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Irritable bowel syndrome (IBS) is a gut-brain disorder involving alterations in intestinal sensitivity and motility. Serotonin 5-HT4 receptors are promising candidates in IBS pathophysiology since they regulate gut motor function and stool consistency, and targeted 5-HT4R selective drug intervention has been proven beneficial in subgroups of patients. We identified a single nucleotide polymorphism (SNP) (rs201253747) c.*61 T > C within the 5-HT4 receptor gene \(HTR4\) to be predominantly present in diarrhoea-IBS patients (IBS-D). It affects a binding site for the miR-16 family and miR-103/miR-107 within the isoforms \({HTR4b/i}\) and putatively impairs \(HTR4\) expression. Subsequent miRNA profiling revealed downregulation of miR-16 and miR-103 in the jejunum of IBS-D patients correlating with symptoms. \(In\) \(vitro\) assays confirmed expression regulation via three 3′UTR binding sites. The novel isoform \(HTR4b\_2\) lacking two of the three miRNA binding sites escapes miR-16/103/107 regulationin SNP carriers. We provide the first evidence that \(HTR4\) expression is fine-tuned by miRNAs, and that this regulation is impaired either by the SNP c.*61 T > C or bydiminished levels of miR-16 and miR-103 suggesting that \(HTR4\) might be involved in the development of IBS-D.
Background
Herpesviruses can infect a wide range of animal species. Herpes simplex virus 1 (HSV-1) is one of the eight herpesviruses that can infect humans and is prevalent worldwide. Herpesviruses have evolved multiple ways to adapt the infected cells to their needs, but knowledge about these transcriptional and post-transcriptional modifications is sparse.
Results
Here, we show that HSV-1 induces the expression of about 1000 antisense transcripts from the human host cell genome. A subset of these is also activated by the closely related varicella zoster virus. Antisense transcripts originate either at gene promoters or within the gene body, and they show different susceptibility to the inhibition of early and immediate early viral gene expression. Overexpression of the major viral transcription factor ICP4 is sufficient to turn on a subset of antisense transcripts. Histone marks around transcription start sites of HSV-1-induced and constitutively transcribed antisense transcripts are highly similar, indicating that the genetic loci are already poised to transcribe these novel RNAs. Furthermore, an antisense transcript overlapping with the BBC3 gene (also known as PUMA) transcriptionally silences this potent inducer of apoptosis in cis.
Conclusions
We show for the first time that a virus induces widespread antisense transcription of the host cell genome. We provide evidence that HSV-1 uses this to downregulate a strong inducer of apoptosis. Our findings open new perspectives on global and specific alterations of host cell transcription by viruses.
We present charged-particle distributions sensitive to the underlying event, measured by the ATLAS detector in proton-proton collisions at a centre-of-mass energy of 13 TeV, in low-luminosity Large Hadron Collider fills corresponding to an integrated luminosity of 1.6 nb\(^{−1}\). The distributions were constructed using charged particles with absolute pseudorapidity less than 2.5 and with transverse momentum greater than 500 MeV, in events with at least one such charged particle with transverse momentum above 1 GeV. These distributions characterise the angular distribution of energy and particle flows with respect to the charged particle with highest transverse momentum, as a function of both that momentum and of charged-particle multiplicity. The results have been corrected for detector effects and are compared to the predictions of various Monte Carlo event generators, experimentally establishing the level of underlying-event activity at LHC Run 2 energies and providing inputs for the development of event generator modelling. The current models in use for UE modelling typically describe this data to 5% accuracy, compared with data uncertainties of less than 1%.
A measurement of the \(t\)-channel single-top-quark and single-top-antiquark production cross-sections in the lepton+jets channel is presented, using 3.2 fb\(^{−1}\) of proton-proton collision data at a centre-of-mass energy of 13 TeV, recorded with the ATLAS detector at the LHC in 2015. Events are selected by requiring one charged lepton (electron or muon), missing transverse momentum, and two jets with high transverse momentum, exactly one of which is required to be \(b\)-tagged. Using a binned maximum-likelihood fit to the discriminant distribution of a neural network, the cross-sections are determined to be \({σ(tq)}\) = 156 ± 5 (stat.) ± 27 (syst.) ± 3 (lumi.) pb for single top-quark production and \(σ(\overline{t}q)\) = 91 ± 4 (stat.) ± 18 (syst.) ± 2 (lumi.) pb for single top-antiquark production, assuming a top-quark mass of 172.5 GeV. The cross-section ratio is measured to be \(R_{t}\) = \(σ(tq)/σ(\overline{t}q)\) = 1.72 ± 0.09 (stat.) ± 0.18 (syst.). All results are in agreement with Standard Model predictions.
Borderline personality disorder (BPD) patients’ hypersensitivity for emotionally relevant stimuli has been suggested be due to abnormal activity and connectivity in (para-)limbic and prefrontal brain regions during stimulus processing. The neuropeptide oxytocin has been shown to modulate activity and functional connectivity in these brain regions, thereby optimizing the processing of emotional and neutral stimuli. To investigate whether oxytocin would be capable of attenuating BPD patients’ hypersensitivity for such stimuli, we recorded brain activity and gaze behavior during the processing of complex scenes in 51 females with and 48 without BPD after intranasal application of either oxytocin or placebo. We found divergent effects of oxytocin on BPD and healthy control (HC) participants’ (para-)limbic reactivity to emotional and neutral scenes: Oxytocin decreased amygdala and insula reactivity in BPD participants but increased it in HC participants, indicating an oxytocin-induced normalization of amygdala and insula activity during scene processing. In addition, oxytocin normalized the abnormal coupling between amygdala activity and gaze behavior across all scenes in BPD participants. Overall, these findings suggest that oxytocin may be capable of attenuating BPD patients’ hypersensitivity for complex scenes, irrespective of their valence.
Maize cropping systems mapping using RapidEye observations in agro-ecological landscapes in Kenya
(2017)
Cropping systems information on explicit scales is an important but rarely available variable in many crops modeling routines and of utmost importance for understanding pests and disease propagation mechanisms in agro-ecological landscapes. In this study, high spatial and temporal resolution RapidEye bio-temporal data were utilized within a novel 2-step hierarchical random forest (RF) classification approach to map areas of mono- and mixed maize cropping systems. A small-scale maize farming site in Machakos County, Kenya was used as a study site. Within the study site, field data was collected during the satellite acquisition period on general land use/land cover (LULC) and the two cropping systems. Firstly, non-cropland areas were masked out from other land use/land cover using the LULC mapping result. Subsequently an optimized RF model was applied to the cropland layer to map the two cropping systems (2nd classification step). An overall accuracy of 93% was attained for the LULC classification, while the class accuracies (PA: producer’s accuracy and UA: user’s accuracy) for the two cropping systems were consistently above 85%. We concluded that explicit mapping of different cropping systems is feasible in complex and highly fragmented agro-ecological landscapes if high resolution and multi-temporal satellite data such as 5 m RapidEye data is employed. Further research is needed on the feasibility of using freely available 10–20 m Sentinel-2 data for wide-area assessment of cropping systems as an important variable in numerous crop productivity models.
TNF receptor type 2 (TNFR2) has gained attention as a costimulatory receptor for T cells and as critical factor for the development of regulatory T cells (Treg) and myeloid suppressor cells. Using the TNFR2-specific agonist TNCscTNF80, direct effects of TNFR2 activation on myeloid cells and T cells were investigated in mice. \(In\) \(vitro\), TNCscTNF80 induced T cell proliferation in a costimulatory fashion, and also supported \(in\) \(vitro\) expansion of Treg cells. In addition, activation of TNFR2 retarded differentiation of bone marrow-derived immature myeloid cells in culture and reduced their suppressor function. \(In\) \(vivo\) application of TNCscTNF80-induced mild myelopoiesis in naïve mice without affecting the immune cell composition. Already a single application expanded Treg cells and improved suppression of CD4 T cells in mice with chronic inflammation. By contrast, multiple applications of the TNFR2 agonist were required to expand Treg cells in naïve mice. Improved suppression of T cell proliferation depended on expression of TNFR2 by T cells in mice repeatedly treated with TNCscTNF80, without a major contribution of TNFR2 on myeloid cells. Thus, TNFR2 activation on T cells in naïve mice can lead to immune suppression \(in\) \(vivo\). These findings support the important role of TNFR2 for Treg cells in immune regulation.
Oligopeptides incorporating \(N3\)-(4-methoxyfumaroyl)-L-2,3-diaminopropanoic acid (FMDP), an inhibitor of glucosamine-6-phosphate synthase, exhibited growth inhibitory activity against \(Candida\) \(albicans\), with minimal inhibitory concentration values in the 0.05–50 μg mL\(^{-1}\) range. Uptake by the peptide permeases was found to be the main factor limiting an anticandidal activity of these compounds. Di- and tripeptide containing FMDP (F2 and F3) were transported by Ptr2p/Ptr22p peptide transporters (PTR) and FMDP-containing hexa-, hepta-, and undecapeptide (F6, F7, and F11) were taken up by the oligopeptide transporters (OPT) oligopeptide permeases, preferably by Opt2p/Opt3p. A phenotypic, apparent resistance of \(C. albicans\) to FMDP-oligopeptides transported by OPT permeases was triggered by the environmental factors, whereas resistance to those taken up by the PTR system had a genetic basis. Anticandidal activity of longer FMDP-oligopeptides was strongly diminished in minimal media containing easily assimilated ammonium sulfate or L-glutamine as the nitrogen source, both known to downregulate expression of the OPT genes. All FMDP-oligopeptides tested were more active at lower pH and this effect was slightly more remarkable for peptides F6, F7, and F11, compared to F2 and F3. Formation of isolated colonies was observed inside the growth inhibitory zones induced by F2 and F3 but not inside those induced by F6, F7, and F11. The vast majority (98%) of those colonies did not originate from truly resistant cells. The true resistance of 2% of isolates was due to the impaired transport of di- and to a lower extent, tripeptides. The resistant cells did not exhibit a lower expression of \(PTR2\), \(PTR22\), or \(OPT1–3\) genes, but mutations in the \(PTR2\) gene resulting in T422H, A320S, D119V, and A320S substitutions in the amino acid sequence of Ptr2p were found.
To probe the \(W tb\) vertex structure, top-quark and \(W\)-boson polarisation observables are measured from \(t\)-channel single-top-quark events produced in proton-proton collisions at a centre-of-mass energy of 8 TeV. The dataset corresponds to an integrated luminosity of 20.2 fb\(^{−1}\), recorded with the ATLAS detector at the LHC. Selected events contain one isolated electron or muon, large missing transverse momentum and exactly two jets, with one of them identified as likely to contain a \(b\)-hadron. Stringent selection requirements are applied to discriminate \(t\)-channel single-top-quark events from background. The polarisation observables are extracted from asymmetries in angular distributions measured with respect to spin quantisation axes appropriately chosen for the top quark and the \(W\) boson. The asymmetry measurements are performed at parton level by correcting the observed angular distributions for detector effects and hadronisation after subtracting the background contributions. The measured top-quark and \(W\)-boson polarisation values are in agreement with the Standard Model predictions. Limits on the imaginary part of the anomalous coupling \(g_R\) are also set from model independent measurements.
The production of a \(Z\) boson and a photon in association with a high-mass dijet system is studied using 20.2 fb\(^{−1}\) of proton-proton collision data at a centre-of-mass energy of \(\sqrt{s}\) = 8 TeV recorded with the ATLAS detector in 2012 at the Large Hadron Collider. Final states with a photon and a Z boson decaying into a pair of either electrons, muons, or neutrinos are analysed. Electroweak and total \(pp\) → \(Zγjj\) cross-sections are extracted in two fiducial regions with different sensitivities to electroweak production processes. Quartic couplings of vector bosons are studied in regions of phase space with an enhanced contribution from pure electroweak production, sensitive to vector-boson scattering processes \(V V → Zγ\). No deviations from Standard Model predictions are observed and constraints are placed on anomalous couplings parameterized by higher-dimensional operators using effective field theory.