+) T cells, CD8(+) T cells and B cells) immune systems. The mechanisms of IL-10 regulation operate at several stages including chromatin remodelling at the Il10 locus, transcriptional regulation of Il10 expression and post-transcriptional regulation of Il10 mRNA. In addition, whereas some aspects of Il10 gene regulation are conserved between different immune cell types, several are cell type- or stimulus-specific. Here, we outline the complexity of IL-10 production by discussing what is known about its regulation in macrophages, monocytes, DCs and CD4(+) T helper cells

A prospective study on neonatal mortality and its predictors in a rural area in Burkina Faso: can MDG-4 be met by 2015?

OBJECTIVE: To measure the neonatal mortality rate (NMR) and investigate its predictors in a rural area of Burkina Faso. STUDY DESIGN: A cohort of infants born in 24 villages in Banfora region was followed until the children were 6 months old. We estimated the risk of neonatal death and used logistic regression to identify its predictors. RESULT: Among 864 live births followed to day 28, there were 40 neonatal deaths, a NMR of 46.3 per 1000 live births (95% confidence intervals (CI): 22 to 70). Multivariable regression identified twin birth (OR=11.5, 95% CI: 4.5 to 29.8), having a nulliparous mother (odds ratio (OR)=4.3, 95% CI: 1.5 to 12.1), and birth into a polygynous household (OR=2.1, 95% CI: 1.0 to 4.7) as main predictors of neonatal death. CONCLUSION: The burden of neonatal mortality in rural Burkina Faso is very high and the observed NMRs in a predominantly rural country suggest that it is unlikely Burkina will meet fourth Millennium Development Goal (MDG-4) by 2015

Stable isotope constraints on Holocene carbon cycle changes from an Antarctic ice core

Reconstructions of atmospheric CO2 concentrations based on Antarctic ice cores1,2 reveal significant changes during the Holocene epoch, but the processes responsible for these changes in CO2 concentrations have not been unambiguously identified. Distinct characteristics in the carbon isotope signatures of the major carbon reservoirs (ocean, biosphere, sediments and atmosphere) constrain variations in the CO2 fluxes between those reservoirs. Here we present a highly resolved atmospheric δ13C record for the past 11,000 years from measurements on atmospheric CO2 trapped in an Antarctic ice core. From mass-balance inverse model calculations3,4 performed with a simplified carbon cycle model, we show that the decrease in atmospheric CO2 of about 5 parts per million by volume (p.p.m.v.). The increase in δ13C of about 0.25‰ during the early Holocene is most probably the result of a combination of carbon uptake of about 290 gigatonnes of carbon by the land biosphere and carbon release from the ocean in response to carbonate compensation of the terrestrial uptake during the termination of the last ice age. The 20 p.p.m.v. increase of atmospheric CO2 and the small decrease in δ13C of about 0.05‰ during the later Holocene can mostly be explained by contributions from carbonate compensation of earlier land-biosphere uptake and coral reef formation, with only a minor contribution from a small decrease of the land-biosphere carbon inventory

Ethnicity and child health in northern Tanzania: Maasai pastoralists are disadvantaged compared to neighbouring ethnic groups.

The Maasai of northern Tanzania, a semi-nomadic ethnic group predominantly reliant on pastoralism, face a number of challenges anticipated to have negative impacts on child health, including marginalisation, vulnerabilities to drought, substandard service provision and on-going land grabbing conflicts. Yet, stemming from a lack of appropriate national survey data, no large-scale comparative study of Maasai child health has been conducted. Savannas Forever Tanzania surveyed the health of over 3500 children from 56 villages in northern Tanzania between 2009 and 2011. The major ethnic groups sampled were the Maasai, Sukuma, Rangi, and the Meru. Using multilevel regression we compare each ethnic group on the basis of (i) measurements of child health, including anthropometric indicators of nutritional status and self-reported incidence of disease; and (ii) important proximate determinants of child health, including food insecurity, diet, breastfeeding behaviour and vaccination coverage. We then (iii) contrast households among the Maasai by the extent to which subsistence is reliant on livestock herding. Measures of both child nutritional status and disease confirm that the Maasai are substantially disadvantaged compared to neighbouring ethnic groups, Meru are relatively advantaged, and Rangi and Sukuma intermediate in most comparisons. However, Maasai children were less likely to report malaria and worm infections. Food insecurity was high throughout the study site, but particularly severe for the Maasai, and reflected in lower dietary intake of carbohydrate-rich staple foods, and fruits and vegetables. Breastfeeding was extended in the Maasai, despite higher reported consumption of cow's milk, a potential weaning food. Vaccination coverage was lowest in Maasai and Sukuma. Maasai who rely primarily on livestock herding showed signs of further disadvantage compared to Maasai relying primarily on agriculture. We discuss the potential ecological, socioeconomic, demographic and cultural factors responsible for these differences and the implications for population health research and policy

Multiple greenhouse-gas feedbacks from the land biosphere under future climate change scenarios

Atmospheric concentrations of the three important greenhouse gases (GHGs) CO2, CH4 and N2O are mediated by processes in the terrestrial biosphere that are sensitive to climate and CO2. This leads to feedbacks between climate and land and has contributed to the sharp rise in atmospheric GHG concentrations since pre-industrial times. Here, we apply a process-based model to reproduce the historical atmospheric N2O and CH4 budgets within their uncertainties and apply future scenarios for climate, land-use change and reactive nitrogen (Nr) inputs to investigate future GHG emissions and their feedbacks with climate in a consistent and comprehensive framework1. Results suggest that in a business-as-usual scenario, terrestrial N2O and CH4 emissions increase by 80 and 45%, respectively, and the land becomes a net source of C by AD 2100. N2O and CH4 feedbacks imply an additional warming of 0.4–0.5 °C by AD 2300; on top of 0.8–1.0 °C caused by terrestrial carbon cycle and Albedo feedbacks. The land biosphere represents an increasingly positive feedback to anthropogenic climate change and amplifies equilibrium climate sensitivity by 22–27%. Strong mitigation limits the increase of terrestrial GHG emissions and prevents the land biosphere from acting as an increasingly strong amplifier to anthropogenic climate change