Impact of perinatal factors on continuous early monitoring of brain electrocortical activity in very preterm newborns by amplitude-integrated EEG.

Background:Amplitude-integrated electroencephalogram (aEEG) is increasingly used for neuromonitoring in preterms. We aimed to quantify the effects of gestational age (GA), postnatal age (PNA), and other perinatal factors on the development of aEEG early after birth in very preterm newborns with normal cerebral ultrasounds.Methods:Continuous aEEG was prospectively performed in 96 newborns (mean GA: 29.5 (range: 24.4-31.9) wk, birth weight 1,260 (580-2,120) g) during the first 96 h of life. aEEG tracings were qualitatively (maturity scores) and quantitatively (amplitudes) evaluated using preestablished criteria.Results:A significant increase in all aEEG measures was observed between day 1 and day 4 and for increasing GA (P < 0.001). The effect of PNA on aEEG development was 6.4- to 11.3-fold higher than that of GA. In multivariate regression, GA and PNA were associated with increased qualitative and quantitative aEEG measures, whereas small-for-GA status was independently associated with increased maximum aEEG amplitude (P = 0.003). Morphine administration negatively affected all aEEG measures (P < .05), and caffeine administration negatively affected qualitative aEEG measures (P = 0.02).Conclusion:During the first few days after birth, aEEG activity in very preterm infants significantly develops and is strongly subjected to the effect of PNA. Perinatal factors may alter the early aEEG tracing and interfere with its interpretation.

Gac/Rsm signal transduction pathway of gamma-proteobacteria: from RNA recognition to regulation of social behaviour.

In many gamma-proteobacteria, the conserved GacS/GacA (BarA/UvrY) two-component system positively controls the expression of one to five genes specifying small RNAs (sRNAs) that are characterized by repeated unpaired GGA motifs but otherwise appear to belong to several independent families. The GGA motifs are essential for binding small, dimeric RNA-binding proteins of a single conserved family designated RsmA (CsrA). These proteins, which also occur in bacterial species outside the gamma-proteobacteria, act as translational repressors of certain mRNAs when these contain an RsmA/CsrA binding site at or near the Shine-Dalgarno sequence plus additional binding sites located in the 5' untranslated leader mRNA. Recent structural data have established that the RsmA-like protein RsmE of Pseudomonas fluorescens makes specific contacts with an RNA consensus sequence 5'-(A)/(U)CANGGANG(U)/(A)-3' (where N is any nucleotide). Interaction with an RsmA/CsrA protein promotes the formation of a short stem supporting an ANGGAN loop. This conformation hinders access of 30S ribosomal subunits and hence translation initiation. The output of the Gac/Rsm cascade varies widely in different bacterial species and typically involves management of carbon storage and expression of virulence or biocontrol factors. Unidentified signal molecules co-ordinate the activity of the Gac/Rsm cascade in a cell population density-dependent manner.

Specific inhibition of the JNK pathway promotes locomotor recovery and neuroprotection after mouse spinal cord injury.

Limiting the development of secondary damage represents one of the major goals of neuroprotective therapies after spinal cord injury. Here, we demonstrate that specific JNK inhibition via a single intraperitoneal injection of the cell permeable peptide D-JNKI1 6h after lesion improves locomotor recovery assessed by both the footprint and the BMS tests up to 4 months post-injury in mice. JNK inhibition prevents c-jun phosphorylation and caspase-3 cleavage, has neuroprotective effects and results in an increased sparing of white matter at the lesion site. Lastly, D-JNKI1 treated animals show a lower increase of erythrocyte extravasation and blood brain barrier permeability, thus indicating protection of the vascular system. In total, these results clearly point out JNK inhibition as a promising neuroprotective strategy for preventing the evolution of secondary damage after spinal cord injury.

IL-6 activated integrated BATF/IRF4 functions in lymphocytes are T-bet-independent and reversed by subcutaneous immunotherapy.

IL-6 plays a central role in supporting pathological TH2 and TH17 cell development and inhibiting the protective T regulatory cells in allergic asthma. TH17 cells have been demonstrated to regulate allergic asthma in general and T-bet-deficiency-induced asthma in particular. Here we found an inverse correlation between T-bet and Il-6 mRNA expression in asthmatic children. Moreover, experimental subcutaneous immunotherapy (SIT) in T-bet((-/-)) mice inhibited IL-6, IL-21R and lung TH17 cells in a setting of asthma. Finally, local delivery of an anti-IL-6R antibody in T-bet((-/-)) mice resulted in the resolution of this allergic trait. Noteworthy, BATF, crucial for the immunoglobulin-class-switch and TH2,TH17 development, was found down-regulated in the lungs of T-bet((-/-)) mice after SIT and after treatment with anti-IL-6R antibody, indicating a critical role of IL-6 in controlling BATF/IRF4 integrated functions in TH2, TH17 cells and B cells also in a T-bet independent fashion in allergic asthma.

Zymosan induced arthritis in mice is biphasic and acts through the TLR2 pathway

Zymosan induced arthritis is thought to be dependent on activation of the alternative pathway of complement and is short lived. Recently it has been demonstrated that zymosan is capable of activating the innate immune system via toll-like receptor 2 (TLR2) and TLR6. These receptors play a role in linking the innate to the adaptive immune response. We have therefore reinvestigated the mechanisms by which zymosan induces arthritis by analyzing the kinetic of inflammation, the joint histology, lymphocyte proliferation in wild type and TLR2 deficient mice.

Control of the peroxisomal beta-oxidation pathway by a novel family of nuclear hormone receptors.

Three novel members of the Xenopus nuclear hormone receptor superfamily have been cloned. They are related to each other and similar to the group of receptors that includes those for thyroid hormones, retinoids, and vitamin D3. Their transcriptional activity is regulated by agents causing peroxisome proliferation and carcinogenesis in rodent liver. All three Xenopus receptors activate the promoter of the acyl coenzyme A oxidase gene, which encodes the key enzyme of peroxisomal fatty acid beta-oxidation, via a cognate response element that has been identified. Therefore, peroxisome proliferators may exert their hypolipidemic effects through these receptors, which stimulate the peroxisomal degradation of fatty acids. Finally, the multiplicity of these receptors suggests the existence of hitherto unknown cellular signaling pathways for xenobiotics and putative endogenous ligands.

CD44 attenuates activation of the hippo signaling pathway and is a prime therapeutic target for glioblastoma.

Glioblastoma multiforme (GBM) is the most aggressive brain tumor that, by virtue of its resistance to chemotherapy and radiotherapy, is currently incurable. Identification of molecules whose targeting may eliminate GBM cells and/or sensitize glioblastoma cells to cytotoxic drugs is therefore urgently needed. CD44 is a major cell surface hyaluronan receptor and cancer stem cell marker that has been implicated in the progression of a variety of cancer types. However, the major downstream signaling pathways that mediate its protumor effects and the role of CD44 in the progression and chemoresponse of GBM have not been established. Here we show that CD44 is upregulated in GBM and that its depletion blocks GBM growth and sensitizes GBM cells to cytotoxic drugs in vivo. Consistent with this observation, CD44 antagonists potently inhibit glioma growth in preclinical mouse models. We provide the first evidence that CD44 functions upstream of the mammalian Hippo signaling pathway and that CD44 promotes tumor cell resistance to reactive oxygen species-induced and cytotoxic agent-induced stress by attenuating activation of the Hippo signaling pathway. Together, our results identify CD44 as a prime therapeutic target for GBM, establish potent antiglioma efficacy of CD44 antagonists, uncover a novel CD44 signaling pathway, and provide a first mechanistic explanation as to how upregulation of CD44 may constitute a key event in leading to cancer cell resistance to stresses of different origins. Finally, our results provide a rational explanation for the observation that functional inhibition of CD44 augments the efficacy of chemotherapy and radiation therapy.

Functional implication of the vitamin A signaling pathway in the brain.

Vitamin A is necessary for normal embryonic development, but its role in the adult brain is poorly understood. Vitamin A derivatives, retinoids, are involved in a complex signaling pathway that regulates gene expression and, in the central nervous system, controls neuronal differentiation and neural tube patterning. Although a major functional implication of retinoic signaling has been repeatedly suggested in synaptic plasticity, learning and memory, sleep, schizophrenia, depression, Parkinson disease, and Alzheimer disease, the targets and the underlying mechanisms in the adult brain remain elusive.

Fas-associated death domain protein (FADD) and caspase-8 mediate up-regulation of c-Fos by Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) via a FLICE inhibitory protein (FLIP)-regulated pathway.

Fas, a death domain-containing member of the tumor necrosis factor receptor family and its ligand FasL have been predominantly studied with respect to their capability to induce cell death. However, a few studies indicate a proliferation-inducing signaling activity of these molecules too. We describe here a novel signaling pathway of FasL and the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) that triggers transcriptional activation of the proto-oncogene c-fos, a typical target gene of mitogenic pathways. FasL- and TRAIL-mediated up-regulation of c-Fos was completely dependent on the presence of Fas-associated death domain protein (FADD) and caspase-8, but caspase activity seemed to be dispensable as a pan inhibitor of caspases had no inhibitory effect. Upon overexpression of the long splice form of cellular FADD-like interleukin-1-converting enzyme (FLICE) inhibitory protein (cFLIP) in Jurkat cells, FasL- and TRAIL-induced up-regulation of c-Fos was almost completely blocked. The short splice form of FLIP, however, showed a rather stimulatory effect on c-Fos induction. Together these data demonstrate the existence of a death receptor-induced, FADD- and caspase-8-dependent pathway leading to c-Fos induction that is inhibited by the long splice form FLIP-L.

Interaction of Fas(Apo-1/CD95) with proteins implicated in the ubiquitination pathway.

Fas(Apo-1/CD95), a receptor belonging to the tumor necrosis factor receptor family, induces apoptosis when triggered by Fas ligand. Upon its activation, the cytoplasmic domain of Fas binds several proteins which transmit the death signal. We used the yeast two-hybrid screen to isolate Fas-associated proteins. Here we report that the ubiquitin-conjugating enzyme UBC9 binds to Fas at the interface between the death domain and the membrane-proximal region of Fas. This interaction is also seen in vivo. UBC9 transiently expressed in HeLa cells bound to the co-expressed cytoplasmic segment of Fas. FAF1, a Fas-associated protein that potentiates apoptosis (Chu et al. (1996) Proc. Natl. Acad. Sci. USA 92, 11894-11898), was found to contain sequences similar to ubiquitin. These results suggest that proteins related to the ubiquitination pathway may modulate the Fas signaling pathway.

FGF21 signalling pathway and metabolic traits - genetic association analysis.

Fibroblast growth factor 21 (FGF21) is a novel master regulator of metabolic profile. The biological actions of FGF21 are elicited upon its klotho beta (KLB)-facilitated binding to FGF receptor 1 (FGFR1), FGFR2 and FGFR3. We hypothesised that common polymorphisms in the FGF21 signalling pathway may be associated with metabolic risk. At the screening stage, we examined associations between 63 common single-nucleotide polymorphisms (SNPs) in five genes of this pathway (FGF21, KLB, FGFR1, FGFR2, FGFR3) and four metabolic phenotypes (LDL cholesterol - LDL-C, HDL-cholesterol - HDL-C, triglycerides and body mass index) in 629 individuals from Silesian Hypertension Study (SHS). Replication analyses were performed in 5478 unrelated individuals of the Swiss CoLaus cohort (imputed genotypes) and in 3030 directly genotyped individuals of the German Myocardial Infarction Family Study (GerMIFS). Of 54 SNPs that met quality control criteria after genotyping in SHS, 4 (rs4733946 and rs7012413 in FGFR1; rs2071616 in FGFR2 and rs7670903 in KLB) showed suggestive association with LDL-C (P=0.0006, P=0.0013, P=0.0055, P=0.011, respectively) and 1 (rs2608819 in KLB) was associated with body mass index (P=0.011); all with false discovery rate q<0.5. Of these, only one FGFR2 polymorphism (rs2071616) showed replicated association with LDL-C in both CoLaus (P=0.009) and men from GerMIFS (P=0.017). The direction of allelic effect of rs2071616 upon LDL-C was consistent in all examined populations. These data show that common genetic variations in FGFR2 may be associated with LDL-C in subjects of white European ancestry.

Constant p53 pathway inactivation in a large series of soft tissue sarcomas with complex genetics.

Alterations of the p53 pathway are among the most frequent aberrations observed in human cancers. We have performed an exhaustive analysis of TP53, p14, p15, and p16 status in a large series of 143 soft tissue sarcomas, rare tumors accounting for around 1% of all adult cancers, with complex genetics. For this purpose, we performed genomic studies, combining sequencing, copy number assessment, and expression analyses. TP53 mutations and deletions are more frequent in leiomyosarcomas than in undifferentiated pleomorphic sarcomas. Moreover, 50% of leiomyosarcomas present TP53 biallelic inactivation, whereas most undifferentiated pleomorphic sarcomas retain one wild-type TP53 allele (87.2%). The spectrum of mutations between these two groups of sarcomas is different, particularly with a higher rate of complex mutations in undifferentiated pleomorphic sarcomas. Most tumors without TP53 alteration exhibit a deletion of p14 and/or lack of mRNA expression, suggesting that p14 loss could be an alternative genotype for direct TP53 inactivation. Nevertheless, the fact that even in tumors altered for TP53, we could not detect p14 protein suggests that other p14 functions, independent of p53, could be implicated in sarcoma oncogenesis. In addition, both p15 and p16 are frequently codeleted or transcriptionally co-inhibited with p14, essentially in tumors with two wild-type TP53 alleles. Conversely, in TP53-altered tumors, p15 and p16 are well expressed, a feature not incompatible with an oncogenic process.

Anaerobic activation of the entire denitrification pathway in Pseudomonas aeruginosa requires Anr, an analog of Fnr.

The Pseudomonas aeruginosa gene anr, which encodes a structural and functional analog of the anaerobic regulator Fnr in Escherichia coli, was mapped to the SpeI fragment R, which is at about 59 min on the genomic map of P. aeruginosa PAO1. Wild-type P. aeruginosa PAO1 grew under anaerobic conditions with nitrate, nitrite, and nitrous oxide as alternative electron acceptors. An anr deletion mutant, PAO6261, was constructed. It was unable to grow with these alternative electron acceptors; however, its ability to denitrify was restored upon the introduction of the wild-type anr gene. In addition, the activities of two enzymes in the denitrification pathway, nitrite reductase and nitric oxide reductase, were not detectable under oxygen-limiting conditions in strain PAO6261 but were restored when complemented with the anr+ gene. These results indicate that the anr gene product plays a key role in anaerobically activating the entire denitrification pathway.

Jasmonate biochemical pathway.

Plants possess an interrelated family of potent fatty acid-derived regulators-the jasmonates. These compounds, which play roles in both defense and development, are derived from tri-unsaturated fatty acids [alpha-linolenic acid (18:3) or 7Z,10Z,13Z-hexadecatrienoic acid (16:3)]. The lipoxygenase-catalyzed addition of molecular oxygen to alpha-linolenic acid initiates jasmonate synthesis by providing a 13-hydroperoxide substrate for the formation of an unstable allene oxide that is then subject to enzyme-guided cyclization to produce 12-oxo-phytodienoic acid (OPDA). OPDA has several fates, including esterification into plastid lipids or transformation into the 12-carbon co-regulator jasmonic acid (JA). JA, the best-characterized member of the family, regulates both male and female fertility (depending on the plant species) and is an important mediator of defense gene expression. JA is itself a substrate for further diverse modifications. Genetic dissection of the pathway is revealing how the different jasmonates modulate different physiological processes. Each new family member that is discovered provides another key to understanding the fine control of gene expression in immune responses, in the initiation and maintenance of long-distance signal transfer in response to wounding, in the regulation of fertility, and in the turnover, inactivation, and sequestration of jasmonates, among other processes. The Jasmonate Biochemical Pathway provides an overview of the growing jasmonate family, and new members will be included in future versions of the Connections Map.