The constitutively active serine/threonine kinase Pim-1 is upregulated in different cancer types, mainly based on the action of several interleukines and growth factors at the transcriptional level. ...So far, a regulation of oncogenic Pim-1 by microRNAs (miRNAs) has not been reported. Here, we newly establish miR-33a as a miRNA with potential tumor suppressor activity, acting through inhibition of Pim-1. A screen for miRNA expression in K562 lymphoma, LS174T colon carcinoma and several other cell lines revealed generally low endogenous miR-33a levels relative to other miRNAs. Transfection of K562 and LS174T cells with a miR-33a mimic reduced Pim-1 levels substantially. In contrast, the cell-cycle regulator cyclin-dependent kinase 6 predicted to be a conserved miR-33a target, was not downregulated by the miR-33a mimic. Seed mutagenesis of the Pim-1 3'-untranslated region in a luciferase reporter construct and in a Pim-1 cDNA expressed in Pim-1-deficient Skov-3 cells demonstrated specific and direct downregulation of Pim-1 by the miR-33a mimic. The persistence of this effect was comparable to that of a small interfering RNA-mediated knockdown of Pim-1, resulting in decelerated cell proliferation. In conclusion, we demonstrate the potential of miR-33a to act as a tumor suppressor miRNA, which suggests miR-33a replacement therapy through delivery of miR mimics as a novel therapeutic strategy.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Since the pioneering work of Ramsey, atom interferometers are employed for precision metrology, in particular to measure time and to realize the second. In a classical interferometer, an ensemble of ...atoms is prepared in one of the two input states, whereas the second one is left empty. In this case, the vacuum noise restricts the precision of the interferometer to the standard quantum limit (SQL). Here, we propose and experimentally demonstrate a novel clock configuration that surpasses the SQL by squeezing the vacuum in the empty input state. We create a squeezed vacuum state containing an average of 0.75 atoms to improve the clock sensitivity of 10000 atoms by 2.05_{-0.37}^{+0.34} dB. The SQL poses a significant limitation for today's microwave fountain clocks, which serve as the main time reference. We evaluate the major technical limitations and challenges for devising a next generation of fountain clocks based on atomic squeezed vacuum.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UM
Comparisons of satisfaction rates following total knee arthroplasty (TKA) among large, age-differentiated, rigorously matched cohorts are lacking. Therefore, we compared satisfaction rates following ...TKA in large, age-differentiated, propensity score-matched cohorts.
We identified primary TKAs performed for non-inflammatory arthritis in patients of ages 18-55 or 65-75, yielding 529 younger and 2001 older patients. Patient-reported outcomes were recorded pre-operatively and 2 years post-operatively. 1:1 propensity score matching between groups yielded 529 patient pairs. Matching was based on gender, body mass index, American Society of Anesthesiologists grade, Charlson Comorbidity Index, and Short Form 12 Mental Health Component score. Outcomes were compared between matched groups using t-test and Wilcoxon rank-sum test.
Satisfaction with knee surgery was 86% among younger patients and 91% among older patients. Distribution of satisfaction responses was shifted toward greater satisfaction in older patients (P < .001). Overall quality of life (QOL) improvement was 91% among younger patients and 96% among older patients. Pre-operative and post-operative knee-related QOL was better among older patients (P < .0001). Post-operative global health-related QOL was equivalent between groups based on Short Form 12 Physical Component Score and Mental Health Component score (P = .6646 and P = .5705, respectively) and QOL improvement questionnaires (P = .181). Younger patients reported greater knee-related dysfunction and higher activity levels pre-operatively and post-operatively (P ≤ .0002).
Satisfaction with knee surgery was over 85% regardless of age. Younger patients perceived more knee-related dysfunction and dissatisfaction after surgery despite higher levels of self-reported activity pre-operatively and post-operatively.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Opioids are regularly administered in acute and cancer pain. In chronic non‐cancer pain (CNCP), however, their use is controversial. Previous meta‐analyses and randomized controlled trials (RCTs) ...lack methodological homogeneity and comparable data. Here we analysed the maximum analgesic efficacies of opioids and non‐opioids compared with placebo, and of physiotherapy and psychotherapy compared with active or waiting‐list controls. We screened 3647 citations and included RCTs if treatment duration was at least 3 weeks, data were sufficient for meta‐analysis, and criteria for high quality were met. Only 46 studies (10 742 patients) met the criteria. Weighted and standardized mean differences (WMD, SMD) between pain intensities were pooled to conduct separate meta‐analyses for each treatment category. At the end of treatment the WMD for pain reduction (100‐point scale) was 12.0 for ‘strong’ opioids, 10.6 for ‘weak’ opioids, 8.4 for non‐opioids (each vs. placebo), 5.5 for psychotherapy and 4.5 for physiotherapy (each vs. active controls). Dropout rates were high in pharmacological studies. The 95% confidence intervals using the outcomes of control groups did not indicate statistical differences between efficacies of the five interventions. Because not enough eligible head‐to‐head trials were available, our analysis is limited to adjusted indirect comparisons. The heterogeneity of pre‐post pain differences in control groups did not allow the definition of a common comparator. In conclusion, although there were statistically significant differences between maximum treatment efficacies, no intervention per se produced clinically important improvements in average pain intensity. Thus, opioids alone are inappropriate and multimodal treatment programmes may be required for CNCP.
Linked Articles
This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Context . The signatures of polycyclic aromatic hydrocarbons (PAHs) have been observed in protoplanetary discs, and their emission features obtained from spectral energy distributions (SED) have been ...used in the literature to characterise their size and determine their abundance. Aims . Two simple disc models (uniform PAH distribution against a PAH gap in the inner disc) are compared to investigate the difference of their SED and obtainable information. Methods . We used the radiative transfer code RADMC-3D to model the SED of two protoplanetary discs orbiting a typical Herbig star, one of which features a depletion of PAHs in the inner disc. We further created artificial images of the discs at face-on view to extract radial profiles of the PAH emission in the infrared. Results . We find that the extracted PAH features from an SED provide limited information about the PAHs in protoplanetary disc environments, except for the ionisation state. The distribution of PAHs in a protoplanetary disc influences the total observed PAH luminosity in a non-linear fashion and alters the relative strength between the 3.3 µm and 11.3 µm features. Furthermore, we produced radial profiles at the 3 µm, 6 µm and, 11 µm PAH emission features and find that they follow a double power-law profile where the slope reflects the radiative environment (single photon regime vs. multi-photon regime) in which the PAHs lie. Conclusions . Using spatially resolved techniques such as IFU or imaging in the era of the James Webb Space Telescope, we find that multi-wavelength radial emission profiles will not only provide information on the spatial distribution of the PAHs, but may also provide information on their size and underlying UV environment, which is crucial for photo-evaporative disc wind models.
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This chapter reviews results of clinical and functional imaging studies which investigated the time-course of cortical and subcortical activation during the acquisition of motor a skill.
During the ...early phases of learning by trial and error, activation in prefrontal areas, especially in the dorsolateral prefrontal cortex, is has been reported. The role of these areas is presumably related to explicit working memory and the establishment of a novel association between visual cues and motor commands. Furthermore, motor associated areas of the right hemisphere and distributed cerebellar areas reveal strong activation during the early motor learning. Activation in superior–posterior parietal cortex presumably arises from visuospatial processes, while sensory feedback is coded in the anterior–inferior parietal cortex and the neocerebellar structures.
With practice, motor associated areas of the left-hemisphere reveal increased activity. This shift to the left hemisphere has been observed regardless of the hand used during training, indicating a left-hemispheric dominance in the storage of visuomotor skills. Concerning frontal areas, learned actions of sequential character are represented in the caudal part of the supplementary motor area (SMA proper), whereas the lateral premotor cortex appears to be responsible for the coding of the association between visuo-spatial information and motor commands.
Functional imaging studies which investigated the activation patterns of motor learning under implicit conditions identified for the first, a motor circuit which includes lateral premotor cortex and SMA proper of the left hemisphere and primary motor cortex, for the second, a cognitive loop which consists of basal ganglia structures of the right hemisphere. Finally, activity patterns of intermanual transfer are discussed. After right-handed training, activity in motor associated areas maintains during performance of the mirror version, but is increased during the performance of the original-oriented version with the left hand. In contrary, increased activity during the mirror reversed action, but not during the original-oriented performance of the untrained right hand is observed after left-handed training.
These results indicate the transfer of acquired right-handed information which reflects the mirror symmetry of the body, whereas spatial information is mainly transferred after left-handed training. Taken together, a combined approach of clinical lesion studies and functional imaging is a promising tool for identifying the cerebral regions involved in the process of motor learning and provides insight into the mechanisms underlying the generalisation of actions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Despite the reported low expression of the primary SARS-CoV-2 receptor ACE2 in distinct ocular tissues, some clinical evidence suggests that SARS-CoV-2 can infect the eye. In this study, we explored ...potential entry sites for SARS-CoV-2 by viral S protein histochemistry on various ocular tissues and compared the staining patterns with RNA and protein expression of TMPRSS2 and ACE2. Potential viral entry sites were investigated by histochemistry using tagged recombinant viral S protein on 52 ocular tissue samples including specimens of the cornea, conjunctiva, lid margin, lacrimal gland tissue, retina, choroid, and RPE. In addition, ACE2 and TMPRSS2 immunohistochemistry were performed on the same ocular tissue, each with distinct antibodies binding to different epitopes. Lung tissue samples were used as positive controls. Finally, bulk RNA sequencing (RNA-Seq) was used to determine the expression of ACE2 and its auxiliary factors in the tissues mentioned above. S protein histochemistry revealed a positive staining in lung tissue but absent staining in the cornea, the conjunctiva, eye lid samples, the lacrimal glands, the retina and the optic nerve which was supported by hardly any immunoreactivity for ACE2 and TMPRSS2 and scarce ACE2 and TMPRSS2 RNA expression. Negligible staining with antibodies targeting ACE2 or TMPRSS2 was seen in the main and accessory lacrimal glands. In contrast, ocular staining (S protein, ACE2, TMPRSS2) was distinctly present in pigmented cells of the RPE and choroid, as well as in the ciliary body and the iris stroma. S protein histochemistry revealed hardly any SARS-CoV-2 entry sites in all ocular tissues examined. Similarly, no significant ACE2 or TMPRSS2 expression was found in extra- and intraocular tissue. While this study suggest a rather low risk of ocular infection with SARS-CoV-2, it should be noted, that potential viral entry sites may increase in response to inflammation or in certain disease states.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Elementary chemistry distinguishes two kinds of strong bonds between atoms in molecules: the covalent bond, where bonding arises from valence electron pairs shared between neighboring atoms, and the ...ionic bond, where transfer of electrons from one atom to another leads to Coulombic attraction between the resulting ions. We present a third, distinct bonding mechanism: perpendicular paramagnetic bonding, generated by the stabilization of antibonding orbitals in their perpendicular orientation relative to an external magnetic field. In strong fields such as those present in the atmospheres of white dwarfs (on the order of 10 5 teslas) and other stellar objects, our calculations suggest that this mechanism underlies the strong bonding of H 2 in the $^ 3\sum \display _{u} ^{+} (1 \sigma _g 1 \sigma _{u} ^{*})$ triplet state and of He 2 in the $^ 1\sum \display _{g} ^{+} (1 \sigma _{g} ^{2} 1 \sigma _{u} ^{*2} )$ singlet state, as well as their preferred perpendicular orientation in the external field.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Context.
The infrared signature of polycyclic aromatic hydrocarbons (PAHs) is present in many protostellar discs, and these species are thought to play an important role in the heating of the gas in ...the photosphere.
Aims.
We consider PAH cluster formation as one possible cause for non-detections of PAH features in protoplanetary discs. We test the necessary conditions for cluster formation and cluster dissociation by stellar optical and far-UV photons in protoplanetary discs using a Herbig Ae/Be and a T Tauri star disc model.
Methods.
We perform Monte Carlo and statistical calculations to determine dissociation rates for coronene, circumcoronene, and circumcoronene clusters with sizes of between 2 and 200 cluster members. By applying general disc models to our Herbig Ae/Be and T Tauri star model, we estimate the formation rate of PAH dimers and compare these with the dissociation rates.
Results.
We show that the formation of PAH dimers can take place in the inner 100 AU of protoplanetary discs in sub-photospheric layers. Dimer formation takes seconds to years, allowing them to grow beyond dimer size in a short time. We further demonstrate that PAH clusters increase their stability while they grow when they are located beyond a critical distance that depends on stellar properties and PAH species. The comparison with the local vertical mixing timescale allows a determination of the minimum cluster size necessary for the survival of PAH clusters.
Conclusions.
Considering the PAH cluster formation sites, cluster survival in the photosphere of the inner disc of Herbig stars is unlikely because of the high UV radiation. For the T Tauri stars, survival of coronene, circumcoronene, and circumcircumcoronene clusters is possible, and cluster formation should be considered as one possible explanation for low PAH detection rates in T Tauri star discs.
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