1,630 research outputs found
Genome wide mapping reveals PDE4B as an IL-2 induced STAT5 target gene in activated human PBMCs and lymphoid cancer cells
IL-2 is the primary growth factor for promoting survival and proliferation of activated T cells that occurs following engagement of the Janus Kinase (JAK)1-3/and Signal Transducer and Activator of Transcription (STAT) 5 signaling pathway. STAT5 has two isoforms: STAT5A and STAT5B ( commonly referred to as STAT5) which, in T cells, play redundant roles transcribing cell cycle and survival genes. As such, inhibition of STAT5 by a variety of mechanisms can rapidly induce apoptosis in certain lymphoid tumor cells, suggesting that it and its target genes represent therapeutic targets to control certain lymphoid diseases. To search for these molecules we aligned IL-2 regulated genes detected by Affymetrix gene expression microarrays with the STAT5 cistrome identified by chip-on-ChIP analysis in an IL-2-dependent human leukemia cell line, Kit225. Select overlapping genes were then validated using qRT(2)PCR medium-throughput arrays in human PHA-activated PBMCs. Of 19 putative genes, one key regulator of T cell receptor signaling, PDE4B, was identified as a novel target, which was readily up-regulated at the protein level (3 h) in IL-2 stimulated, activated human PBMCs. Surprisingly, only purified CD8+ primary T-cells expressed PDE4B, but not CD4+ cells. Moreover, PDE4B was found to be highly expressed in CD4+ lymphoid cancer cells, which suggests that it may represent a physiological role unique to the CD8+ and lymphoid cancer cells and thus might represent a target for pharmaceutical intervention for certain lymphoid diseases
Genome Wide Transcriptome Analysis of Dendritic Cells Identifies Genes with Altered Expression in Psoriasis
Activation of dendritic cells by different pathogens induces the secretion of proinflammatory mediators resulting in
local inflammation. Importantly, innate immunity must be properly controlled, as its continuous activation leads to the
development of chronic inflammatory diseases such as psoriasis. Lipopolysaccharide (LPS) or peptidoglycan (PGN)
induced tolerance, a phenomenon of transient unresponsiveness of cells to repeated or prolonged stimulation,
proved valuable model for the study of chronic inflammation. Thus, the aim of this study was the identification of the
transcriptional diversity of primary human immature dendritic cells (iDCs) upon PGN induced tolerance. Using SAGESeq
approach, a tag-based transcriptome sequencing method, we investigated gene expression changes of primary
human iDCs upon stimulation or restimulation with Staphylococcus aureus derived PGN, a widely used TLR2 ligand.
Based on the expression pattern of the altered genes, we identified non-tolerizeable and tolerizeable genes. Gene
Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (Kegg) analysis showed marked enrichment of
immune-, cell cycle- and apoptosis related genes. In parallel to the marked induction of proinflammatory mediators,
negative feedback regulators of innate immunity, such as TNFAIP3, TNFAIP8, Tyro3 and Mer are markedly
downregulated in tolerant cells. We also demonstrate, that the expression pattern of TNFAIP3 and TNFAIP8 is
altered in both lesional, and non-lesional skin of psoriatic patients. Finally, we show that pretreatment of immature
dendritic cells with anti-TNF-α inhibits the expression of IL-6 and CCL1 in tolerant iDCs and partially releases the
suppression of TNFAIP8. Our findings suggest that after PGN stimulation/restimulation the host cell utilizes different
mechanisms in order to maintain critical balance between inflammation and tolerance. Importantly, the transcriptome
sequencing of stimulated/restimulated iDCs identified numerous genes with altered expression to date not associated
with role in chronic inflammation, underlying the relevance of our in vitro model for further characterization of IFNprimed
iDCs
Sisyphus Cooling of Electrically Trapped Polyatomic Molecules
The rich internal structure and long-range dipole-dipole interactions
establish polar molecules as unique instruments for quantum-controlled
applications and fundamental investigations. Their potential fully unfolds at
ultracold temperatures, where a plethora of effects is predicted in many-body
physics, quantum information science, ultracold chemistry, and physics beyond
the standard model. These objectives have inspired the development of a wide
range of methods to produce cold molecular ensembles. However, cooling
polyatomic molecules to ultracold temperatures has until now seemed
intractable. Here we report on the experimental realization of opto-electrical
cooling, a paradigm-changing cooling and accumulation method for polar
molecules. Its key attribute is the removal of a large fraction of a molecule's
kinetic energy in each step of the cooling cycle via a Sisyphus effect,
allowing cooling with only few dissipative decay processes. We demonstrate its
potential by reducing the temperature of about 10^6 trapped CH_3F molecules by
a factor of 13.5, with the phase-space density increased by a factor of 29 or a
factor of 70 discounting trap losses. In contrast to other cooling mechanisms,
our scheme proceeds in a trap, cools in all three dimensions, and works for a
large variety of polar molecules. With no fundamental temperature limit
anticipated down to the photon-recoil temperature in the nanokelvin range, our
method eliminates the primary hurdle in producing ultracold polyatomic
molecules. The low temperatures, large molecule numbers and long trapping times
up to 27 s will allow an interaction-dominated regime to be attained, enabling
collision studies and investigation of evaporative cooling toward a BEC of
polyatomic molecules
Generation and physiological roles of linear ubiquitin chains
Ubiquitination now ranks with phosphorylation as one of the best-studied post-translational modifications of proteins with broad regulatory roles across all of biology. Ubiquitination usually involves the addition of ubiquitin chains to target protein molecules, and these may be of eight different types, seven of which involve the linkage of one of the seven internal lysine (K) residues in one ubiquitin molecule to the carboxy-terminal diglycine of the next. In the eighth, the so-called linear ubiquitin chains, the linkage is between the amino-terminal amino group of methionine on a ubiquitin that is conjugated with a target protein and the carboxy-terminal carboxy group of the incoming ubiquitin. Physiological roles are well established for K48-linked chains, which are essential for signaling proteasomal degradation of proteins, and for K63-linked chains, which play a part in recruitment of DNA repair enzymes, cell signaling and endocytosis. We focus here on linear ubiquitin chains, how they are assembled, and how three different avenues of research have indicated physiological roles for linear ubiquitination in innate and adaptive immunity and suppression of inflammation
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Testing the arousal hypothesis of neonatal imitation in infant rhesus macaques
Neonatal imitation is the matching of (often facial) gestures by newborn infants. Some studies suggest that performance of facial gestures is due to general arousal, which may produce false positives on neonatal imitation assessments. Here we examine whether arousal is linked to facial gesturing in newborn infant rhesus macaques (Macaca mulatta). We tested 163 infants in a neonatal imitation paradigm in their first postnatal week and analyzed their lipsmacking gestures (a rapid opening and closing of the mouth), tongue protrusion gestures, and yawn responses (a measure of arousal). Arousal increased during dynamic stimulus presentation compared to the static baseline across all conditions, and arousal was higher in the facial gestures conditions than the nonsocial control condition. However, even after controlling for arousal, we found a condition-specific increase in facial gestures in infants who matched lipsmacking and tongue protrusion gestures. Thus, we found no support for the arousal hypothesis. Consistent with reports in human newborns, imitators’ propensity to match facial gestures is based on abilities that go beyond mere arousal. We discuss optimal testing conditions to minimize potentially confounding effects of arousal on measurements of neonatal imitation
Estimating total body water content in suckling and lactating llamas (Lama glama) by isotope dilution
Total body water (TBW) in 17 suckling and six lactating llamas was estimated from isotope dilution at three different post natum and lactation stages using both 18O and deuterium oxide (D2O). In total, 69 TBW measurements were undertaken. While TBW in lactating dams, expressed in kilogram, remained stable during the three measurement periods (91.8 ± 15.0 kg), the body water fraction (TBW expressed in percent of body mass) increased slightly (P = 0.042) from 62.9% to 65.8%. In contrast, TBW (kilogram) in suckling llamas increased significantly (P < 0.001) with age and decreased slightly when expressed as a percentage of body mass (P = 0.016). Relating TBW to body mass across all animals yielded a highly significant regression equation (TBW in kilogram = 2.633 + 0.623 body mass in kilogram, P < 0.001, n = 69) explaining 99.5% of the variation. The water fraction instead decreased in a curve linear fashion with increasing body mass (TBW in percent of body mass = 88.23 body mass in kilogram−0.064, P < 0.001, R2 = 0.460). The present results on TBW can serve as reference values for suckling and lactating llamas, e.g., for the evaluation of fluid losses during disease. Additionally, the established regression equations can be used to predict TBW from body mass, providing that the body masses fall inside the range of masses used to derive the equations
Empowerment or Engagement? Digital Health Technologies for Mental Healthcare
We argue that while digital health technologies (e.g. artificial intelligence, smartphones, and virtual reality) present significant opportunities for improving the delivery of healthcare, key concepts that are used to evaluate and understand their impact can obscure significant ethical issues related to patient engagement and experience. Specifically, we focus on the concept of empowerment and ask whether it is adequate for addressing some significant ethical concerns that relate to digital health technologies for mental healthcare. We frame these concerns using five key ethical principles for AI ethics (i.e. autonomy, beneficence, non-maleficence, justice, and explicability), which have their roots in the bioethical literature, in order to critically evaluate the role that digital health technologies will have in the future of digital healthcare
Treatment of post-traumatic degenerative changes of the radio-carpal and distal radio-ulnar joints by combining radius, scaphoid, and lunate (RSL) fusion with ulnar head replacement
Distal radial fractures are a common type of fracture. In the case of intra-articular fractures, they often result in post-traumatic arthrosis. The objective of this study is to describe a novel alternative to the established salvage techniques for the treatment of post-traumatic arthrosis of the radio-carpal and distal radio-ulnar joints (DRUJ). Six patients with radio-carpal and DRUJ arthrosis were treated with a combined radius, scaphoid, and lunate (RSL) arthrodesis and as a Herbert ulnar head prosthesis. Follow-up consisted of both radiographic and functional assessments. Functional measurements were noted both pre- and postoperatively. No non-union or pseudoarthrosis was seen; neither did any of the ulnar head prostheses show loosening. Clinical examination showed an improvement in strength, pain, and range of movement, as well as a decrease in disability. Combining RSL arthrodesis with a Herbert ulnar head prosthesis, which deals with pain while retaining partial wrist movement, can be an alternative to established salvage procedures
Emergent global patterns of ecosystem structure and function from a mechanistic general ecosystem model
Anthropogenic activities are causing widespread degradation of ecosystems worldwide, threatening the ecosystem services upon which all human life depends. Improved understanding of this degradation is urgently needed to improve avoidance and mitigation measures. One tool to assist these efforts is predictive models of ecosystem structure and function that are mechanistic: based on fundamental ecological principles. Here we present the first mechanistic General Ecosystem Model (GEM) of ecosystem structure and function that is both global and applies in all terrestrial and marine environments. Functional forms and parameter values were derived from the theoretical and empirical literature where possible. Simulations of the fate of all organisms with body masses between 10 µg and 150,000 kg (a range of 14 orders of magnitude) across the globe led to emergent properties at individual (e.g., growth rate), community (e.g., biomass turnover rates), ecosystem (e.g., trophic pyramids), and macroecological scales (e.g., global patterns of trophic structure) that are in general agreement with current data and theory. These properties emerged from our encoding of the biology of, and interactions among, individual organisms without any direct constraints on the properties themselves. Our results indicate that ecologists have gathered sufficient information to begin to build realistic, global, and mechanistic models of ecosystems, capable of predicting a diverse range of ecosystem properties and their response to human pressures
Blocking human fear memory with the matrix metalloproteinase inhibitor doxycycline
Learning to predict threat is a fundamental ability of many biological organisms, and a laboratory model for anxiety disorders. Interfering with such memories in humans would be of high clinical relevance. On the basis of studies in cell cultures and slice preparations, it is hypothesised that synaptic remodelling required for threat learning involves the extracellular enzyme matrix metalloproteinase (MMP) 9. However, in vivo evidence for this proposal is lacking. Here we investigate human Pavlovian fear conditioning under the blood-brain barrier crossing MMP inhibitor doxycyline in a pre-registered, randomised, double-blind, placebo-controlled trial. We find that recall of threat memory, measured with fear-potentiated startle 7 days after acquisition, is attenuated by ~60% in individuals who were under doxycycline during acquisition. This threat memory impairment is also reflected in increased behavioural surprise signals to the conditioned stimulus during subsequent re-learning, and already late during initial acquisition. Our findings support an emerging view that extracellular signalling pathways are crucially required for threat memory formation. Furthermore, they suggest novel pharmacological methods for primary prevention and treatment of posttraumatic stress disorder.Molecular Psychiatry advance online publication, 4 April 2017; doi:10.1038/mp.2017.65
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