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One of the major problems in evolutionary biology is to elucidate the relationships between historical events and the tempo and mode of lineage divergence. The development of relaxed molecular clock models and the increasing availability of DNA sequences resulted in more accurate estimations of taxa divergence times. However, finding the link between competing historical events and divergence is still challenging. Here we investigate assigning constrained-age priors to nodes of interest in a time-calibrated phylogeny as a means of hypothesis comparison. These priors are equivalent to historic scenarios for lineage origin. The hypothesis that best explains the data can be selected by comparing the likelihood values of the competing hypotheses, modelled with different priors. A simulation approach was taken to evaluate the performance of the prior-based method and to compare it with an unconstrained approach. We explored the effect of DNA sequence length and the temporal placement and span of competing hypotheses (i.e. historic scenarios) on selection of the correct hypothesis and the strength of the inference. Competing hypotheses were compared applying a posterior simulation analogue of the Akaike Information Criterion and Bayes factors (obtained after calculation of the marginal likelihood with three estimators: Harmonic Mean, Stepping Stone and Path Sampling). We illustrate the potential application of the prior-based method on an empirical data set to compare competing geological hypotheses explaining the biogeographic patterns in Pleurodeles newts. The correct hypothesis was selected on average 89% times. The best performance was observed with DNA sequence length of 3500-10000 bp. The prior-based method is most reliable when the hypotheses compared are not temporally too close. The strongest inferences were obtained when using the Stepping Stone and Path Sampling estimators. The prior-based approach proved effective in discriminating between competing hypotheses when used on empirical data. The unconstrained analyses performed well but it probably requires additional computational effort. Researchers applying this approach should rely only on inferences with moderate to strong support. The prior-based approach could be applied on biogeographical and phylogeographical studies where robust methods for historical inferences are still lacking.
The entire chemical modification repertoire of yeast ribosomal RNAs and the enzymes responsible for it have recently been identified. Nonetheless, in most cases the precise roles played by these chemical modifications in ribosome structure, function and regulation remain totally unclear. Previously, we demonstrated that yeast Rrp8 methylates m1A645 of 25S rRNA in yeast. Here, using mung bean nuclease protection assays in combination with quantitative RP-HPLC and primer extension, we report that 25S/28S rRNA of S. pombe, C. albicans and humans also contain a single m1A methylation in the helix 25.1. We characterized nucleomethylin (NML) as a human homolog of yeast Rrp8 and demonstrate that NML catalyzes the m1A1322 methylation of 28S rRNA in humans. Our in vivo structural probing of 25S rRNA, using both DMS and SHAPE, revealed that the loss of the Rrp8-catalyzed m1A modification alters the conformation of domain I of yeast 25S rRNA causing translation initiation defects detectable as halfmers formation, likely because of incompetent loading of 60S on the 43S-preinitiation complex. Quantitative proteomic analysis of the yeast Δrrp8 mutant strain using 2D-DIGE, revealed that loss of m1A645 impacts production of specific set of proteins involved in carbohydrate metabolism, translation and ribosome synthesis. In mouse, NML has been characterized as a metabolic disease-associated gene linked to obesity. Our findings in yeast also point to a role of Rrp8 in primary metabolism. In conclusion, the m1A modification is crucial for maintaining an optimal 60S conformation, which in turn is important for regulating the production of key metabolic enzymes.
Summary statement When echolocating under demanding conditions e.g. noisy, narrow space, or cluttered environments, frugivorous bats adapt their call pattern by increasing the call rate within biosonar groups.
Abstract For orientation, echolocating bats emit biosonar calls and use echoes arising from call reflections. They often pattern their calls into groups which increases the rate of sensory feedback over time. Insectivorous bats emit call groups at a higher rate when orienting in cluttered compared to uncluttered environments. Frugivorous bats increase the rate of call group emission when they echolocate in noisy environments. Here, calls emitted by conspecifics potentially interfere with the bat’s biosonar signals and complicate the echolocation behavior. To minimize the information loss followed by signal interference, bats may profit from a temporally increased sensory acquisition rate, as it is the case for the call groups. In frugivorous bats, it remains unclear if call group emission represents an exclusive adaptation to avoid interference by signals from other bats or if it represents an adaptation that allows to orient under demanding environmental conditions. Here, we compared the emission pattern of the frugivorous bat Carollia perspicillata when the bats were flying in noisy versus silent, narrow versus wide or cluttered versus non-cluttered corridors. According to our results, the bats emitted larger call groups and they increased the call rate within the call groups when navigating in narrow, cluttered, or noisy environments. Thus, call group emission represents an adaptive behavior when the bats orient in complex environments.
Charged-particle spectra at midrapidity are measured in Pb-Pb collisions at the centre-of-mass energy per nucleon-nucleon pair sNN−−−√ = 5.02 TeV and presented in centrality classes ranging from most central (0-5%) to most peripheral (95-100%) collisions. Possible medium effects are quantified using the nuclear modification factor (RAA) by comparing the measured spectra with those from proton-proton collisions, scaled by the number of independent nucleon-nucleon collisions obtained from a Glauber model. At large transverse momenta (8<pT<20 GeV/c), the average RAA is found to increase from about 0.15 in 0-5% central to a maximum value of about 0.8 in 75-85% peripheral collisions, beyond which it falls off strongly to below 0.2 for the most peripheral collisions. Furthermore, RAA initially exhibits a positive slope as a function of pT in the 8-20 GeV/c interval, while for collisions beyond the 80% class the slope is negative. To reduce uncertainties related to event selection and normalization, we also provide the ratio of RAA in adjacent centrality intervals. Our results in peripheral collisions are consistent with a PYTHIA-based model without nuclear modification, demonstrating that biases caused by the event selection and collision geometry can lead to the apparent suppression in peripheral collisions. This explains the unintuitive observation that RAA is below unity in peripheral Pb-Pb, but equal to unity in minimum-bias p-Pb collisions despite similar charged-particle multiplicities.
The elliptic (v2), triangular (v3), and quadrangular (v4) flow coefficients of π±, K±, p+p¯¯¯, Λ+Λ¯¯¯¯, K0S, and the ϕ-meson are measured in Pb-Pb collisions at sNN−−−√=5.02 TeV. Results obtained with the scalar product method are reported for the rapidity range |y|< 0.5 as a function of transverse momentum, pT, at different collision centrality intervals between 0-70%, including ultra-central (0-1%) collisions for π±, K±, and p+p¯¯¯. For pT<3 GeV/c, the flow coefficients exhibit a particle mass dependence. At intermediate transverse momenta (3<pT<~8-10 GeV/c), particles show an approximate grouping according to their type (i.e., mesons and baryons). The ϕ-meson v2, which tests both particle mass dependence and type scaling, follows p+p¯¯¯ v2 at low pT and π± v2 at intermediate pT. The evolution of the shape of vn(pT) as a function of centrality and harmonic number n is studied for the various particle species. Flow coefficients of π±, K±, and p+p¯¯¯ for pT<3 GeV/c are compared to iEBE-VISHNU and MUSIC hydrodynamical calculations coupled to a hadronic cascade model (UrQMD). The iEBE-VISHNU calculations describe the results fairly well for pT<2.5 GeV/c, while MUSIC calculations reproduce the measurements for pT<1 GeV/c. A comparison to vn coefficients measured in Pb-Pb collisions at sNN−−−√ = 2.76 TeV is also provided.
Objectives Supersaturating formulations hold great promise for delivery of poorly soluble active pharmaceutical ingredients (APIs). To profit from supersaturating formulations, precipitation is hindered with precipitation inhibitors (PIs), maintaining drug concentrations for as long as possible. This review provides a brief overview of supersaturation and precipitation, focusing on precipitation inhibition. Trial-and-error PI selection will be examined alongside established PI screening techniques. Primarily, however, this review will focus on recent advances that utilise advanced analytical techniques to increase mechanistic understanding of PI action and systematic PI selection.
Key Findings. Advances in mechanistic understanding have been made possible by the use of analytical tools such as spectroscopy, microscopy and mathematical and molecular modelling, which have been reviewed herein. Using these techniques, PI selection can instead be guided by molecular rationale. However, more work is required to see wide-spread application of such an approach for PI selection.
Conclusions PIs are becoming increasingly important in enabling formulations. Trial-and-error approaches have seen success thus far. However, it is essential to learn more about the mode of action of PIs if the most optimal formulations are to be realised. Robust analytical tools, and the knowledge of where and how they can be applied, will be essential in this endeavour.
Autosomal recessive Ataxia Telangiectasia (A-T) is characterized by radiosensitivity, immunodeficiency and cerebellar neurodegeneration. A-T is caused by inactivating mutations in the Ataxia-Telangiectasia-Mutated (ATM) gene, a serine-threonine protein kinase involved in DNA-damage response and excitatory neurotransmission. The selective vulnerability of cerebellar Purkinje neurons (PN) to A-T is not well understood.
Angular correlations between heavy-flavour decay electrons and charged particles at mid-rapidity (|η|<0.8) are measured in p-Pb collisions at sNN−−−√ = 5.02 TeV. The analysis is carried out for the 0-20% (high) and 60-100% (low) multiplicity ranges. The jet contribution in the correlation distribution from high-multiplicity events is removed by subtracting the distribution from low-multiplicity events. An azimuthal modulation remains after removing the jet contribution, similar to previous observations in two-particle angular correlation measurements for light-flavour hadrons. A Fourier decomposition of the modulation results in a positive second-order coefficient (v2) for heavy-flavour decay electrons in the transverse momentum interval 1.5<pT<4 GeV/c in high-multiplicity events, with a significance larger than 5σ. The results are compared with those of charged particles at mid-rapidity and of inclusive muons at forward rapidity. The v2 measurement of open heavy-flavour particles at mid-rapidity in small collision systems could provide crucial information to help interpret the anisotropies observed in such systems.
Multiplex families with a high prevalence of a psychiatric disorder are often examined to identify rare genetic variants with large effect sizes. In the present study, we analysed whether the risk for bipolar disorder (BD) in BD multiplex families is influenced by common genetic variants. Furthermore, we investigated whether this risk is conferred mainly by BD-specific risk variants or by variants also associated with the susceptibility to schizophrenia or major depression. In total, 395 individuals from 33 Andalusian BD multiplex families as well as 438 subjects from an independent, sporadic BD case-control cohort were analysed. Polygenic risk scores (PRS) for BD, schizophrenia, and major depression were calculated and compared between the cohorts. Both the familial BD cases and unaffected family members had significantly higher PRS for all three psychiatric disorders than the independent controls, suggesting a high baseline risk for several psychiatric disorders in the families. Moreover, familial BD cases showed significantly higher BD PRS than unaffected family members and sporadic BD cases. A plausible hypothesis is that, in multiplex families with a general increase in risk for psychiatric disease, BD development is attributable to a high burden of common variants that confer a specific risk for BD. The present analyses, therefore, demonstrated that common genetic risk variants for psychiatric disorders are likely to contribute to the high incidence of affective psychiatric disorders in the multiplex families. The PRS explained only part of the observed phenotypic variance and rare variants might have also contributed to disease development.
Bleaching-independent, whole-cell, 3D and multi-color STED imaging with exchangeable fluorophores
(2018)
We demonstrate bleaching-independent STED microscopy using fluorogenic labels that reversibly bind to their target structure. A constant exchange of labels guarantees the removal of photobleached fluorophores and their replacement by intact fluorophores, thereby circumventing bleaching-related limitations of STED super-resolution imaging in fixed and living cells. Foremost, we achieve a constant labeling density and demonstrate a fluorescence signal for long and theoretically unlimited acquisition times. Using this concept, we demonstrate whole-cell, 3D, multi-color and live cell STED microscopy with up to 100 min acquisition time.
In this Letter, the ALICE Collaboration presents the first measurements of the charged-particle multiplicity density, dNch/dη, and total charged-particle multiplicity, Ntotch, in Xe-Xe collisions at a centre-of-mass energy per nucleon--nucleon pair of sNN−−−√ = 5.44 TeV. The measurements are performed as a function of collision centrality over a wide pseudorapidity range of −3.5<η<5. The values of dNch/dη at mid-rapidity and Ntotch for central collisions, normalised to the number of nucleons participating in the collision (Npart) as a function of sNN−−−√, follow the trends established in previous heavy-ion measurements. The same quantities are also found to increase as a function of Npart, and up to the 10% most central collisions the trends are the same as the ones observed in Pb-Pb at a similar energy. For more central collisions, the Xe-Xe scaled multiplicities exceed those in Pb-Pb for a similar Npart. The results are compared to phenomenological models and theoretical calculations based on different mechanisms for particle production in nuclear collisions. All considered models describe the data reasonably well within 20%.
We report the differential charged jet cross section and jet fragmentation distributions measured with the ALICE detector in proton-proton collisions at a centre-of-mass energy s√= 7 TeV. Jets with pseudo-rapidity |η|<0.5 are reconstructed from charged particles using the anti-kT jet finding algorithm with a resolution parameter R = 0.4. The jet cross section is measured in the transverse momentum interval 5 ≤pchjetT< 100 GeV/c. Jet fragmentation is studied measuring the scaled transverse momentum spectra of the charged constituents of jets in four intervals of jet transverse momentum between 5 GeV/c and 30 GeV/c. The measurements are compared to calculations from the PYTHIA model as well as next-to-leading order perturbative QCD calculations with POWHEG + PYTHIA8. The charged jet cross section is described by POWHEG for the entire measured range of pchjetT. For pchjetT > 40 GeV/c, the PYTHIA calculations also agree with the measured charged jet cross section. PYTHIA6 simulations describe the fragmentation distributions to 15%. Larger discrepancies are observed for PYTHIA8.
Charged-particle pseudorapidity density at mid-rapidity in p–Pb collisions at √sNN = 8.16 TeV
(2018)
The pseudorapidity density of charged particles, dNch/dη, in p-Pb collisions has been measured at a centre-of-mass energy per nucleon-nucleon pair of sNN−−−√ = 8.16 TeV at mid-pseudorapidity for non-single-diffractive events. The results cover 3.6 units of pseudorapidity, |η|<1.8. The dNch/dη value is 19.1±0.7 at |η|<0.5. This quantity divided by ⟨Npart⟩/2, is 4.73±0.20, which is 9.5% higher than the corresponding value for p-Pb collisions at sNN−−−√ = 5.02 TeV. Measurements are compared with models based on different mechanisms for particle production. All models agree within uncertainties with data in the Pb-going side, while HIJING overestimates, showing a symmetric behaviour, and EPOS underestimates the p-going side of the dNch/dη distribution. Saturation-based models reproduce the distributions well for η>−1.3. The dNch/dη is also measured for different centrality estimators, based both on the charged-particle multiplicity and on the energy deposited in the Zero-Degree Calorimeters. A study of the implications of the large multiplicity fluctuations due to the small number of participants for systems like p-Pb in the centrality calculation for multiplicity-based estimators is discussed, demonstrating the advantages of determining the centrality with energy deposited near beam rapidity.
The debate on effects of globalization on welfare states is extensive. Often couched in terms of a battle between the compensation and the efficiency thesis, the scholarly literature has provided contradictory arguments and findings. This article contributes to the scholarly debate by exploring in greater detail the micro-level foundations of compensation theory. More specifically, we distinguish between individual policy preferences for compensatory social policies (unemployment insurance) and human capital-focused social investment policies (education) and expect globalization to mainly affect demand for educational investment. A multi-level analysis of ISSP survey data provides empirical support for this hypothesis. This finding provides an important revision and extension of the classical analytical perspective of compensation theory, because it shows that citizens value the social investment function of the welfare state above and beyond simple compensation via social transfers. This might be particularly relevant in today's skill-centered knowledge economies.
Changes in the efficacies of synapses are thought to be the neurobiological basis of learning and memory. The efficacy of a synapse depends on its current number of neurotransmitter receptors. Recent experiments have shown that these receptors are highly dynamic, moving back and forth between synapses on time scales of seconds and minutes. This suggests spontaneous fluctuations in synaptic efficacies and a competition of nearby synapses for available receptors. Here we propose a mathematical model of this competition of synapses for neurotransmitter receptors from a local dendritic pool. Using minimal assumptions, the model produces a fast multiplicative scaling behavior of synapses. Furthermore, the model explains a transient form of heterosynaptic plasticity and predicts that its amount is inversely related to the size of the local receptor pool. Overall, our model reveals logistical tradeoffs during the induction of synaptic plasticity due to the rapid exchange of neurotransmitter receptors between synapses.
Interest in time-resolved connectivity in fMRI has grown rapidly in recent years. The most widely used technique for studying connectivity changes over time utilizes a sliding windows approach. There has been some debate about the utility of shorter versus longer windows, the use of fixed versus adaptive windows, as well as whether observed resting state dynamics during wakefulness may be predominantly due to changes in sleep state and subject head motion. In this work we use an independent component analysis (ICA)-based pipeline applied to concurrent EEG/fMRI data collected during wakefulness and various sleep stages and show: 1) connectivity states obtained from clustering sliding windowed correlations of resting state functional network time courses well classify the sleep states obtained from EEG data, 2) using shorter sliding windows instead of longer non-overlapping windows improves the ability to capture transition dynamics even at windows as short as 30 seconds, 3) motion appears to be mostly associated with one of the states rather than spread across all of them 4) a fixed tapered sliding window approach outperforms an adaptive dynamic conditional correlation approach, and 5) consistent with prior EEG/fMRI work, we identify evidence of multiple states within the wakeful condition which are able to be classified with high accuracy. Classification of wakeful only states suggest the presence of time-varying changes in connectivity in fMRI data beyond sleep state or motion. Results also inform about advantageous technical choices, and the identification of different clusters within wakefulness that are separable suggest further studies in this direction.
The azimuthal anisotropy coefficient v2 of prompt D0, D+, D∗+ and D+s mesons was measured in mid-central (30-50% centrality class) Pb-Pb collisions at a centre-of-mass energy per nucleon pair sNN−−−√=5.02 TeV, with the ALICE detector at the LHC. The D mesons were reconstructed via their hadronic decays at mid-rapidity, |y|<0.8, in the transverse momentum interval 1<pT<24 GeV/c. The measured D-meson v2 has similar values as that of charged pions. The D+s v2, measured for the first time, is found to be compatible with that of non-strange D mesons. The measurements are compared with theoretical calculations of charm-quark transport in a hydrodynamically expanding medium and have the potential to constrain medium parameters.
The outstanding speed of language comprehension necessitates a highly efficient implementation of cognitive-linguistic processes. The domain-general theory of Predictive Coding suggests that our brain solves this problem by continuously forming linguistic predictions about expected upcoming input. The neurophysiological implementation of these predictive linguistic processes, however, is not yet understood. Here, we use EEG (human participants, both sexes) to investigate the existence and nature of online-generated, category-level semantic representations during sentence processing. We conducted two experiments in which some nouns – embedded in a predictive spoken sentence context – were unexpectedly delayed by 1 second. Target nouns were either abstract/concrete (Experiment 1) or animate/inanimate (Experiment 2). We hypothesized that if neural prediction error signals following (temporary) omissions carry specific information about the stimulus, the semantic category of the upcoming target word is encoded in brain activity prior to its presentation. Using time-generalized multivariate pattern analysis, we demonstrate significant decoding of word category from silent periods directly preceding the target word, in both experiments. This provides direct evidence for predictive coding during sentence processing, i.e., that information about a word can be encoded in brain activity before it is perceived. While the same semantic contrast could also be decoded from EEG activity elicited by isolated words (Experiment 1), the identified neural patterns did not generalize to pre-stimulus delay period activity in sentences. Our results not only indicate that the brain processes language predictively, but also demonstrate the nature and sentence-specificity of category-level semantic predictions preactivated during sentence comprehension.
The measurement of dielectron production is presented as a function of invariant mass and transverse momentum (pT) at midrapidity (|ye|<0.8) in proton-proton (pp) collisions at a centre-of-mass energy of s√=13 TeV. The contributions from light-hadron decays are calculated from their measured cross sections in pp collisions at s√=7 TeV or 13 TeV. The remaining continuum stems from correlated semileptonic decays of heavy-flavour hadrons. Fitting the data with templates from two different MC event generators, PYTHIA and POWHEG, the charm and beauty cross sections at midrapidity are extracted for the first time at this collision energy: dσcc¯/dy|y=0=974±138(stat.)±140(syst.) μb and dσbb¯/dy|y=0=79±14(stat.)±11(syst.) μb using PYTHIA simulations and dσcc¯/dy|y=0=1417±184(stat.)±204(syst.) μb and dσbb¯/dy|y=0=48±14(stat.)±7(syst.) μb for POWHEG. These values, whose uncertainties are fully correlated between the two generators, are consistent with extrapolations from lower energies. The different results obtained with POWHEG and PYTHIA imply different kinematic correlations of the heavy-quark pairs in these two generators. Furthermore, comparisons of dielectron spectra in inelastic events and in events collected with a trigger on high charged-particle multiplicities are presented in various pT intervals. The differences are consistent with the already measured scaling of light-hadron and open-charm production at high charged-particle multiplicity as a function of pT. Upper limits for the contribution of virtual direct photons are extracted at 90% confidence level and found to be in agreement with pQCD calculations.
The first measurement of e+e− pair production at mid-rapidity (|ηe| < 0.8) in pp collisions at s√=7 TeV with ALICE at the LHC is presented. The dielectron production is studied as a function of the invariant mass (mee < 3.3 GeV/c2), the pair transverse momentum (pT,ee < 8 GeV/c), and the pair transverse impact parameter (DCAee), i.e., the average distance of closest approach of the reconstructed electron and positron tracks to the collision vertex, normalised to its resolution. The results are compared with the expectations from a cocktail of known hadronic sources and are well described when PYTHIA is used to generate the heavy-flavour contributions. In the low-mass region (0.14 < mee < 1.1 GeV/c2), prompt and non-prompt e+e− sources can be separated via the DCAee. In the intermediate-mass region (1.1 < mee < 2.7 GeV/c2), a double-differential fit to the data in mee and pT,ee and a fit of the DCAee distribution allow the total cc¯¯ and bb¯¯¯ cross sections to be extracted. Two different event generators, PYTHIA and POWHEG, can reproduce the shape of the two-dimensional mee and pT,ee spectra, as well as the shape of the DCAee distribution, reasonably well. However, differences in the cc¯¯ and bb¯¯¯ cross sections are observed when using the generators to extrapolate to full phase space. Finally, the ratio of inclusive to decay photons is studied via the measurement of virtual direct photons in the transverse-momentum range 1 < pT < 8 GeV/c. This is found to be unity within the statistical and systematic uncertainties and consistent with expectations from next-to-leading order perturbative quantum chromodynamic calculations.