Relationship between inflammatory cytokines and self-report measures of training overload

It has been purported that inflammatory cytokines may be responsible for the aetiology of overtraining. The aim of the present study was to investigate the relationship between self-reported measures of overtraining and inflammatory cytokines. Eight elite male rowers were monitored in their natural training environment for 8 weeks prior to the 2007 Rowing World Championships. During this period of intense endurance training, self-report measures of overtraining and inflammatory cytokines (Interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-12p70, and Tumor Necrosis Factor (TNF)-) were assessed fortnightly. Consistent with previous findings, proinflammatory cytokines IL-1β and TNF- were significantly associated (p ≤ 0.05) with measures of depressed mood, sleep disturbances, and stress. Similarly, IL-6 was significantly associated (p ≤ 0.01) with measures of depressed mood, sleep disturbances, and fatigue. These results are consistent with previous hypotheses describing how overtraining may be caused by excessive cytokine release, and lend further support for a cytokine hypothesis of overtraining.

Regulation of granulocyte colony-stimulating factor and its receptor in skeletal muscle is dependent upon the type of inflammatory stimulus

The cytokine granulocyte colony-stimulating factor (G-CSF) binds to its receptor (G-CSFR) to stimulate hematopoietic stem cell mobilization, myelopoiesis, and the production and activation of neutrophils. In response to exercise-induced muscle damage, G-CSF is increased in circulation and G-CSFR has recently been identified in skeletal muscle cells. While G-CSF/G-CSFR activation mediates pro- and anti-inflammatory responses, our understanding of the role and regulation in the muscle is limited. The aim of this study was to investigate, in vitro and in vivo, the role and regulation of G-CSF and G-CSFR in skeletal muscle under conditions of muscle inflammation and damage. First, C2C12 myotubes were treated with lipopolysaccharide (LPS) with and without G-CSF to determine if G-CSF modulates the inflammatory response. Second, the regulation of G-CSF and its receptor was measured following eccentric exercise-induced muscle damage and the expression levels we investigated for redox sensitivity by administering the antioxidant N-acetylcysteine (NAC). LPS stimulation of C2C12 myotubes resulted in increases in G-CSF, interleukin (IL)-6, monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-α (TNFα) messenger RNA (mRNA) and an increase in G-CSF, IL-6, and MCP-1 release from C2C12 myotubes. The addition of G-CSF following LPS stimulation of C2C12 myotubes increased IL-6 mRNA and cytokine release into the media, however it did not affect MCP-1 or TNFα. Following eccentric exercise-induced muscle damage in humans, G-CSF levels were either marginally increased in circulation or remain unaltered in skeletal muscle. Similarly, G-CSFR levels remained unchanged in response to damaging exercise and G-CSF/G-CSFR did not change in response to NAC. Collectively, these findings suggest that G-CSF may cooperate with IL-6 and potentially promote muscle regeneration in vitro, whereas in vivo aseptic inflammation induced by exercise did not change G-CSF and G-CSFR responses. These observations suggest that different models of inflammation produce a different G-CSF response.

Translocation of the socially complex black-eared miner manorina melanotis: a trial using hard and soft release techniques

We translocated five colonies of the highly social and co-operatively breeding Black-eared Miner Manorina melanotis, an endangered Australian honeyeater. Two colonies were released immediately (hard release) and two colonies were housed in aviaries for up to a week on-site and then supplied with food for a further week following release (soft release). A fifth colony was released using a combination of methods. All four hard and soft released colonies contained dependent fledglings at the time of release. This appears to be the first translocation of a co-operative species where intact colonies containing multiple breeding females, each with a suite of helpers have been translocated successfully. Both hard and soft release treatments appeared equally successful during an initial monitoring period of up to two months. All four colonies maintained social cohesion, and displayed high levels of survival and site fidelity. Both hard release and one soft release colony attempted to breed within 600 m of their release site within eight weeks of release. The other soft release colony bred 12 months later. We believe the inclusion of dependent young in each translocated colony provided a focus for translocated colonies that promoted site faithfulness and colony cohesion. Results of long-term monitoring remain inconclusive and it is recommended that monitoring be repeated during several future breeding events. Given our findings, we recommend that when translocating highly social species every effort is made to translocate the entire group, hard release techniques be applied and stimuli that enhance group cohesion and site faithfulness (the presence of dependent young) be exploited.

Scallop size does not predict amount or rate of induced sperm release

Within populations of broadcast spawning marine invertebrates such as scallops, larger animals typically have larger gonads. Presumably, this means those larger males have more sperm to release than small males. However, there has never been a direct test of whether larger males actually release more sperm, at a higher rate, during spawning. To address this, we compared the allometry of induced sperm release with that of reproductive investment (gonad weight) in ripe males of 2 species of scallops, Chlamys bifrons and Chlamys asperrima. We did not find that larger scallops released more sperm or released it faster than small scallops, and were able to reject the hypothesis that instantaneous sperm release was related to body size in the same way as gonad weight. Consequently, we speculate that if larger broadcast spawning males do release more sperm, they may do so by spawning on more occasions within a reproductive season.

Genetic variation in selenoprotein S influences inflammatory response

Chronic inflammation has a pathological role in many common diseases and is influenced by both genetic and environmental factors. Here we assess the role of genetic variation in selenoprotein S (SEPS1, also called SELS or SELENOS), a gene involved in stress response in the endoplasmic reticulum and inflammation control. After resequencing SEPS1, we genotyped 13 SNPs in 522 individuals from 92 families. As inflammation biomarkers, we measured plasma levels of IL-6, IL-1b and TNF-a. Bayesian quantitative trait nucleotide analysis identified associations between SEPS1 polymorphisms and all three proinflammatory
cytokines. One promoter variant, 105G-A, showed strong evidence for an association with each cytokine (multivariate P = 0.0000002). Functional analysis of this polymorphism showed that the A variant significantly impaired SEPS1 expression after exposure to endoplasmic reticulum stress agents (P = 0.00006). Furthermore, suppression of SEPS1 by short interfering RNA in macrophage cells increased the release of IL-6 and TNF-a. To investigate further the significance of the observed associations, we genotyped 105G-A in 419 Mexican American individuals from 23 families for replication. This analysis confirmed a significant
association with both TNF-a (P = 0.0049) and IL-1b (P = 0.0101). These results provide a direct mechanistic link between SEPS1 and the production of inflammatory cytokines and suggest that SEPS1 has a role in mediating inflammation.

Evolution of class I cytokine receptors

Background
The Class I cytokine receptors have a wide range of actions, including a major role in the development and function of immune and blood cells. However, the evolution of the genes encoding them remains poorly understood. To address this we have used bioinformatics to analyze the Class I receptor repertoire in sea squirt (Ciona intestinalis) and zebrafish (Danio rerio).
Results
Only two Class I receptors were identified in sea squirt, one with homology to the archetypal GP130 receptor, and the other with high conservation with the divergent orphan receptor CLF-3. In contrast, 36 Class I cytokine receptors were present in zebrafish, including representative members for each of the five structural groups found in mammals. This allowed the identification of 27 core receptors belonging to the last common ancestor of teleosts and mammals.
Conclusion
This study suggests that the majority of diversification of this receptor family occurred after the divergence of urochordates and vertebrates approximately 794 million years ago (MYA), but before the divergence of ray-finned from lobe-finned fishes around 476 MYA. Since then, only relatively limited lineage-specific diversification within the different Class I receptor structural groups has occurred.

Cytokine receptor signaling through the Jak-Stat-Socs pathway in disease

The complexity of multicellular organisms is dependent on systems enabling cells to respond to specific stimuli. Cytokines and their receptors are one such system, whose perturbation can lead to a variety of disease states. This review represents an overview of our current understanding of the cytokine receptors, Janus kinases (Jaks), Signal transducers and activators of transcription (Stats) and Suppressors of cytokine signaling (Socs), focussing on their contribution to diseases of an immune or hematologic nature.

The myeloproliferative disorder-associated JAK2 V617F mutant escapes negative regulation by suppressor of cytokine signaling 3

The somatic JAK2 valine-to-phenylalanine (V617F) mutation has been detected in up to 90% of patients with polycythemia and in a sizeable proportion of patients with other myeloproliferative disorders such as essential thrombocythemia and idiopathic myelofibrosis. Suppressor of cytokine signaling 3 (SOCS3) is known to be a strong negative regulator of erythropoietin (EPO) signaling through interaction with both the EPO receptor (EPOR) and JAK2. We report here that JAK2 V617F cannot be regulated and that its activation is actually potentiated in the presence of SOCS3. Instead of acting as a suppressor, SOCS3 enhanced the proliferation of cells expressing both JAK2 V617F and EPOR. Additionally, although SOCS1 and SOCS2 are degraded in the presence of JAK2 V617F, turnover of SOCS3 is inhibited by the JAK2 mutant kinase and this correlated with marked tyrosine phosphorylation of SOCS3 protein. We also observed constitutive tyrosine phosphorylation of SOCS3 in peripheral blood mononuclear cells (PBMCs) derived from patients homozygous for the JAK2 V617F mutant. These findings suggest that the JAK2 V617F has overcome normal SOCS regulation by hyperphosphorylating SOCS3, rendering it unable to inhibit the mutant kinase. Thus, JAK2 V617F may even exploit SOCS3 to potentiate its myeloproliferative capacity.

End-Permian catastrophe by a bolide impact: evidence of a gigantic release of sulfur from the mantle

Our studies in southern China have revealed a remarkable sulfur and strontium isotope excursion at the end of the Permian, along with a coincident concentration of impact- metamorphosed grains and kaolinite and a significant decrease in manganese, phosphorous, calcium, and microfossils (foraminifera). These data suggest that an asteroid or a comet hit the ocean at the end of Permian time and caused a rapid and massive release of sulfur from the mantle to the ocean-atmosphere system, leading to significant oxygen consumption, acid rain, and the most severe biotic crisis in the history of life on Earth.

The suppressor of cytokine signaling 3 inhibits leptin activation of AMP-Kinase in cultured skeletal muscle of obese humans

Context: Leptin is thought to regulate whole-body adiposity and insulin sensitivity, at least in part, by stimulating fatty acid metabolism via activation of AMP-kinase (AMPK) in skeletal muscle. Human obesity is associated with leptin resistance, and recent studies have demonstrated that hypothalamic expression of the suppressors of cytokine signaling 3 (SOCS3) regulates leptin sensitivity in rodents.

Objective: The objective of the study was to investigate the effects of leptin on fatty acid oxidation and AMPK signaling in primary myotubes derived from lean and obese skeletal muscle and evaluate the contribution of SOCS3 to leptin resistance and AMPK signaling in obese humans.

Results: We demonstrate that leptin stimulates AMPK activity and increases AMPK Thr172 and acetyl-CoA carboxylase-ß Ser222 phosphorylation and fatty acid oxidation in lean myotubes but that in obese subjects leptin-dependent AMPK signaling and fatty acid oxidation are suppressed. Reduced activation of AMPK was associated with elevated expression of IL-6 (~3.5-fold) and SOCS3 mRNA (~2.5-fold) in myotubes of obese subjects. Overexpression of SOCS3 via adenovirus-mediated infection in lean myotubes to a similar degree as observed in obese myotubes prevented leptin but not AICAR (5-amino-imidazole-4-carboxamide-1-ß-D-ribofuranoside) activation of AMPK signaling.

Conclusions: These data demonstrate that SOCS3 inhibits leptin activation of AMPK. These data suggest that this impairment of leptin signaling in skeletal muscle may contribute to the aberrant regulation of fatty acid metabolism observed in obesity and that pharmacological activation of AMPK may be an effective therapy to bypass SOCS3-mediated skeletal muscle leptin resistance for the treatment of obesity-related disorders.

Disease fingerprinting with cDNA microarrays reveals distinct gene expression profiles in lethal type 1 and type 2 cytokine-mediated inflammatory reactions

Development of polarized immune responses controls resistance and susceptibility to many microorganisms. However, studies of several infectious, allergic, and autoimmune diseases have shown that chronic type-1 and type-2 cytokine responses can also cause significant morbidity and mortality if left unchecked. We used mouse cDNA microarrays to molecularly phenotype the gene expression patterns that characterize two disparate but equally lethal forms of liver pathology that develop in Schistosoma mansoni infected mice polarized for type-1 and type-2 cytokine responses. Hierarchical clustering analysis identified at least three groups of genes associated with a polarized type-2 response and two linked with an extreme type-1 cytokine phenotype. Predictions about liver fibrosis,  apoptosis, and granulocyte recruitment and activation generated by the microarray studies were confirmed later by traditional biological assays. The data show that cDNA microarrays are useful not only for determining  coordinated gene expression profiles but are also highly effective for molecularly “fingerprinting” diseased tissues. Moreover, they illustrate the potential of genome-wide approaches for generating comprehensive views on the molecular and biochemical mechanisms regulating infectious  disease pathogenesis.

Estimating post-release survival and the influential factors for recreationally caught Black Bream (Acanthopagrus butcheri) in the Glenelg River, south eastern Australia

Black bream (Acanthopagrus butcheri) is the main target species amongst the estuarine recreational fisheries of Victoria, Australia. The A. butcheri fishery is managed through legal-minimum length and daily bag limits. The success of this management strategy requires that the survival rate for released fish is high. This study used the most common angling practices to estimate post-release survival and identify influential factors for undersized A. butcheri in Victoria. In total 1557 and 923 A. butcheri were caught and monitored for initial (≤1 h) and delayed (72 h) survival, respectively. Fish were caught across 3 years, with each year separated into cold and warm water periods with 8 fishing trial days in total. Only 1 of the 266 controls used to assess confinement effects died. Total survival was 95% (S.E. ± 0.8%) for shallow- and 74% (S.E. ± 3%) for deep-hooked fish and decreased as fish length increased. A post-mortem (PM) procedure was developed and showed that throat and gill injuries were the most frequent cause of deep-hooking death. It revealed that 97% of hooks left in fish remained there after 72 h and identified hooking location inaccuracies recorded at the time of capture. Total survival for deep-hooked fish was 20% higher when hooks were left in the fish. Deep-hooked fish were more likely to bleed when hooks were removed and total survival was lower for fish that bleed (58%) than fish that did not bleed (80%). Shallow-hooking rates decreased as fish length increased and were higher during warm water compared to cold water trials. The high shallow-hooking and survival rates observed suggest that A. butcheri survival in the fishery would be high, but deep-hooking has the potential to undermine the management strategy. Determining the shallow-hooking rate in the fishery would help clarify the impact of these findings at the fishery level.