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A candidate gene cluster for the bioactive natural product gyrophoric acid in lichen-forming fungi
(2022)
Natural products of lichen-forming fungi are structurally diverse and have a variety of medicinal properties. Despite this, they a have limited implementation in industry, because the corresponding genes remain unknown for most of the natural products. Here we implement a long-read sequencing and bioinformatic approach to identify the biosynthetic gene cluster of the bioactive natural product gyrophoric acid (GA). Using 15 high-quality genomes representing nine GA-producing species of the lichen-forming fungal genus Umbilicaria, we identify the most likely GA cluster and investigate cluster gene organization and composition across the nine species. Our results show that GA clusters are promiscuous within Umbilicaria, with only three genes that are conserved across species, including the PKS gene. In addition, our results suggest that the same cluster codes for different but structurally similar NPs, i.e., GA, umbilicaric acid and hiascic acid, bringing new evidence that lichen metabolite diversity is also generated through regulatory mechanisms at the molecular level. Ours is the first study to identify the most likely GA cluster, and thus provides essential information to open new avenues for biotechnological approaches to producing and modifying GA and similar lichen-derived compounds. We show that bioinformatics approaches are useful in linking genes and potentially associated natural products. Genome analyses help unlocking the pharmaceutical potential of organisms such as lichens, which are biosynthetically diverse but slow growing, and difficult to cultivate due to their symbiotic nature.
The human brain achieves visual object recognition through multiple stages of nonlinear transformations operating at a millisecond scale. To predict and explain these rapid transformations, computational neuroscientists employ machine learning modeling techniques. However, state-of-the-art models require massive amounts of data to properly train, and to the present day there is a lack of vast brain datasets which extensively sample the temporal dynamics of visual object recognition. Here we collected a large and rich dataset of high temporal resolution EEG responses to images of objects on a natural background. This dataset includes 10 participants, each with 82,160 trials spanning 16,740 image conditions. Through computational modeling we established the quality of this dataset in five ways. First, we trained linearizing encoding models that successfully synthesized the EEG responses to arbitrary images. Second, we correctly identified the recorded EEG data image conditions in a zero-shot fashion, using EEG synthesized responses to hundreds of thousands of candidate image conditions. Third, we show that both the high number of conditions as well as the trial repetitions of the EEG dataset contribute to the trained models’ prediction accuracy. Fourth, we built encoding models whose predictions well generalize to novel participants. Fifth, we demonstrate full end-to-end training of randomly initialized DNNs that output M/EEG responses for arbitrary input images. We release this dataset as a tool to foster research in visual neuroscience and computer vision.
Glutathione (GSH) is the main determinant of intracellular redox potential and participates in multiple cellular signaling pathways. Achieving a detailed understanding of intracellular GSH trafficking and regulation depends on the development of tools to map GSH compartmentalization and intra-organelle fluctuations. Herein, we present a new GSH sensing platform, TRaQ-G, for live-cell imaging. This small-molecule/protein hybrid sensor possesses a unique reactivity turn-on mechanism that ensures that the small molecule is only sensitive to GSH in the desired location. Furthermore, TRaQ-G can be fused to a fluorescent protein of choice to give a ratiometric response. Using TRaQ-G-mGold, we demonstrated that the nuclear and cytosolic GSH pools are independently regulated during cell proliferation. We also used this sensor, in combination with roGFP, to quantify redox potential and GSH concentration simultaneously in the endoplasmic reticulum. Finally, by exchanging the fluorescent protein, we created a near-infrared, targetable and quantitative GSH sensor.
Although new advances in neuroscience allow the study of vocal communication in awake animals, substantial progress in the processing of vocalizations has been made from brains of anaesthetized preparations. Thus, understanding how anaesthetics affect neuronal responses is of paramount importance. Here, we used electrophysiological recordings and computational modelling to study how the auditory cortex of bats responds to vocalizations under anaesthesia and in wakefulness. We found that multifunctional neurons that process echolocation and communication sounds were affected by ketamine anaesthesia in a manner that could not be predicted by known anaesthetic effects. In wakefulness, acoustic contexts (preceding echolocation or communication sequences) led to stimulus-specific suppression of lagging sounds, accentuating neuronal responses to sound transitions. However, under anaesthesia, communication contexts (but not echolocation) led to a global suppression of responses to lagging sounds. Such asymmetric effect was dependent on the frequency composition of the contexts and not on their temporal patterns. We constructed a neuron model that could replicate the data obtained in vivo. In the model, anaesthesia modulates spiking activity in a channel-specific manner, decreasing responses of cortical inputs tuned to high-frequency sounds and increasing adaptation in the respective cortical synapses. Combined, our findings obtained in vivo and in silico reveal that ketamine anaesthesia does not reduce uniformly the neurons’ responsiveness to low and high frequency sounds. This effect depends on combined mechanisms that unbalance cortical inputs and ultimately affect how auditory cortex neurons respond to natural sounds in anaesthetized preparations.
Precisely estimating event timing is essential for survival, yet temporal distortions are ubiquitous in our daily sensory experience. Here, we tested whether the relative position, relative duration and relative distance in time of two sequentially-organized events —standard S, with constant duration, and comparison C, varying trial-by-trial— are causal factors in generating temporal distortions. We found that temporal distortions emerge when the first event is shorter than the second event. Importantly, a significant interaction suggests that a longer ISI helps counteracting such serial distortion effect only the constant S is in first position, but not if the unpredictable C is in first position. These results suggest the existence of a perceptual bias in perceiving ordered event durations, mechanistically contributing to distortion in time perception. We simulated our behavioral results with a Bayesian model and replicated the finding that participants disproportionately expand first-position dynamic (unpredictable) short events. Our results clarify the mechanics generating time distortions by identifying a hitherto unknown duration-dependent encoding inefficiency in human serial temporal perception, akin to a strong prior that can be overridden for highly predictable sensory events but unfolds for unpredictable ones.
The neural mechanisms that unfold when humans form a large group defined by an overarching context, such as audiences in theater or sports, are largely unknown and unexplored. This is mainly due to the lack of availability of a scalable system that can record the brain activity from a significantly large portion of such an audience simultaneously. Although the technology for such a system has been readily available for a long time, the high cost as well as the large overhead in human resources and logistic planning have prohibited the development of such a system. However, during the recent years reduction in technology costs and size have led to the emergence of low-cost, consumer-oriented EEG systems, developed primarily for recreational use. Here by combining such a low-cost EEG system with other off-the-shelve hardware and tailor-made software, we develop in the lab and test in a cinema such a scalable EEG hyper-scanning system. The system has a robust and stable performance and achieves accurate unambiguous alignment of the recorded data of the different EEG headsets. These characteristics combined with small preparation time and low-cost make it an ideal candidate for recording large portions of audiences.
Orientation hypercolumns in the visual cortex are delimited by the repeating pinwheel patterns of orientation selective neurons. We design a generative model for visual cortex maps that reproduces such orientation hypercolumns as well as ocular dominance maps while preserving retinotopy. The model uses a neural placement method based on t–distributed stochastic neighbour embedding (t–SNE) to create maps that order common features in the connectivity matrix of the circuit. We find that, in our model, hypercolumns generally appear with fixed cell numbers independently of the overall network size. These results would suggest that existing differences in absolute pinwheel densities are a consequence of variations in neuronal density. Indeed, available measurements in the visual cortex indicate that pinwheels consist of a constant number of ∼30, 000 neurons. Our model is able to reproduce a large number of characteristic properties known for visual cortex maps. We provide the corresponding software in our MAPStoolbox for Matlab.
Difficulty producing intelligible speech is a common and debilitating symptom of Parkinson’s disease (PD). Yet, both the robust evaluation of speech impairments and the identification of the affected brain systems are challenging. We examine the spectral and spatial definitions of the functional neuropathology underlying reduced speech quality in patients with PD using a new approach to characterize speech impairments and a novel brain-imaging marker. We found that the interactive scoring of speech impairments in PD (N=59) is reliable across non-expert raters, and better related to the hallmark motor and cognitive impairments of PD than automatically-extracted acoustical features. By relating these speech impairment ratings to neurophysiological deviations from healthy adults (N=65), we show that articulation impairments in patients with PD are robustly predicted from aberrant activity in the left inferior frontal cortex, and that functional connectivity of this region with somatomotor cortices mediates the influence of cognitive decline on speech deficits.
Targeted protein degradation is a drug modality represented by compounds that recruit a target to an E3 ubiquitin ligase to promote target ubiquitination and proteasomal degradation. Historically, the field distinguishes monovalent degraders from bifunctional degraders (PROTACs) that connect target and ligase via separate binding ligands joined via a linker1–4. Here, we elucidate the mechanism of action of a PROTAC-like degrader of the transcriptional coactivator BRD4, composed of a BRD4 ligand linked to a ligand for the E3 ligase CRL4DCAF15. Using orthogonal CRISPR/Cas9 screens we identify the degrader activity is independent of DCAF15, and relies on a different CRL4 substrate receptor, DCAF16. We demonstrate an intrinsic affinity between BRD4 and DCAF16, which is dependent on the tandem bromodomains of BRD4 and further increased by the degrader without physically engaging DCAF16 in isolation. Structural characterization of the resulting ternary complex reveals both BRD4 bromodomains are bivalently engaged in cis by the degrader and are bound to DCAF16 through several interfacial BRD4-DCAF16 and degrader-DCAF16 contacts. Our findings demonstrate that intramolecularly bridging domains can confer glue-type stabilization of intrinsic target-E3 interactions, and we propose this as a general strategy to modulate the surface topology of target proteins to nucleate co-opting of E3 ligases or other cellular effector proteins for effective proximity-based pharmacology.
Anisotropic flow and flow fluctuations of identified hadrons in Pb–Pb collisions at √sNN = 5.02 TeV
(2022)
The first measurements of elliptic flow of π±, K±, p+p¯¯¯, K0S, Λ+Λ¯¯¯¯, ϕ, Ξ−+Ξ+, and Ω−+Ω+ using multiparticle cumulants in Pb−Pb collisions at sNN−−−√ = 5.02 TeV are presented. Results obtained with two- (v2{2}) and four-particle cumulants (v2{4}) are shown as a function of transverse momentum, pT, for various collision centrality intervals. Combining the data for both v2{2} and v2{4} also allows us to report the first measurements of the mean elliptic flow, elliptic flow fluctuations, and relative elliptic flow fluctuations for various hadron species. These observables probe the event-by-event eccentricity fluctuations in the initial state and the contributions from the dynamic evolution of the expanding quark-gluon plasma. The characteristic features observed in previous pT-differential anisotropic flow measurements for identified hadrons with two-particle correlations, namely the mass ordering at low pT and the approximate scaling with the number of constituent quarks at intermediate pT, are similarly present in the four-particle correlations and the combinations of v2{2} and v2{4}. In addition, a particle species dependence of flow fluctuations is observed that could indicate a significant contribution from final state hadronic interactions. The comparison between experimental measurements and CoLBT model calculations, which combine the various physics processes of hydrodynamics, quark coalescence, and jet fragmentation, illustrates their importance over a wide pT range.
Measurements of elliptic (v2) and triangular (v3) flow coefficients of π±, K±, p+p¯¯¯, K0S, and Λ+Λ¯¯¯¯ obtained with the scalar product method in Xe-Xe collisions at sNN−−−√ = 5.44 TeV are presented. The results are obtained in the rapidity range |y|<0.5 and reported as a function of transverse momentum, pT, for several collision centrality classes. The flow coefficients exhibit a particle mass dependence for pT<3 GeV/c, while a grouping according to particle type (i.e., meson and baryon) is found at intermediate transverse momenta (3< pT <8 GeV/c). The magnitude of the baryon v2 is larger than that of mesons up to pT = 6 GeV/c. The centrality dependence of the shape evolution of the pT-differential v2 is studied for the various hadron species. The v2 coefficients of π±, K±, and p+p¯¯¯ are reproduced by MUSIC hydrodynamic calculations coupled to a hadronic cascade model (UrQMD) for pT<1 GeV/c. A comparison with vn measurements in the corresponding centrality intervals in Pb-Pb collisions at sNN−−−√ = 5.02 TeV yields an enhanced v2 in central collisions and diminished value in semicentral collisions.
The measurement of the azimuthal-correlation function of prompt D mesons with charged particles in pp collisions at s√ = 5.02 TeV and p-Pb collisions at sNN−−−√ = 5.02 TeV with the ALICE detector at the LHC is reported. The D0, D+, and D∗+ mesons, together with their charge conjugates, were reconstructed at midrapidity in the transverse momentum interval 3 < pT < 24 GeV/c and correlated with charged particles having pT > 0.3 GeV/c and pseudorapidity |η|< 0.8. The properties of the correlation peaks appearing in the near- and away-side regions (for Δφ≈ 0 and Δφ≈π, respectively) were extracted via a fit to the azimuthal correlation functions. The shape of the correlation functions and the near- and away-side peak features are found to be consistent in pp and p-Pb collisions, showing no modifications due to nuclear effects within uncertainties. The results are compared with predictions from Monte Carlo simulations performed with the PYTHIA, POWHEG+PYTHIA, HERWIG, and EPOS 3 event generators.
We have investigated the systematic differences introduced when performing a Bayesian-inference analysis of the equation of state of neutron stars employing either variable- or constant-likelihood functions. The former have the advantage that it retains the full information on the distributions of the measurements, making an exhaustive usage of the data. The latter, on the other hand, have the advantage of a much simpler implementation and reduced computational costs. In both approaches, the EOSs have identical priors and have been built using the sound-speed parameterization method so as to satisfy the constraints from X-ray and gravitationalwaves observations, as well as those from Chiral Effective Theory and perturbative QCD. In all cases, the two approaches lead to very similar results and the 90%-confidence levels are essentially overlapping. Some differences do appear, but in regions where the probability density is extremely small and are mostly due to the sharp cutoff set on the binary tidal deformability Λ˜ ≤ 720 employed in the constant-likelihood analysis. Our analysis has also produced two additional results. First, a clear inverse correlation between the normalized central number density of a maximally massive star, nc,TOV/ns, and the radius of a maximally massive star, RTOV. Second, and most importantly, it has confirmed the relation between the chirp mass Mchirp and the binary tidal deformability Λ˜. The importance of this result is that it relates a quantity that is measured very accurately, Mchirp, with a quantity that contains important information on the micro-physics, Λ˜. Hence, once Mchirp is measured in future detections, our relation has the potential of setting tight constraints on Λ˜.
HER2 belongs to the ErbB sub-family of receptor tyrosine kinases and regulates cellular proliferation and growth. Different from other ErbB receptors, HER2 has no known ligand. Activation occurs through heterodimerization with other ErbB receptors and their cognate ligands. This suggests several possible activation paths of HER2 with ligand-specific, differential response, which so far remained unexplored. Using single-molecule tracking and the diffusion profile of HER2 as a proxy for activity, we measured the activation strength and temporal profile in live cells. We found that HER2 is strongly activated by EGFR-targeting ligands EGF and TGFα, yet with a distinguishable temporal fingerprint. The HER4-targeting ligands EREG and NRGβ1 showed weaker activation of HER2, a preference for EREG and a delayed response to NRGβ1. Our results indicate a selective ligand response of HER2 that may serve as a regulatory element. Our experimental approach is easily transferable to other membrane receptors targeted by multiple ligands.
Highlights
HER2 exhibits heterogeneous motion in the plasma membrane
The fraction of immobile HER2 correlates with phosphorylation levels
Diffusion properties serve as proxies for HER2 activation
HER2 exhibits ligand-specific activation strength and temporal profiles
The electrical and computational properties of neurons in our brains are determined by a rich repertoire of membrane-spanning ion channels and elaborate dendritic trees. However, the precise reason for this inherent complexity remains unknown. Here, we generated large stochastic populations of biophysically realistic hippocampal granule cell models comparing those with all 15 ion channels to their reduced but functional counterparts containing only 5 ion channels. Strikingly, valid parameter combinations in the full models were more frequent and more stable in the face of perturbations to channel expression levels. Scaling up the numbers of ion channels artificially in the reduced models recovered these advantages confirming the key contribution of the actual number of ion channel types. We conclude that the diversity of ion channels gives a neuron greater flexibility and robustness to achieve target excitability.
Hydrogen is a promising fuel in a carbon-neutral economy, and many efforts are currently undertaken to produce hydrogen. One of the challenges is to store and transport the highly explosive gas in a safe and easy way. One option that is intensively analyzed by chemists and biologists is the conversion of hydrogen and CO2 to formic acid, the liquid organic hydrogen carrier. Here, we demonstrate for the first time that a bio-based system, using Acetobacterium woodii as the biocatalyst, allows multiple cycles of bi-directional hydrogenation of CO2 to formic acid in one bioreactor. The process was kept running over 2 weeks producing and oxidizing 330 mM formic acid in total. Unwanted side-product formation of acetic acid was prevented through metabolic engineering of the organism. The demonstrated process design can be considered as a future “bio-battery” for the reversible storage of electrons in the form of H2 in formic acid, a versatile compound.
The NVX-CoV2373-vaccine has recently been licensed, although data on vaccine-induced humoral and cellular immunity towards the parental strain and variants of concern (VOCs) in comparison to dual-dose mRNA-regimens are limited. In this observational study including 66 participants, we show that NVX-CoV2373-induced IgG-levels were lower than after vaccination with BNT162b2 or mRNA-1273 (n=22 each, p=0.006). Regardless of the vaccine and despite different IgG-levels, neutralizing activity towards VOCs was highest for Delta, followed by BA.2 and BA.1. Interestingly, spike-specific CD8 T-cell levels after NVX-CoV2373-vaccination were significantly lower and were detectable in 3/22 (14%) individuals only. In contrast, spike-specific CD4 T-cells were induced in 18/22 (82%) individuals. However, CD4 T-cell levels were lower (p<0.001), had lower CTLA-4 expression (p<0.0001) and comprised less multifunctional cells co-expressing IFNγ, TNFαα and IL-2 (p=0.0007) as compared to mRNA-vaccinated individuals. Unlike neutralizing antibodies, NVX-CoV2373-induced CD4 T cells cross-reacted to all tested VOCs from Alpha to Omicron, which may hold promise to protect from severe disease.
Correlations between mean transverse momentum [pT] and anisotropic flow coefficients v2 or v3 are measured as a function of centrality in Pb−Pb and Xe−Xe collisions at sNN−−−√=5.02 TeV and 5.44 TeV, respectively, with ALICE. In addition, the recently proposed higher-order correlation between [pT], v2, and v3 is measured for the first time, which shows an anticorrelation for the presented centrality ranges. These measurements are compared with hydrodynamic calculations using IP-Glasma and TRENTo initial-state shapes, the former based on the Color Glass Condensate effective theory with gluon saturation, and the latter a parameterized model with nucleons as the relevant degrees of freedom. The data are better described by the IP-Glasma rather than the TRENTo based calculations. In particular, Trajectum and JETSCAPE predictions, both based on the TRENTo initial state model but with different parameter settings, fail to describe the measurements. As the correlations between [pT] and vn are mainly driven by the correlations of the size and the shape of the system in the initial state, these new studies pave a novel way to characterize the initial state and help pin down the uncertainty of the extracted properties of the quark−gluon plasma recreated in relativistic heavy-ion collisions.
Measurements of event-by-event fluctuations of charged-particle multiplicities in Pb-Pb collisions at sNN−−−√ = 2.76 TeV using the ALICE detector at the CERN Large Hadron Collider (LHC) are presented in the pseudorapidity range |η|<0.8 and transverse momentum 0.2<pT<2.0 GeV/c. The amplitude of the fluctuations is expressed in terms of the variance normalized by the mean of the multiplicity distribution. The η and pT dependences of the fluctuations and their evolution with respect to collision centrality are investigated. The multiplicity fluctuations tend to decrease from peripheral to central collisions. The results are compared to those obtained from HIJING and AMPT Monte Carlo event generators as well as to experimental data at lower collision energies. Additionally, the measured multiplicity fluctuations are discussed in the context of the isothermal compressibility of the high-density strongly-interacting system formed in central Pb-Pb collisions.
Recent pT-integrated cross section measurements of the ground-state charm mesons and baryons, D0, D+, D+s, Λ+c, and Ξ0c, are used to evaluate the charm fragmentation fractions and production cross section per unit of rapidity at midrapidity (|y|<0.5), in pp collisions at s√=5.02 TeV at the LHC. The latter is dσcc¯¯¯/dy||y|<0.5 =1165 ±44(stat)+134−101(syst) μb. These measurements were obtained for the first time in hadronic collisions at the LHC including the charm baryon states, recently measured by ALICE at midrapidity. The charm fragmentation fractions differ significantly from the values measured in e+e− and ep collisions, providing evidence of the dependence of the parton-to-hadron fragmentation fractions on the collision system, indicating that the assumption of their universality is not supported by the measured cross sections. An increase of a factor of about 3.3 for the fragmentation fraction for the Λ+c with a significance of 5σ between the values obtained in pp collisions and those obtained in e+e− (ep) collisions is reported. The fragmentation fraction for the Ξ0c was obtained for the first time in any collision system. The measured fragmentation fractions were used to update the cc¯¯ cross sections per unit of rapidity at |y|<0.5 at s√=2.76 and 7 TeV, which are about 40% higher than the previously published results. The data were compared with perturbative-QCD calculations and lie at the upper edge of the theoretical bands.
The most basic behavioural states of animals can be described as active or passive. However, while high-resolution observations of activity patterns can provide insights into the ecology of animal species, few methods are able to measure the activity of individuals of small taxa in their natural environment. We present a novel approach in which the automated VHF radio-tracking of small vertebrates fitted with lightweight transmitters (< 0.2 g) is used to distinguish between active and passive behavioural states.
A dataset containing > 3 million VHF signals was used to train and test a random forest model in the assignment of either active or passive behaviour to individuals from two forest-dwelling bat species (Myotis bechsteinii (n = 50) and Nyctalus leisleri (n = 20)). The applicability of the model to other taxonomic groups was demonstrated by recording and classifying the behaviour of a tagged bird and by simulating the effect of different types of vertebrate activity with the help of humans carrying transmitters. The random forest model successfully classified the activity states of bats as well as those of birds and humans, although the latter were not included in model training (F-score 0.96–0.98).
The utility of the model in tackling ecologically relevant questions was demonstrated in a study of the differences in the daily activity patterns of the two bat species. The analysis showed a pronounced bimodal activity distribution of N. leisleri over the course of the night while the night-time activity of M. bechsteinii was relatively constant. These results show that significant differences in the timing of species activity according to ecological preferences or seasonality can be distinguished using our method.
Our approach enables the assignment of VHF signal patterns to fundamental behavioural states with high precision and is applicable to different terrestrial and flying vertebrates. To encourage the broader use of our radio-tracking method, we provide the trained random forest models together with an R-package that includes all necessary data-processing functionalities. In combination with state-of-the-art open-source automated radio-tracking, this toolset can be used by the scientific community to investigate the activity patterns of small vertebrates with high temporal resolution, even in dense vegetation.
Fluctuation measurements are important sources of information on the mechanism of particle production at LHC energies. This article reports the first experimental results on third-order cumulants of the net-proton distributions in Pb−Pb collisions at a center-of-mass energy sNN−−−√=5.02 TeV recorded by the ALICE detector. The results on the second-order cumulants of net-proton distributions at sNN−−−√=2.76 and 5.02 TeV are also discussed in view of effects due to the global and local baryon number conservation. The results demonstrate the presence of long-range rapidity correlations between protons and antiprotons. Such correlations originate from the early phase of the collision. The experimental results are compared with HIJING and EPOS model calculations, and the dependence of the fluctuation measurements on the phase-space coverage is examined in the context of lattice quantum chromodynamics (LQCD) and hadron resonance gas (HRG) model estimations. The measured third-order cumulants are consistent with zero within experimental uncertainties of about 4% and are described well by LQCD and HRG predictions.
In a dynamic environment, the already limited information that human working memory can maintain needs to be constantly updated to optimally guide behaviour. Indeed, previous studies showed that working memory representations are continuously being transformed during delay periods leading up to a response. This goes hand-in-hand with the removal of task-irrelevant items. However, does such removal also include veridical, original stimuli, as they were prior to transformation? Here we aimed to assess the neural representation of task-relevant transformed representations, compared to the no-longer-relevant veridical representations they originated from. We applied multivariate pattern analysis to electroencephalographic data during maintenance of orientation gratings with and without mental rotation. During maintenance, we perturbed the representational network by means of a visual impulse stimulus, and were thus able to successfully decode veridical as well as imaginary, transformed orientation gratings from impulse-driven activity. On the one hand, the impulse response reflected only task-relevant (cued), but not task-irrelevant (uncued) items, suggesting that the latter were quickly discarded from working memory. By contrast, even though the original cued orientation gratings were also no longer task-relevant after mental rotation, these items continued to be represented next to the rotated ones, in different representational formats. This seemingly inefficient use of scarce working memory capacity was associated with reduced probe response times and may thus serve to increase precision and flexibility in guiding behaviour in dynamic environments.
Systematic studies of charge-dependent two- and three-particle correlations in Pb-Pb collisions at sNN−−−√= 2.76 and 5.02 TeV used to probe the Chiral Magnetic Effect (CME) are presented. These measurements are performed for charged particles in the pseudorapidity (η) and transverse momentum (pT) ranges |η|<0.8 and 0.2<pT<5 GeV/c. A significant charge-dependent signal that becomes more pronounced for peripheral collisions is reported for the CME-sensitive correlators γ1,1=⟨cos(φα+φβ−2Ψ2)⟩ and γ1,−3=⟨cos(φα−3φβ+2Ψ2)⟩. The results are used to estimate the contribution of background effects, associated with local charge conservation coupled to anisotropic flow modulations, to measurements of the CME. A blast-wave parametrisation that incorporates local charge conservation tuned to reproduce the centrality dependent background effects is not able to fully describe the measured γ1,1. Finally, the charge and centrality dependence of mixed-harmonics three-particle correlations, of the form γ1,2=⟨cos(φα+2φβ−3Ψ3)⟩, which are insensitive to the CME signal, verify again that background contributions dominate the measurement of γ1,1.
The interaction of K− with protons is characterised by the presence of several coupled channels, systems like K¯¯¯¯0n and πΣ with a similar mass and the same quantum numbers as the K−p state. The strengths of these couplings to the K−p system are of crucial importance for the understanding of the nature of the Λ(1405) resonance and of the attractive K−p strong interaction. In this article, we present measurements of the K−p correlation functions in relative momentum space obtained in pp collisions at s√ = 13 TeV, in p-Pb collisions at sNN−−−√ = 5.02 TeV, and (semi)peripheral Pb-Pb collisions at sNN−−−√ = 5.02 TeV. The emitting source size, composed of a core radius anchored to the K+p correlation and of a resonance halo specific to each particle pair, varies between 1 and 2 fm in these collision systems. The strength and the effects of the K¯¯¯¯0n and πΣ inelastic channels on the measured K−p correlation function are investigated in the different colliding systems by comparing the data with state-of-the-art models of chiral potentials. A novel approach to determine the conversion weights ω, necessary to quantify the amount of produced inelastic channels in the correlation function, is presented. In this method, particle yields are estimated from thermal model predictions, and their kinematic distribution from blast-wave fits to measured data. The comparison of chiral potentials to the measured K−p interaction indicates that, while the πΣ−K−p dynamics is well reproduced by the model, the coupling to the K¯¯¯¯0n channel in the model is currently underestimated.
Coronavirus disease 2019 (COVID-19) is caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and can affect multiple organs, among which is the circulatory system. Inflammation and mortality risk markers were previously detected in COVID-19 plasma and red blood cells (RBCs) metabolic and proteomic profiles. Additionally, biophysical properties, such as deformability, were found to be changed during the infection. Based on such data, we aim to better characterize RBC functions in COVID-19. We evaluate the flow properties of RBCs in severe COVID-19 patients admitted to the intensive care unit by using in vitro microfluidic techniques and automated methods, including artificial neural networks, for an unbiased RBC analysis. We find strong flow and RBC shape impairment in COVID-19 samples and demonstrate that such changes are reversible upon suspension of COVID-19 RBCs in healthy plasma. Vice versa, healthy RBCs immediately resemble COVID-19 RBCs when suspended in COVID-19 plasma. Proteomics and metabolomics analyses allow us to detect the effect of plasma exchanges on both plasma and RBCs and demonstrate a new role of RBCs in maintaining plasma equilibria at the expense of their flow properties. Our findings provide a framework for further investigations of clinical relevance for therapies against COVID-19 and possibly other infectious diseases.
Coronavirus disease 2019 (COVID-19) is caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and can affect multiple organs, among which is the circulatory system. Inflammation and mortality risk markers were previously detected in COVID-19 plasma and red blood cells (RBCs) metabolic and proteomic profiles. Additionally, biophysical properties, such as deformability, were found to be changed during the infection. Based on such data, we aim to better characterize RBC functions in COVID-19. We evaluate the flow properties of RBCs in severe COVID-19 patients admitted to the intensive care unit by using in vitro microfluidic techniques and automated methods, including artificial neural networks, for an unbiased RBC analysis. We find strong flow and RBC shape impairment in COVID-19 samples and demonstrate that such changes are reversible upon suspension of COVID-19 RBCs in healthy plasma. Vice versa, healthy RBCs immediately resemble COVID-19 RBCs when suspended in COVID-19 plasma. Proteomics and metabolomics analyses allow us to detect the effect of plasma exchanges on both plasma and RBCs and demonstrate a new role of RBCs in maintaining plasma equilibria at the expense of their flow properties. Our findings provide a framework for further investigations of clinical relevance for therapies against COVID-19 and possibly other infectious diseases.
Intrinsically disordered regions (IDRs) are essential for membrane receptor regulation but often remain unresolved in structural studies. TRPV4, a member of the TRP vanilloid channel family involved in thermo- and osmosensation, has a large N-terminal IDR of approximately 150 amino acids. With an integrated structural biology approach, we analyze the structural ensemble of the TRPV4 IDR and identify a network of regulatory elements that modulate channel activity in a hierarchical lipid-dependent manner through transient long-range interactions. A highly conserved autoinhibitory patch acts as a master regulator by competing with PIP2 binding to attenuate channel activity. Molecular dynamics simulations show that loss of the interaction between the PIP2-binding site and the membrane reduces the force exerted by the IDR on the structured core of TRPV4. This work demonstrates that IDR structural dynamics are coupled to TRPV4 activity and highlights the importance of IDRs for TRP channel function and regulation.
mRNA localization to subcellular compartments has been reported across all kingdoms of life and it is generally believed to promote asymmetric protein synthesis and localization. In striking contrast to previous observations, we show that in S. cerevisiae the B-type cyclin CLB2 mRNA is localized and translated in the yeast bud, while the Clb2 protein, a key regulator of mitosis progression, is concentrated in the mother nucleus. Using single-molecule RNA imaging in fixed (smFISH) and living cells (MS2 system), we show that the CLB2 mRNA is transported to the yeast bud by the She2-She3 complex, via an mRNA ZIP-code situated in the coding sequence. In CLB2 mRNA localization mutants, Clb2 protein synthesis in the bud is decreased resulting in changes in cell cycle distribution and genetic instability. Altogether, we propose that CLB2 mRNA localization acts as a sensor for bud development to couple cell growth and cell cycle progression, revealing a novel function for mRNA localization.
Speech imagery (the ability to generate internally quasi-perceptual experiences of speech) is a fundamental ability linked to cognitive functions such as inner speech, phonological working memory, and predictive processing. Speech imagery is also considered an ideal tool to test theories of overt speech. The study of speech imagery is challenging, primarily because of the absence of overt behavioral output as well as the difficulty in temporally aligning imagery events across trials and individuals. We used magnetoencephalography (MEG) paired with temporal-generalization-based neural decoding and a simple behavioral protocol to determine the processing stages underlying speech imagery. We monitored participants’ lip and jaw micromovements during mental imagery of syllable production using electromyography. Decoding participants’ imagined syllables revealed a sequence of task-elicited representations. Importantly, participants’ micromovements did not discriminate between syllables. The decoded sequence of neuronal patterns maps well onto the predictions of current computational models of overt speech motor control and provides evidence for hypothesized internal and external feedback loops for speech planning and production, respectively. Additionally, the results expose the compressed nature of representations during planning which contrasts with the natural rate at which internal productions unfold. We conjecture that the same sequence underlies the motor-based generation of sensory predictions that modulate speech perception as well as the hypothesized articulatory loop of phonological working memory. The results underscore the potential of speech imagery, based on new experimental approaches and analytical methods, and further pave the way for successful non-invasive brain-computer interfaces.
The phase diagram of the (1+1)-dimensional Gross-Neveu model is reanalyzed for (non-)zero chemical potential and (non-)zero temperature within the mean-field approximation. By investigating the momentum dependence of the bosonic two-point function, the well-known second-order phase transition from the Z2 symmetric phase to the so-called inhomogeneous phase is detected. In the latter phase the chiral condensate is periodically varying in space and translational invariance is broken. This work is a proof of concept study that confirms that it is possible to correctly localize second-order phase transition lines between phases without condensation and phases of spatially inhomogeneous condensation via a stability analysis of the homogeneous phase. To complement other works relying on this technique, the stability analysis is explained in detail and its limitations and successes are discussed in context of the Gross-Neveu model. Additionally, we present explicit results for the bosonic wave-function renormalization in the mean-field approximation, which is extracted analytically from the bosonic two-point function. We find regions -- a so-called moat regime -- where the wave function renormalization is negative accompanying the inhomogeneous phase as expected.
The phase diagram of the (1+1)-dimensional Gross-Neveu model is reanalyzed for (non-)zero chemical potential and (non-)zero temperature within the mean-field approximation. By investigating the momentum dependence of the bosonic two-point function, the well-known second-order phase transition from the Z2 symmetric phase to the so-called inhomogeneous phase is detected. In the latter phase the chiral condensate is periodically varying in space and translational invariance is broken. This work is a proof of concept study that confirms that it is possible to correctly localize second-order phase transition lines between phases without condensation and phases of spatially inhomogeneous condensation via a stability analysis of the homogeneous phase. To complement other works relying on this technique, the stability analysis is explained in detail and its limitations and successes are discussed in context of the Gross-Neveu model. Additionally, we present explicit results for the bosonic wave-function renormalization in the mean-field approximation, which is extracted analytically from the bosonic two-point function. We find regions -- a so-called moat regime -- where the wave function renormalization is negative accompanying the inhomogeneous phase as expected.
Although vaccines are currently used to control the coronavirus disease 2019 (COVID-19) pandemic, treatment options are urgently needed for those who cannot be vaccinated and for future outbreaks involving new severe acute respiratory syndrome coronavirus virus 2 (SARS-CoV-2) strains or coronaviruses not covered by current vaccines. Thus far, few existing antivirals are known to be effective against SARS-CoV-2 and clinically successful against COVID-19.
As part of an immediate response to the COVID-19 pandemic, a high-throughput, high content imaging–based SARS-CoV-2 infection assay was developed in VeroE6-eGFP cells and was used to screen a library of 5676 compounds that passed phase 1 clinical trials. Eight candidates (nelfinavir, RG-12915, itraconazole, chloroquine, hydroxychloroquine, sematilide, remdesivir, and doxorubicin) with in vitro anti–SARS-CoV-2 activity in VeroE6-eGFP and/or Caco-2 cell lines were identified. However, apart from remdesivir, toxicity and pharmacokinetic data did not support further clinical development of these compounds for COVID-19 treatment.
The first measurement of the e+e− pair production at low lepton pair transverse momentum (pT,ee) and low invariant mass (mee) in non-central Pb−Pb collisions at sNN−−−√=5.02 TeV at the LHC is presented. The dielectron production is studied with the ALICE detector at midrapidity (|ηe|<0.8) as a function of invariant mass (0.4≤mee<2.7 GeV/c2) in the 50−70% and 70−90% centrality classes for pT,ee<0.1 GeV/c, and as a function of pT,ee in three mee intervals in the most peripheral Pb−Pb collisions. Below a pT,ee of 0.1 GeV/c, a clear excess of e+e− pairs is found compared to the expectations from known hadronic sources and predictions of thermal radiation from the medium. The mee excess spectra are reproduced, within uncertainties, by different predictions of the photon−photon production of dielectrons, where the photons originate from the extremely strong electromagnetic fields generated by the highly Lorentz-contracted Pb nuclei. Lowest-order quantum electrodynamic (QED) calculations, as well as a model that takes into account the impact-parameter dependence of the average transverse momentum of the photons, also provide a good description of the pT,ee spectra. The measured ⟨p2T,ee⟩−−−−−√ of the excess pT,ee spectrum in peripheral Pb−Pb collisions is found to be comparable to the values observed previously at RHIC in a similar phase-space region.
Different modification pathways for m1A58 incorporation in yeast elongator and initiator tRNAs
(2022)
As essential components of the cellular protein synthesis machineries, tRNAs undergo a tightly controlled biogenesis process, which include the incorporation of a large number of posttranscriptional chemical modifications. Maturation defaults resulting in lack of modifications in the tRNA core may lead to the degradation of hypomodified tRNAs by the rapid tRNA decay (RTD) and nuclear surveillance pathways. Although modifications are typically introduced in tRNAs independently of each other, several modification circuits have been identified in which one or more modifications stimulate or repress the incorporation of others. We previously identified m1A58 as a late modification introduced after more initial modifications, such as Ѱ55 and T54 in yeast elongator tRNAPhe. However, previous reports suggested that m1A58 is introduced early along the tRNA modification process, with m1A58 being introduced on initial transcripts of initiator tRNAiMet, and hence preventing its degradation by the nuclear surveillance and RTD pathways. Here, aiming to reconcile this apparent inconsistency on the temporality of m1A58 incorporation, we examined the m1A58 modification pathways in yeast elongator and initiator tRNAs. For that, we first implemented a generic approach enabling the preparation of tRNAs containing specific modifications. We then used these specifically modified tRNAs to demonstrate that the incorporation of T54 in tRNAPhe is directly stimulated by Ѱ55, and that the incorporation of m1A58 is directly and individually stimulated by Ѱ55 and T54, thereby reporting on the molecular aspects controlling the Ѱ55 → T54 → m1A58 modification circuit in yeast elongator tRNAs. We also show that m1A58 is efficiently introduced on unmodified tRNAiMet, and does not depend on prior modifications. Finally, we show that the m1A58 single modification has tremendous effects on the structural properties of yeast tRNAiMet, with the tRNA elbow structure being properly assembled only when this modification is present. This rationalizes on structural grounds the degradation of hypomodified tRNAiMet lacking m1A58 by the nuclear surveillance and RTD pathways.
In particle collider experiments, elementary particle interactions with large momentum transfer produce quarks and gluons (known as partons) whose evolution is governed by the strong force, as described by the theory of quantum chromodynamics (QCD). These partons subsequently emit further partons in a process that can be described as a parton shower which culminates in the formation of detectable hadrons. Studying the pattern of the parton shower is one of the key experimental tools for testing QCD. This pattern is expected to depend on the mass of the initiating parton, through a phenomenon known as the dead-cone effect, which predicts a suppression of the gluon spectrum emitted by a heavy quark of mass mQ and energy E, within a cone of angular size mQ/E around the emitter. Previously, a direct observation of the dead-cone effect in QCD had not been possible, owing to the challenge of reconstructing the cascading quarks and gluons from the experimentally accessible hadrons. We report the direct observation of the QCD dead cone by using new iterative declustering techniques to reconstruct the parton shower of charm quarks. This result confirms a fundamental feature of QCD. Furthermore, the measurement of a dead-cone angle constitutes a direct experimental observation of the non-zero mass of the charm quark, which is a fundamental constant in the standard model of particle physics.
Spatial attention increases both inter-areal synchronization and spike rates across the visual hierarchy. To investigate whether these attentional changes reflect distinct or common mechanisms, we performed simultaneous laminar recordings of identified cell classes in macaque V1 and V4. Enhanced V4 spike rates were expressed by both excitatory neurons and fast-spiking interneurons, and were most prominent and arose earliest in time in superficial layers, consistent with a feedback modulation. By contrast, V1-V4 gamma-synchronization reflected feedforward communication and surprisingly engaged only fast-spiking interneurons in the V4 input layer. In mouse visual cortex, we found a similar motif for optogenetically identified inhibitory-interneuron classes. Population decoding analyses further indicate that feedback-related increases in spikes rates encoded attention more reliably than feedforward-related increases in synchronization. These findings reveal distinct, cell-type-specific feedforward and feedback pathways for the attentional modulation of inter-areal synchronization and spike rates, respectively.
From early to middle childhood, brain regions that underlie memory consolidation undergo profound maturational changes. However, there is little empirical investigation that directly relates age-related differences in brain structural measures to the memory consolidation processes. The present study examined system-level memory consolidations of intentionally studied object-location associations after one night of sleep (short delay) and after two weeks (long delay) in normally developing 5-to-7-year-old children (n = 50) and young adults (n = 39). Behavioural differences in memory consolidation were related to structural brain measures. Our results showed that children, in comparison to young adults, consolidate correctly learnt object-location associations less robustly over short and long delay. Moreover, using partial least squares correlation method, a unique multivariate profile comprised of specific neocortical (prefrontal, parietal, and occipital), cerebellar, and hippocampal subfield structures was found to be associated with variation in short-delay memory consolidation. A different multivariate profile comprised of a reduced set of brain structures, mainly consisting of neocortical (prefrontal, parietal, and occipital), and selective hippocampal subfield structures (CA1-2 and subiculum) was associated with variation in long-delay memory consolidation. Taken together, the results suggest that multivariate structural pattern of unique sets of brain regions are related to variations in short- and long-delay memory consolidation across children and young adults.
RESEARCH HIGHLIGHTS
* Short- and long-delay memory consolidation is less robust in children than in young adults
* Short-delay brain profile comprised of hippocampal, cerebellar, and neocortical brain regions
* Long-delay brain profile comprised of neocortical and selected hippocampal brain regions.
* Brain profiles differ between children and young adults.
Membrane receptors are central to cell-cell communication. Receptor clustering at the plasma membrane modulates physiological responses, and mesoscale receptor organization is critical for downstream signaling. Spatially restricted cluster formation of the neuropeptide Y2 hormone receptor (Y2R) was observed in vivo; however, the relevance of this confinement is not fully understood. Here, we controlled Y2R clustering in situ by a chelator nanotool. Due to the multivalent interaction, we observed a dynamic exchange in the microscale confined regions. Fast Y2R enrichment in clustered areas triggered a ligand-independent downstream signaling determined by an increase in cytosolic calcium, cell spreading, and migration. We revealed that the cell response to ligand-induced activation was amplified when cells were pre-clustered by the nanotool. Ligand-independent signaling by clustering differed from ligand-induced activation in the binding of arrestin-3 as downstream effector, which was recruited to the confined regions only in the presence of the ligand. This approach enables in situ clustering of membrane receptors and raises the possibility to explore different modalities of receptor activation.
Wastewater-based SARS-CoV-2 epidemiology (WBE) has been established as an important tool to support individual testing strategies. Omicron sub-variants BA.4/5 have spread globally displacing the predeceasing variants. Due to the severe transmissibility and immune escape potential of BA.4/5, early monitoring was required to asses and implement countermeasures in time.
In this study, we monitored the prevalence of SARS-CoV-2 BA.4/5 at six municipal wastewater treatment plants (WWTPs) in the Federal State of North-Rhine-Westphalia (NRW, Germany) in May and June 2022. Initially, L452R-specific primers/probes originally designed for SARS-CoV-2 Delta detection were validated using inactivated authentic viruses and evaluated for their suitability to detect BA.4/5. Subsequently, the assay was used for RT-qPCR analysis of RNA purified from wastewater obtained twice a week at six WWTPs. The occurrence of L452R carrying RNA was detected in early May 2022 and the presence of BA.4/5 was confirmed by variant-specific single nucleotide polymorphism PCR (SNP-PCR) targeting E484A/F486V. Finally, the mutant fractions were quantitatively monitored by digital PCR confirming BA.4/5 as the majority variant by 5th June 2022.
In conclusions, the successive workflow using RT-qPCR, variant-specific SNP-PCR, and RT-dPCR demonstrates the strength of WBE as a versatile tool to rapidly monitor variant spreading independent of individual test capacities.
Wastewater-based SARS-CoV-2 epidemiology (WBE) has been established as an important tool to support individual testing strategies. Omicron sub-variants BA.4/5 have spread globally displacing the predeceasing variants. Due to the severe transmissibility and immune escape potential of BA.4/5, early monitoring was required to asses and implement countermeasures in time.
In this study, we monitored the prevalence of SARS-CoV-2 BA.4/5 at six municipal wastewater treatment plants (WWTPs) in the Federal State of North-Rhine-Westphalia (NRW, Germany) in May and June 2022. Initially, L452R-specific primers/probes originally designed for SARS-CoV-2 Delta detection were validated using inactivated authentic viruses and evaluated for their suitability to detect BA.4/5. Subsequently, the assay was used for RT-qPCR analysis of RNA purified from wastewater obtained twice a week at six WWTPs. The occurrence of L452R carrying RNA was detected in early May 2022 and the presence of BA.4/5 was confirmed by variant-specific single nucleotide polymorphism PCR (SNP-PCR) targeting E484A/F486V. Finally, the mutant fractions were quantitatively monitored by digital PCR confirming BA.4/5 as the majority variant by 5th June 2022.
In conclusions, the successive workflow using RT-qPCR, variant-specific SNP-PCR, and RT-dPCR demonstrates the strength of WBE as a versatile tool to rapidly monitor variant spreading independent of individual test capacities.
The mammalian frontal and auditory cortices are important for vocal behaviour. Here, using local field potential recordings, we demonstrate for the first time that the timing and spatial pattern of oscillations in the fronto-auditory cortical network of vocalizing bats (Carollia perspicillata) predict the purpose of vocalization: echolocation or communication. Transfer entropy analyses revealed predominantly top-down (frontal-to-auditory cortex) information flow during spontaneous activity and pre-vocal periods. The dynamics of information flow depended on the behavioural role of the vocalization and on the timing relative to vocal onset. Remarkably, we observed the emergence of predominantly bottom-up (auditory-to-frontal cortex) information transfer patterns specific echolocation production, leading to self-directed acoustic feedback. Electrical stimulation of frontal areas selectively enhanced responses to echolocation sounds in auditory cortex. These results reveal unique changes in information flow across sensory and frontal cortices, potentially driven by the purpose of the vocalization in a highly vocal mammalian model.
Effective spectral functions of the ρ meson are reconstructed by considering the lifetimes inside different media using the hadronic transport SMASH (Simulating Many Accelerated Strongly-interacting Hadrons). Due to inelastic scatterings, resonance lifetimes are dynamically shortened (collisional broadening), even though the employed approach assumes vacuum resonance properties. Analyzing the ρ meson lifetimes allows to quantify an effective broadening of the decay width and spectral function, which is important in order to distinguish dynamical effects from additional genuine medium modifications to the spectral functions, indicating e.g. an onset of chiral symmetry restoration. The broadening of the spectral function in a thermalized system is shown to be consistent with other theoretical calculations. The effective ρ meson spectral function is also presented for the dynamical evolution of heavy-ion collisions, finding a clear correlation of the broadening to system size, which is explained by an observed dependence of the width on the local hadron density. Furthermore, the difference in the results between the thermal system and full collision dynamics is explored, which may point to non-equilibrium effects.
Measurements of the elliptic flow coefficient relative to the collision plane defined by the spectator neutrons v2{ΨSP} in collisions of Pb ions at center-of-mass energy per nucleon-nucleon pair sNN−−−√=2.76 TeV and Xe ions at sNN−−−√=5.44 TeV are reported. The results are presented for charged particles produced at midrapidity as a function of centrality and transverse momentum. The ratio between v2{ΨSP} and the elliptic flow coefficient relative to the participant plane v2{4}, estimated using four-particle correlations, deviates by up to 20% from unity depending on centrality. This observation differs strongly from the magnitude of the corresponding eccentricity ratios predicted by the TRENTo and the elliptic power models of initial state fluctuations that are tuned to describe the participant plane anisotropies. The differences can be interpreted as a decorrelation of the neutron spectator plane and the reaction plane because of fragmentation of the remnants from the colliding nuclei, which points to an incompleteness of current models of initial state fluctuations. A significant transverse momentum dependence of the ratio v2{ΨSP}/v2{4} is observed in all but the most central collisions, which may help to understand whether momentum anisotropies at low and intermediate transverse momentum have a common origin in initial state fluctuations. The ratios of v2{ΨSP} and v2{4} to the corresponding initial state eccentricities for Xe-Xe and Pb-Pb collisions at similar initial entropy density show a difference of (7.0±0.9)% with an additional variation of +1.8% when including RHIC data in the TRENTo parameter extraction. These observations provide new experimental constraints for viscous effects in the hydrodynamic modeling of the expanding quark-gluon plasma.
The production of ϕ mesons has been studied in pp collisions at LHC energies with the ALICE detector via the dimuon decay channel in the rapidity region 2.5<y<4. Measurements of the differential cross section d2σ/dydpT are presented as a function of the transverse momentum (pT) at the center-of-mass energies s√=5.02, 8 and 13 TeV and compared with the ALICE results at midrapidity. The differential cross sections at s√=5.02 and 13 TeV are also studied in several rapidity intervals as a function of pT, and as a function of rapidity in three pT intervals. A hardening of the pT-differential cross section with the collision energy is observed, while, for a given energy, pT spectra soften with increasing rapidity and, conversely, rapidity distributions get slightly narrower at increasing pT. The new results, complementing the published measurements at s√=2.76 and 7 TeV, allow one to establish the energy dependence of ϕ meson production and to compare the measured cross sections with phenomenological models. None of the considered models manages to describe the evolution of the cross section with pT and rapidity at all the energies.
The transverse-momentum (pT) spectra and coalescence parameters B2 of (anti)deuterons are measured in pp collisions at s√=13 TeV in and out of jets. In this measurement, the direction of the leading particle with the highest pT in the event (pleadT>5 GeV/c) is used as an approximation for the jet axis. The event is consequently divided into three azimuthal regions and the jet signal is obtained as the difference between the Toward region, that contains jet fragmentation products in addition to the underlying event (UE), and the Transverse region, which is dominated by the UE. The coalescence parameter in the jet is found to be approximately a factor of 10 larger than that in the underlying event. This experimental observation is consistent with the coalescence picture and can be attributed to the smaller average phase-space distance between nucleons inside the jet cone as compared to the underlying event. The results presented in this Letter are compared to predictions from a simple nucleon coalescence model, where the phase space distributions of nucleons are generated using PYTHIA 8 with the Monash 2013 tuning, and to predictions from a deuteron production model based on ordinary nuclear reactions with parametrized energy-dependent cross sections tuned on data. The latter model is implemented in PYTHIA 8.3. Both models reproduce the observed large difference between in-jet and out-of-jet coalescence parameters.
The first evidence of spin alignment of vector mesons (K∗0 and ϕ) in heavy-ion collisions at the Large Hadron Collider (LHC) is reported. The spin density matrix element ρ00 is measured at midrapidity (|y|< 0.5) in Pb-Pb collisions at a center-of-mass energy (sNN−−−√) of 2.76 TeV with the ALICE detector. ρ00 values are found to be less than 1/3 (1/3 implies no spin alignment) at low transverse momentum (pT< 2 GeV/c) for K∗0 and ϕ at a level of 3σ and 2σ, respectively. No significant spin alignment is observed for the K0S meson (spin = 0) in Pb-Pb collisions and for the vector mesons in pp collisions. The measured spin alignment is unexpectedly large but qualitatively consistent with the expectation from models which attribute it to a polarization of quarks in the presence of angular momentum in heavy-ion collisions and a subsequent hadronization by the process of recombination.
Several clinically used drugs are derived from microorganisms that often produce them via non-ribosomal peptide synthetases (NRPS), giant megasynthases that activate and connect individual amino acids in an assembly line fashion. Since NRPS are not restricted to the incorporation of the 20 proteinogenic amino acids, their efficient manipulation would allow the biotechnological generation of several different peptides including linear, cyclic and further modified derivatives. Here we describe a detailed phylogenetic analysis of several bacterial NRPS that led to the identification of a new recombination breakpoint within the thiolation (T) domain important in natural NRPS evolution. From this an evolutionary-inspired eXchange Unit between T domains (XUT) approach was developed, which allows the assembly of NRPS fragments over a broad range of GC contents, protein similarities, and extender unit specificities, as was shown for the specific production of a proteasome inhibitor, designed and assembled from five different NRPS fragments.
Many clinically used drugs are derived from or inspired by bacterial natural products that often are biosynthesised via non-ribosomal peptide synthetases (NRPS), giant megasynthases that activate and join individual amino acids in an assembly line fashion. Since NRPS are not limited to the incorporation of the 20 proteinogenic amino acids, their efficient manipulation would allow the biotechnological generation of complex peptides including linear, cyclic and further modified natural product analogues, e.g. to optimise natural product leads. Here we describe a detailed phylogenetic analysis of several bacterial NRPS that led to the identification of a new recombination breakpoint within the thiolation (T) domain that is important for natural NRPS evolution. From this, an evolution-inspired eXchange Unit between T domains (XUT) approach was developed which allows the assembly of NRPS fragments over a broad range of GC contents, protein similarities, and extender unit specificities, as demonstrated for the specific production of a proteasome inhibitor designed and assembled from five different NRPS fragments.
When speech is too fast, the tracking of the acoustic signal along the auditory pathway deteriorates, leading to suboptimal speech segmentation and decoding of speech information. Thus, speech comprehension is limited by the temporal constraints of the auditory system. Here we ask whether individual differences in auditory-motor coupling strength in part shape these temporal constraints. In two behavioral experiments, we characterize individual differences in the comprehension of naturalistic speech as function of the individual synchronization between the auditory and motor systems and the preferred frequencies of the systems. Obviously, speech comprehension declined at higher speech rates. Importantly, however, both higher auditory-motor synchronization and higher spontaneous speech motor production rates were predictive of better speech-comprehension performance. Furthermore, performance increased with higher working memory capacity (Digit Span) and higher linguistic, model-based sentence predictability – particularly so at higher speech rates and for individuals with high auditory-motor synchronization. These findings support the notion of an individual preferred auditory– motor regime that allows for optimal speech processing. The data provide evidence for a model that assigns a central role to motor-system-dependent individual flexibility in continuous speech comprehension.