Antioxidant Machinery Differs between Melanic and Light Nestlings of Two Polymorphic Raptors

Colour polymorphism results from the expression of multiallelic genes generating phenotypes with very distinctive colourations. Most colour polymorphisms are due to differences in the type or amount of melanins present in each morph, which also differ in several behavioural, morphometric and physiological attributes. Melanin-based colour morphs could also differ in the levels of glutathione (GSH), a key intracellular antioxidant, because of the role of this molecule in melanogenesis. As GSH inhibits the synthesis of eumelanin (i.e. the darkest melanin form), individuals of darker morphs are expected to have lower GSH levels than those of lighter morphs. We tested this prediction in nestlings of two polymorphic raptors, the booted eagle Hieraaetus pennatus and the Eleonora's falcon Falco eleonorae, both of which occur in two morphs differing in the extent of eumelanic plumage. As expected, melanic booted eagle nestlings had lower blood GSH levels than light morph eagle nestlings. In the Eleonora's falcon, however, melanic nestlings only had lower GSH levels after controlling for the levels of other antioxidants. We also found that melanic female eagle nestlings had higher levels of antioxidants other than GSH and were in better body condition than light female eagle nestlings. These findings suggest an adaptive response of melanic nestlings to compensate for reduced GSH levels. Nevertheless, these associations were not found in falcons, indicating species-specific particularities in antioxidant machinery. Our results are consistent with previous work revealing the importance of GSH on the expression of melanic characters that show continuous variation, and suggest that this pathway also applies to discrete colour morphs. We suggest that the need to maintain low GSH levels for eumelanogenesis in dark morph individuals may represent a physiological constraint that helps regulate the evolution and maintenance of polymorphisms

Full-Length L1CAM and Not Its Δ2Δ27 Splice Variant Promotes Metastasis through Induction of Gelatinase Expression

Tumour-specific splicing is known to contribute to cancer progression. In the case of the L1 cell adhesion molecule (L1CAM), which is expressed in many human tumours and often linked to bad prognosis, alternative splicing results in a full-length form (FL-L1CAM) and a splice variant lacking exons 2 and 27 (SV-L1CAM). It has not been elucidated so far whether SV-L1CAM, classically considered as tumour-associated, or whether FL-L1CAM is the metastasis-promoting isoform. Here, we show that both variants were expressed in human ovarian carcinoma and that exposure of tumour cells to pro-metastatic factors led to an exclusive increase of FL-L1CAM expression. Selective overexpression of one isoform in different tumour cells revealed that only FL-L1CAM promoted experimental lung and/or liver metastasis in mice. In addition, metastasis formation upon up-regulation of FL-L1CAM correlated with increased invasive potential and elevated Matrix metalloproteinase (MMP)-2 and -9 expression and activity in vitro as well as enhanced gelatinolytic activity in vivo. In conclusion, we identified FL-L1CAM as the metastasis-promoting isoform, thereby exemplifying that high expression of a so-called tumour-associated variant, here SV-L1CAM, is not per se equivalent to a decisive role of this isoform in tumour progression

Observation of associated near-side and away-side long-range correlations in √sNN=5.02 TeV proton-lead collisions with the ATLAS detector

Two-particle correlations in relative azimuthal angle (Δϕ) and pseudorapidity (Δη) are measured in √sNN=5.02  TeV p+Pb collisions using the ATLAS detector at the LHC. The measurements are performed using approximately 1  μb-1 of data as a function of transverse momentum (pT) and the transverse energy (ΣETPb) summed over 3.1<η<4.9 in the direction of the Pb beam. The correlation function, constructed from charged particles, exhibits a long-range (2<|Δη|<5) “near-side” (Δϕ∼0) correlation that grows rapidly with increasing ΣETPb. A long-range “away-side” (Δϕ∼π) correlation, obtained by subtracting the expected contributions from recoiling dijets and other sources estimated using events with small ΣETPb, is found to match the near-side correlation in magnitude, shape (in Δη and Δϕ) and ΣETPb dependence. The resultant Δϕ correlation is approximately symmetric about π/2, and is consistent with a dominant cos⁡2Δϕ modulation for all ΣETPb ranges and particle pT

Methylation matters: binding of Ets-1 to the demethylated Foxp3 gene contributes to the stabilization of Foxp3 expression in regulatory T cells

The forkhead-box protein P3 (Foxp3) is a key transcription factor for the development and suppressive activity of regulatory T cells (Tregs), a T cell subset critically involved in the maintenance of self-tolerance and prevention of over-shooting immune responses. However, the transcriptional regulation of Foxp3 expression remains incompletely understood. We have previously shown that epigenetic modifications in the CpG-rich Treg-specific demethylated region (TSDR) in the Foxp3 locus are associated with stable Foxp3 expression. We now demonstrate that the methylation state of the CpG motifs within the TSDR controls its transcriptional activity rather than a Treg-specific transcription factor network. By systematically mutating every CpG motif within the TSDR, we could identify four CpG motifs, which are critically determining the transcriptional activity of the TSDR and which serve as binding sites for essential transcription factors, such as CREB/ATF and NF-κB, which have previously been shown to bind to this element. The transcription factor Ets-1 was here identified as an additional molecular player that specifically binds to the TSDR in a demethylation-dependent manner in vitro. Disruption of the Ets-1 binding sites within the TSDR drastically reduced its transcriptional enhancer activity. In addition, we found Ets-1 bound to the demethylated TSDR in ex vivo isolated Tregs, but not to the methylated TSDR in conventional CD4+ T cells. We therefore propose that Ets-1 is part of a larger protein complex, which binds to the TSDR only in its demethylated state, thereby restricting stable Foxp3 expression to the Treg lineage

Age-related changes to motor synergies in multi-joint and multi-finger manipulative skills: a meta-analysis

Purpose The aim of the current meta-analysis was to examine the extent to which there are differences in upper extremity motor synergies across different age groups in manipulative tasks. Methods The studies that used the uncontrolled manifold method to examine the effect of age on motor synergies in multijoint and multi-finger tasks were selected. Sixteen relevant studies from 1154 articles were selected for the meta-analysis—4 and 12 studies considered multi-joint kinematics and multi-finger kinetic tasks respectively. Results The results of the meta-analysis suggested reduced strength of synergies in multi-finger task in older adults, but this was not the case for synergies in multi-joint task. Part of this age-related difference in finger function is related to the increased variability in total force in grasping tasks. However, reductions in the strength of multi-finger synergies in hand functions following ageing appear to depend on the characteristics of the task. Conclusions These findings indicate that the cooperation among fingers to stabilise the total required force to apply for grasping and other fine motor skills is less efficient in older adults that might affect the quality of manipulative tasks

The impact of single and pairwise Toll-like receptor activation on neuroinflammation and neurodegeneration

Background Toll-like receptors (TLRs) enable innate immune cells to respond to pathogen- and host-derived molecules. The central nervous system (CNS) exhibits most of the TLRs identified with predominant expression in microglia, the major immune cells of the brain. Although individual TLRs have been shown to contribute to CNS disorders, the consequences of multiple activated TLRs on the brain are unclear. We therefore systematically investigated and compared the impact of sole and pairwise TLR activation on CNS inflammation and injury. Methods Selected TLRs expressed in microglia and neurons were stimulated with their specific TLR ligands in varying combinations. Cell cultures were then analyzed by immunocytochemistry, FlowCytomix, and ELISA. To determine neuronal injury and neuroinflammation in vivo, C57BL/6J mice were injected intrathecally with TLR agonists. Subsequently, brain sections were analyzed by quantitative real-time PCR and immunohistochemistry. Results Simultaneous stimulation of TLR4 plus TLR2, TLR4 plus TLR9, and TLR2 plus TLR9 in microglia by their respective specific ligands results in an increased inflammatory response compared to activation of the respective single TLR in vitro. In contrast, additional activation of TLR7 suppresses the inflammatory response mediated by the respective ligands for TLR2, TLR4, or TLR9 up to 24 h, indicating that specific combinations of activated TLRs individually modulate the inflammatory response. Accordingly, the composition of the inflammatory response pattern generated by microglia varies depending on the identity and combination of the activated TLRs engaged. Likewise, neuronal injury occurs in response to activation of only selected TLRs and TLR combinations in vitro. Activation of TLR2, TLR4, TLR7, and TLR9 in the brain by intrathecal injection of the respective TLR ligand into C57BL/6J mice leads to specific expression patterns of distinct TLR mRNAs in the brain and causes influx of leukocytes and inflammatory mediators into the cerebrospinal fluid to a variable extent. Also, the intensity of the inflammatory response and neurodegenerative effects differs according to the respective activated TLR and TLR combinations used in vivo. Conclusions Sole and pairwise activation of TLRs modifies the pattern and extent of inflammation and neurodegeneration in the CNS, thereby enabling innate immunity to take account of the CNS diseases’ diversity

Significance testing as perverse probabilistic reasoning

Truth claims in the medical literature rely heavily on statistical significance testing. Unfortunately, most physicians misunderstand the underlying probabilistic logic of significance tests and consequently often misinterpret their results. This near-universal misunderstanding is highlighted by means of a simple quiz which we administered to 246 physicians at two major academic hospitals, on which the proportion of incorrect responses exceeded 90%. A solid understanding of the fundamental concepts of probability theory is becoming essential to the rational interpretation of medical information. This essay provides a technically sound review of these concepts that is accessible to a medical audience. We also briefly review the debate in the cognitive sciences regarding physicians' aptitude for probabilistic inference

Metabolic Deficiences Revealed in the Biotechnologically Important Model Bacterium Escherichia coli BL21(DE3)

The Escherichia coli B strain BL21(DE3) has had a profound impact on biotechnology through its use in the production of recombinant proteins. Little is understood, however, regarding the physiology of this important E. coli strain. We show here that BL21(DE3) totally lacks activity of the four [NiFe]-hydrogenases, the three molybdenum- and selenium-containing formate dehydrogenases and molybdenum-dependent nitrate reductase. Nevertheless, all of the structural genes necessary for the synthesis of the respective anaerobic metalloenzymes are present in the genome. However, the genes encoding the high-affinity molybdate transport system and the molybdenum-responsive transcriptional regulator ModE are absent from the genome. Moreover, BL21(DE3) has a nonsense mutation in the gene encoding the global oxygen-responsive transcriptional regulator FNR. The activities of the two hydrogen-oxidizing hydrogenases, therefore, could be restored to BL21(DE3) by supplementing the growth medium with high concentrations of Ni2+ (Ni2+-transport is FNR-dependent) or by introducing a wild-type copy of the fnr gene. Only combined addition of plasmid-encoded fnr and high concentrations of MoO42− ions could restore hydrogen production to BL21(DE3); however, to only 25–30% of a K-12 wildtype. We could show that limited hydrogen production from the enzyme complex responsible for formate-dependent hydrogen evolution was due solely to reduced activity of the formate dehydrogenase (FDH-H), not the hydrogenase component. The activity of the FNR-dependent formate dehydrogenase, FDH-N, could not be restored, even when the fnr gene and MoO42− were supplied; however, nitrate reductase activity could be recovered by combined addition of MoO42− and the fnr gene. This suggested that a further component specific for biosynthesis or activity of formate dehydrogenases H and N was missing. Re-introduction of the gene encoding ModE could only partially restore the activities of both enzymes. Taken together these results demonstrate that BL21(DE3) has major defects in anaerobic metabolism, metal ion transport and metalloprotein biosynthesis

Bipolar disorders

Bipolar disorder is characterized by (hypo)manic episodes and depressive episodes which alternate with euthymic periods. It causes serious disability with poor outcome, increased suicidality risk, and significant societal costs. This chapter describes the findings of the PET/SPECT research efforts and the current ideas on the pathophysiology of bipolar disorder. First, the cerebral blood flow and cerebral metabolism findings in the prefrontal cortex, limbic system, subcortical structures, and other brain regions are discussed, followed by an overview of the corticolimbic theory of mood disorders that explains these observations. Second, the neurotransmitter studies are discussed. The serotonin transporter alterations are described, and the variation in study results is explained, followed by an overview of the results of the various dopamine receptor and transporter molecules studies, taking into account also the relation to psychosis. Third, a concise overview is given of dominant bipolar disorder pathophysiological models, proposing starting points for future molecular imaging studies. Finally, the most important conclusions are summarized, followed by remarks about the observed molecular imaging study designs specific for bipolar disorder.</p