It has become apparent that regulation of protein translation is an important determinant in controlling cell growth and leukemic transformation. The phosphoinositide 3-kinase (PI3K)/phosphatase and ...tensin homologue deleted on chromosome ten (PTEN)/Akt/mammalian target of rapamycin (mTOR) pathway is often implicated in sensitivity and resistance to therapy. Dysregulated signaling through the PI3K/PTEN/Akt/mTOR pathway is often the result of genetic alterations in critical components in this pathway as well as mutations at upstream growth factor receptors. Furthermore, this pathway is activated by autocrine transformation mechanisms. PTEN is a critical tumor suppressor gene and its dysregulation results in the activation of Akt. PTEN is often mutated, silenced and is often haploinsufficient. The mTOR complex1 (mTORC1) regulates the assembly of the eukaryotic initiation factor4F complex, which is critical for the translation of mRNAs that are important for cell growth, prevention of apoptosis and transformation. These mRNAs have long 5'-untranslated regions that are G+C rich, rendering them difficult to translate. Elevated mTORC1 activity promotes the translation of these mRNAs via the phosphorylation of 4E-BP1. mTORC1 is a target of rapamycin and novel active-site inhibitors that directly target the TOR kinase activity. Although rapamycin and novel rapalogs are usually cytostatic and not cytotoxic for leukemic cells, novel inhibitors that target the kinase activities of PI3K and mTOR may prove more effective for leukemia therapy.
Summary Background Chikungunya virus (CHIKV), which is transmitted by Aedes spp mosquitoes, has recently caused several outbreaks on islands in the Indian Ocean and on the Indian subcontinent. We ...report on an outbreak in Italy. Methods After reports of a large number of cases of febrile illness of unknown origin in two contiguous villages in northeastern Italy, an outbreak investigation was done to identify the primary source of infection and modes of transmission. An active surveillance system was also implemented. The clinical case definition was presentation with fever and joint pain. Blood samples were gathered and analysed by PCR and serological assays to identify the causal agent. Locally captured mosquitoes were also tested by PCR. Phylogenetic analysis of the CHIKV E1 region was done. Findings Analysis of samples from human beings and from mosquitoes showed that the outbreak was caused by CHIKV. We identified 205 cases of infection with CHIKV between July 4 and Sept 27, 2007. The presumed index case was a man from India who developed symptoms while visiting relatives in one of the villages. Phylogenetic analysis showed a high similarity between the strains found in Italy and those identified during an earlier outbreak on islands in the Indian Ocean. The disease was fairly mild in nearly all cases, with only one reported death. Interpretation This outbreak of CHIKV disease in a non-tropical area was to some extent unexpected and emphasises the need for preparedness and response to emerging infectious threats in the era of globalisation.
The gut-brain axis and the intestinal microbiota are emerging as key players in health and disease. Shifts in intestinal microbiota composition affect a variety of systems; however, evidence of their ...direct impact on cognitive functions is still lacking. We tested whether faecal microbiota transplant (FMT) from aged donor mice into young adult recipients altered the hippocampus, an area of the central nervous system (CNS) known to be affected by the ageing process and related functions.
Young adult mice were transplanted with the microbiota from either aged or age-matched donor mice. Following transplantation, characterization of the microbiotas and metabolomics profiles along with a battery of cognitive and behavioural tests were performed. Label-free quantitative proteomics was employed to monitor protein expression in the hippocampus of the recipients. We report that FMT from aged donors led to impaired spatial learning and memory in young adult recipients, whereas anxiety, explorative behaviour and locomotor activity remained unaffected. This was paralleled by altered expression of proteins involved in synaptic plasticity and neurotransmission in the hippocampus. Also, a strong reduction of bacteria associated with short-chain fatty acids (SCFAs) production (Lachnospiraceae, Faecalibaculum, and Ruminococcaceae) and disorders of the CNS (Prevotellaceae and Ruminococcaceae) was observed. Finally, the detrimental effect of FMT from aged donors on the CNS was confirmed by the observation that microglia cells of the hippocampus fimbria, acquired an ageing-like phenotype; on the contrary, gut permeability and levels of systemic and local (hippocampus) cytokines were not affected.
These results demonstrate that age-associated shifts of the microbiota have an impact on protein expression and key functions of the CNS. Furthermore, these results highlight the paramount importance of the gut-brain axis in ageing and provide a strong rationale to devise therapies aiming to restore a young-like microbiota to improve cognitive functions and the declining quality of life in the elderly. Video Abstract.
Thigh lift surgery is generally performed in patients with severe weight loss outcomes, particularly those undergoing bariatric surgery. However, there are other congenital malformation conditions ...that may require the same treatment, such as Beckwith Wideman syndrome.
Various signaling pathways exert critical roles in the epithelial to mesenchymal transition (EMT) and cancer stem cells (CSCs). The Wnt/beta-catenin, PI3K/PTEN/Akt/mTORC, Ras/Raf/MEK/ERK, hedgehog ...(Hh), Notch and TP53 pathways elicit essential regulatory influences on cancer initiation, EMT and progression. A common kinase involved in all these pathways is moon-lighting kinase glycogen synthase kinase-3 (GSK-3). These pathways are also regulated by micro-RNAs (miRs). TP53 and components of these pathways can regulate the expression of miRs. Targeting members of these pathways may improve cancer therapy in those malignancies that display their abnormal regulation. This review will discuss the interactions of the multi-functional GSK-3 enzyme in the Wnt/beta-catenin, PI3K/PTEN/Akt/mTORC, Ras/Raf/MEK/ERK, Hh, Notch and TP53 pathways. The regulation of these pathways by miRs and their effects on CSC generation, EMT, invasion and metastasis will be discussed.
Knowing that expression of metabotropic glutamate 2 (mGlu2) receptors in the dorsal root ganglia is regulated by acetylation mechanisms, we examined the effect of two selective and chemically ...unrelated histone deacetylase (HDAC) inhibitors, N-(2-aminophenyl)-4-N-(pyridine-3-ylmethoxy-carbonyl)aminomethylbenzamide (MS-275) and suberoylanilide hydroamic acid (SAHA), in a mouse model of persistent inflammatory pain. Although a single subcutaneous injection of MS-275 (3 mg/kg) or SAHA (5-50 mg/kg) was ineffective, a 5-day treatment with either of the two HDAC inhibitors substantially reduced the nociceptive response in the second phase of the formalin test, which reflects the development of central sensitization in the dorsal horn of the spinal cord. Analgesia was abrogated by a single injection of the mGlu2/3 receptor antagonist (alphaS)-alpha-amino-alpha-(1S,2S)-2-carboxycyclopropyl-9H-xantine-9-propanoic acid (LY341495; 1 mg/kg, i.p.), which was inactive per se. Both MS-275 and SAHA up-regulated the expression of mGlu2 receptors in the dorsal root ganglion (DRG) and spinal cord under conditions in which they caused analgesia, without changing the expression of mGlu1a, mGlu4, or mGlu5 receptors. Induction of DRG mGlu2 receptors in response to SAHA was associated with increased acetylation of p65/RelA on lysine 310, a process that enhances the transcriptional activity of p65/RelA at nuclear factor-kappaB-regulated genes. Transcription of the mGlu2 receptor gene is known to be activated by p65/RelA in DRG neurons. We conclude that HDAC inhibition produces analgesia by up-regulating mGlu2 receptor expression in the DRG, an effect that results from the amplification of NF-kappaB transcriptional activity. These data provide the first evidence that HDAC inhibitors cause analgesia and suggest that HDACs are potential targets for the epigenetic treatment of pain.
There has been growing interest in exploring human performance for situations in which stimuli and/or responses vary along both horizontal and vertical dimensions. Earlier studies indicated that ...there is a prevalence of the horizontal dimension over the vertical dimension in the spatial codes that are used for response selection. We review evidence about spatial coding for 2-D stimulus-response sets and accounts that have been proposed for explaining how it takes place. Particular attention is devoted to the relative salience account, which provides the most comprehensive explanation of 2-D spatial coding. We also evaluate the influence of speed of spatial code formation, number of reference frames, and learning on subjects' performance in 2-D tasks.
Ultrashort flashes of THz light with low photon energies of a few meV, but strong electric or magnetic field transients have recently been employed to prepare various fascinating nonequilibrium ...states in matter. Here we present a new class of sources based on superradiant enhancement of radiation from relativistic electron bunches in a compact electron accelerator that we believe will revolutionize experiments in this field. Our prototype source generates high-field THz pulses at unprecedented quasi-continuous-wave repetition rates up to the MHz regime. We demonstrate parameters that exceed state-of-the-art laser-based sources by more than 2 orders of magnitude. The peak fields and the repetition rates are highly scalable and once fully operational this type of sources will routinely provide 1 MV/cm electric fields and 0.3 T magnetic fields at repetition rates of few 100 kHz. We benchmark the unique properties by performing a resonant coherent THz control experiment with few 10 fs resolution.
Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that participates in an array of critical cellular processes. GSK-3 was first characterized as an enzyme that phosphorylated and ...inactivated glycogen synthase. However, subsequent studies have revealed that this moon-lighting protein is involved in numerous signaling pathways that regulate not only metabolism but also have roles in: apoptosis, cell cycle progression, cell renewal, differentiation, embryogenesis, migration, regulation of gene transcription, stem cell biology and survival. In this review, we will discuss the roles that GSK-3 plays in various diseases as well as how this pivotal kinase interacts with multiple signaling pathways such as: PI3K/PTEN/Akt/mTOR, Ras/Raf/MEK/ERK, Wnt/beta-catenin, hedgehog, Notch and TP53. Mutations that occur in these and other pathways can alter the effects that natural GSK-3 activity has on regulating these signaling circuits that can lead to cancer as well as other diseases. The novel roles that microRNAs play in regulation of the effects of GSK-3 will also be evaluated. Targeting GSK-3 and these other pathways may improve therapy and overcome therapeutic resistance.
•Regulation of GSK-3 Activity by Signaling Pathways•Abnormal Activation of PI3K/PTEN/Akt/mTORC1 and Ras/Raf/MEK/ERK Pathways Can Result in Deregulated GSK-3 Activity•The hedgehog (Hh) Signaling Pathway•The Notch Signaling Pathway and Interactions with GSK-3•Overview of GSK-3 Inhibitors
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