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Parkinson disease (PD), one of the most common neurodegenerative disorder, is believed to be driven by toxic α-synuclein aggregates eventually resulting in selective loss of vulnerable neuron populations, prominent among them, nigrostriatal dopamine (DA) neurons in the lateral substantia nigra (l-SN). How α-synuclein aggregates initiate a pathophysiological cascade selectively in vulnerable neurons is still unclear. Here, we show that the exposure to low nanomolar concentrations of α-synuclein aggregates (i.e. fibrils) but not its monomeric forms acutely and selectively disrupted the electrical pacemaker function of the DA subpopulation most vulnerable in PD. This implies that only dorsolateral striatum projecting l-SN DA neurons were electrically silenced by α-synuclein aggregates, while the activity of neither neighboring DA neurons in medial SN projecting to dorsomedial striatum nor mesolimbic DA neurons in the ventral tegmental area (VTA) were affected. Moreover, we demonstrate functional K-ATP channels comprised of Kir6.2 subunit in DA neurons to be necessary to mediate this acute pacemaker disruption by α-synuclein aggregates. Our study thus identifies a molecularly defined target that quickly translates the presence of α-synuclein aggregates into an immediate impairment of essential neuronal function. This constitutes a novel candidate process how a protein-aggregation-driven sequence in PD is initiated that might eventually lead to selective neurodegeneration.
The SLC26 family of transporters maintains anion equilibria in all kingdoms of life. The family shares a 7 + 7 transmembrane segments inverted repeat architecture with the SLC4 and SLC23 families, but holds a regulatory STAS domain in addition. While the only experimental SLC26 structure is monomeric, SLC26 proteins form structural and functional dimers in the lipid membrane. Here we resolve the structure of an SLC26 dimer embedded in a lipid membrane and characterize its functional relevance by combining PELDOR distance measurements and biochemical studies with MD simulations and spin-label ensemble refinement. Our structural model reveals a unique interface different from the SLC4 and SLC23 families. The functionally relevant STAS domain exerts a stabilizing effect on regions central in this dimer. Characterization of heterodimers indicates that protomers in the dimer functionally interact. The combined structural and functional data define the framework for a mechanistic understanding of functional cooperativity in SLC26 dimers.
YEATS-domain-containing MLLT1 is an acetyl/acyl-lysine reader domain, which is structurally distinct from well-studied bromodomains and has been strongly associated in development of cancer. Here, we characterized piperazine-urea derivatives as an acetyl/acyl-lysine mimetic moiety for MLLT1. Crystal structures revealed distinct interaction mechanisms of this chemotype compared to the recently described benzimidazole-amide based inhibitors, exploiting different binding pockets within the protein. Thus, the piperazine-urea scaffold offers an alternative strategy for targeting the YEATS domain family.
The inclusive J/ψ production in Pb-Pb collisions at the center-of-mass energy per nucleon pair sNN−−−√ = 5.02 TeV, measured with the ALICE detector at the CERN LHC, is reported. The J/ψ meson is reconstructed via the dimuon decay channel at forward rapidity (2.5<y<4) down to zero transverse momentum. The suppression of the J/ψ yield in Pb-Pb collisions with respect to binary-scaled pp collisions is quantified by the nuclear modification factor (RAA). The RAA at sNN−−−√ = 5.02 TeV is presented and compared with previous measurements at sNN−−−√ = 2.76 TeV as a function of the centrality of the collision, and of the J/ψ transverse momentum and rapidity. The inclusive J/ψ RAA shows a suppression increasing toward higher pT, with a steeper dependence for central collisions. The modification of the J/ψ average pT and p2T is also studied. Comparisons with the results of models based on a transport equation and on statistical hadronization are also carried out.
The second (v2) and third (v3) flow harmonic coefficients of J/ψ mesons are measured at forward rapidity (2.5 < y < 4.0) in Pb-Pb collisions at sNN−−−√ = 5.02 TeV with the ALICE detector at the LHC. Results are obtained with the scalar product method and reported as a function of transverse momentum, pT, for various collision centralities. A positive value of J/ψ v3 is observed with 3.7σ significance. The measurements, compared to those of prompt D0 mesons and charged particles at mid-rapidity, indicate an ordering with vn(J/ψ) <vn(D0) <vn(h±) (n = 2, 3) at low and intermediate pT up to 6 GeV/c and a convergence with v2(J/ψ) ≈v2(D0) ≈v2(h±) at high pT above 6-8 GeV/c. In semi-central collisions (5-40% and 10-50% centrality intervals) at intermediate pT between 2 and 6 GeV/c, the ratio v3/v2 of J/ψ mesons is found to be significantly lower (4.6σ) with respect to that of charged particles. In addition, the comparison to the prompt D0-meson ratio in the same pT interval suggests an ordering similar to that of the v2 and v3 coefficients. The J/ψ v2 coefficient is further studied using the Event Shape Engineering technique. The obtained results are found to be compatible with the expected variations of the eccentricity of the initial-state geometry.
Study of the Λ–Λ interaction with femtoscopy correlations in pp and p–Pb collisions at the LHC
(2019)
This work presents new constraints on the existence and the binding energy of a possible Λ-Λ bound state, the H-dibaryon, derived from Λ-Λ femtoscopic measurements by the ALICE collaboration. The results are obtained from a new measurement using the femtoscopy technique in pp collisions at s√=13 TeV and p-Pb collisions at sNN−−−√=5.02 TeV, combined with previously published results from p-Pb collisions at s√=7 TeV. The Λ-Λ scattering parameter space, spanned by the inverse scattering length f−10 and the effective range d0, is constrained by comparing the measured Λ-Λ correlation function with calculations obtained within the Lednicky model. The data are compatible with hypernuclei results and lattice computations, both predicting a shallow attractive interaction, and permit to test different theoretical approaches describing the Λ-Λ interaction. The region in the (f−10,d0) plane which would accommodate a Λ-Λ bound state is substantially restricted compared to previous studies. The binding energy of the possible Λ-Λ bound state is estimated within an effective-range expansion approach and is found to be BΛΛ=3.2+1.6−2.4(stat)+1.8−1.0(syst) MeV.
Study of the Λ–Λ interaction with femtoscopy correlations in pp and p–Pb collisions at the LHC
(2019)
This work presents new constraints on the existence and the binding energy of a possible Λ-Λ bound state, the H-dibaryon, derived from Λ-Λ femtoscopic measurements by the ALICE collaboration. The results are obtained from a new measurement using the femtoscopy technique in pp collisions at s√=13 TeV and p-Pb collisions at sNN−−−√=5.02 TeV, combined with previously published results from p-Pb collisions at s√=7 TeV. The Λ-Λ scattering parameter space, spanned by the inverse scattering length f−10 and the effective range d0, is constrained by comparing the measured Λ-Λ correlation function with calculations obtained within the Lednicky model. The data are compatible with hypernuclei results and lattice computations, both predicting a shallow attractive interaction, and permit to test different theoretical approaches describing the Λ-Λ interaction. The region in the (f−10,d0) plane which would accommodate a Λ-Λ bound state is substantially restricted compared to previous studies. The binding energy of the possible Λ-Λ bound state is estimated within an effective-range expansion approach and is found to be BΛΛ=3.2+1.6−2.4(stat)+1.8−1.0(syst) MeV.
Communication sounds are ubiquitous in the animal kingdom, where they play a role in advertising physiological states and/or socio-contextual scenarios. Distress sounds, for example, are typically uttered in distressful scenarios such as agonistic interactions. Here, we report on the occurrence of superfast temporal periodicities in distress calls emitted by bats (species Carollia perspicillata). Distress vocalizations uttered by this bat species are temporally modulated at frequencies close to 1.7 kHz, that is, ∼17 times faster than modulation rates observed in human screams. Fast temporal periodicities are represented in the bats’ brain by means of frequency following responses, and temporally periodic sounds are more effective in boosting the heart rate of awake bats than their demodulated versions. Altogether, our data suggest that bats, an animal group classically regarded as ultrasonic, can exploit the low frequency portion of the soundscape during distress calling to create spectro-temporally complex, arousing sounds.
The correlations between event-by-event fluctuations of anisotropic flow harmonic amplitudes have been measured in Pb-Pb collisions at sNN−−−√ = 2.76 TeV with the ALICE detector at the Large Hadron Collider. The results are reported in terms of multiparticle correlation observables dubbed Symmetric Cumulants. These observables are robust against biases originating from nonflow effects. The centrality dependence of correlations between the higher order harmonics (the quadrangular v4 and pentagonal v5 flow) and the lower order harmonics (the elliptic v2 and triangular v3 flow) is presented. The transverse momentum dependences of correlations between v3 and v2 and between v4 and v2 are also reported. The results are compared to calculations from viscous hydrodynamics and A Multi-Phase Transport ({AMPT}) model calculations. The comparisons to viscous hydrodynamic models demonstrate that the different order harmonic correlations respond differently to the initial conditions and the temperature dependence of the ratio of shear viscosity to entropy density (η/s). A small average value of η/s is favored independent of the specific choice of initial conditions in the models. The calculations with the AMPT initial conditions yield results closest to the measurements. Correlations between the magnitudes of v2, v3 and v4 show moderate pT dependence in mid-central collisions. This might be an indication of possible viscous corrections to the equilibrium distribution at hadronic freeze-out, which might help to understand the possible contribution of bulk viscosity in the hadronic phase of the system. Together with existing measurements of individual flow harmonics, the presented results provide further constraints on the initial conditions and the transport properties of the system produced in heavy-ion collisions.
Autophagy is a highly conserved catabolic process through which defective or otherwise harmful cellular components are targeted for degradation via the lysosomal route. Regulatory pathways, involving post-translational modifications such as phosphorylation, play a critical role in controlling this tightly orchestrated process. Here, we demonstrate that TBK1 regulates autophagy by phosphorylating autophagy modifiers LC3C and GABARAP-L2 on surface-exposed serine residues (LC3C S93 and S96; GABARAP-L2 S87 and S88). This phosphorylation event impedes their binding to the processing enzyme ATG4 by destabilizing the complex. Phosphorylated LC3C/GABARAP-L2 cannot be removed from liposomes by ATG4 and are thus protected from ATG4-mediated premature removal from nascent autoph-agosomes. This ensures a steady coat of lipidated LC3C/GABARAP-L2 throughout the early steps in autophagosome formation and aids in maintaining a unidirectional flow of the autophagosome to the lysosome. Taken together, we present a new regulatory mechanism of autophagy, which influences the conjugation and de-conjugation of LC3C and GABARAP-L2 to autophagosomes by TBK1-mediated phosphorylation.
The Transition Radiation Detector (TRD) was designed and built to enhance the capabilities of the ALICE detector at the Large Hadron Collider (LHC). While aimed at providing electron identification and triggering, the TRD also contributes significantly to the track reconstruction and calibration in the central barrel of ALICE. In this paper the design, construction, operation, and performance of this detector are discussed. A pion rejection factor of up to 410 is achieved at a momentum of 1 GeV/c in p-Pb collisions and the resolution at high transverse momentum improves by about 40% when including the TRD information in track reconstruction. The triggering capability is demonstrated both for jet, light nuclei, and electron selection.
The Kinase Chemogenomic Set (KCGS): An open science resource for kinase vulnerability identification
(2019)
We describe the assembly and annotation of a chemogenomic set of protein kinase inhibitors as an open science resource for studying kinase biology. The set only includes inhibitors that show potent kinase inhibition and a narrow spectrum of activity when screened across a large panel of kinase biochemical assays. Currently, the set contains 187 inhibitors that cover 215 human kinases. The kinase chemogenomic set (KCGS) is the most highly annotated set of selective kinase inhibitors available to researchers for use in cell-based screens.
The thrombopoietin receptor agonist eltrombopag was successfully used against human cytomegalovirus (HCMV)-associated thrombocytopenia refractory to immunomodulatory and antiviral drugs. These effects were ascribed to effects of eltrombopag on megakaryocytes. Here, we tested whether eltrombopag may also exert direct antiviral effects. Therapeutic eltrombopag concentrations inhibited HCMV replication in human fibroblasts and adult mesenchymal stem cells infected with six different virus strains and drug-resistant clinical isolates. Eltrombopag also synergistically increased the anti-HCMV activity of the mainstay drug ganciclovir. Time-of-addition experiments suggested that eltrombopag interferes with HCMV replication after virus entry. Eltrombopag was effective in thrombopoietin receptor-negative cells, and addition of Fe3+ prevented the anti-HCMV effects, indicating that it inhibits HCMV replication via iron chelation. This may be of particular interest for the treatment of cytopenias after haematopoietic stem cell transplantation, as HCMV reactivation is a major reason for transplantation failure. Since therapeutic eltrombopag concentrations are effective against drug-resistant viruses and synergistically increase the effects of ganciclovir, eltrombopag is also a drug repurposing candidate for the treatment of therapy-refractory HCMV disease.
Abstract
Co-infections by multiple pathogens have important implications in many aspects of health, epidemiology and evolution. However, how to disentangle the contributing factors of the immune response when two infections take place at the same time is largely unexplored. Using data sets of the immune response during influenza-pneumococcal co-infection in mice, we employ here topological data analysis to simplify and visualise high dimensional data sets.
We identified persistent shapes of the simplicial complexes of the data in the three infection scenarios: single viral infection, single bacterial infection, and co-infection. The immune response was found to be distinct for each of the infection scenarios and we uncovered that the immune response during the co-infection has three phases and two transition points. During the first phase, its dynamics is inherited from its response to the primary (viral) infection. The immune response has an early (few hours post co-infection) and then modulates its response to finally react against the secondary (bacterial) infection. Between 18 to 26 hours post co-infection the nature of the immune response changes again and does no longer resembles either of the single infection scenarios.
Author summary
The mapper algorithm is a topological data analysis technique used for the qualitative analysis, simplification and visualisation of high dimensional data sets. It generates a low-dimensional image that captures topological and geometric information of the data set in high dimensional space, which can highlight groups of data points of interest and can guide further analysis and quantification.
To understand how the immune system evolves during the co-infection between viruses and bacteria, and the role of specific cytokines as contributing factors for these severe infections, we use Topological Data Analysis (TDA) along with an extensive semi-unsupervised parameter value grid search, and k-nearest neighbour analysis.
We find persistent shapes of the data in the three infection scenarios, single viral and bacterial infections and co-infection. The immune response is shown to be distinct for each of the infections scenarios and we uncover that the immune response during the co-infection has three phases and two transition points, a previously unknown property regarding the dynamics of the immune response during co-infection.
How is semantic information stored in the human mind and brain? Some philosophers and cognitive scientists argue for vectorial representations of concepts, where the meaning of a word is represented as its position in a high-dimensional neural state space. At the intersection of natural language processing and artificial intelligence, a class of very successful distributional word vector models has developed that can account for classic EEG findings of language, i.e., the ease vs. difficulty of integrating a word with its sentence context. However, models of semantics have to account not only for context-based word processing, but should also describe how word meaning is represented. Here, we investigate whether distributional vector representations of word meaning can model brain activity induced by words presented without context. Using EEG activity (event-related brain potentials) collected while participants in two experiments (English, German) read isolated words, we encode and decode word vectors taken from the family of prediction-based word2vec algorithms. We find that, first, the position of a word in vector space allows the prediction of the pattern of corresponding neural activity over time, in particular during a time window of 300 to 500 ms after word onset. Second, distributional models perform better than a human-created taxonomic baseline model (WordNet), and this holds for several distinct vector-based models. Third, multiple latent semantic dimensions of word meaning can be decoded from brain activity. Combined, these results suggest that empiricist, prediction-based vectorial representations of meaning are a viable candidate for the representational architecture of human semantic knowledge.
Transverse momentum (pT) spectra of charged particles at mid-pseudorapidity in Xe-Xe collisions at sNN−−−√ = 5.44 TeV measured with the ALICE apparatus at the Large Hadron Collider are reported. The kinematic range 0.15<pT<50 GeV/c and |η|<0.8 is covered. Results are presented in nine classes of collision centrality in the 0-80% range. For comparison, a pp reference at the collision energy of s√ = 5.44 TeV is obtained by interpolating between existing \pp measurements at s√ = 5.02 and 7 TeV. The nuclear modification factors in central Xe-Xe collisions and Pb-Pb collisions at a similar center-of-mass energy of sNN−−−√ = 5.02 TeV, and in addition at 2.76 TeV, at analogous ranges of charged particle multiplicity density ⟨dNch/dη⟩ show a remarkable similarity at pT>10 GeV/c. The centrality dependence of the ratio of the average transverse momentum ⟨pT⟩ in Xe-Xe collisions over Pb-Pb collision at s√ = 5.02 TeV is compared to hydrodynamical model calculations.
We present measurements of two-particle differential number correlation functions R2 and transverse momentum correlation functions P2, obtained from p-Pb collisions at 5.02 TeV and Pb-Pb collisions at 2.76 TeV. The results are obtained using charged particles in the pseudorapidity range |η|< 1.0, and transverse momentum range 0.2<pT<2.0 GeV/c as a function of pair separation in pseudorapidity, |Δη|, azimuthal angle, Δφ, and for several charged-particle multiplicity classes. Measurements are carried out for like-sign and unlike-sign charged-particle pairs separately and combined to obtain charge-independent and charge-dependent correlation functions. We study the evolution of the width of the near-side peak of these correlation functions with collision centrality. Additionally, we study Fourier decompositions of the correlators in Δφ as a function of the pair separation |Δη|. Significant differences in the dependence of their harmonic coefficients on multiplicity classes are found. These differences can be exploited, in theoretical models, to obtain further insight into charged-particle production and transport in heavy-ion collisions. Moreover, an upper limit of non-flow contributions to flow coefficients vn measured in Pb-Pb collisions based on the relative strength of Fourier coefficients measured in p-Pb interactions is estimated.
De novo fatty acid biosynthesis in humans is accomplished by a multidomain protein, the type I fatty acid synthase (FAS). Although ubiquitously expressed in all tissues, fatty acid synthesis is not essential in normal healthy cells due to sufficient supply with fatty acids by the diet. However, FAS is overexpressed in cancer cells and correlates with tumor malignancy, which makes FAS an attractive selective therapeutic target in tumorigenesis. Herein, we present a crystal structure of the condensing part of murine FAS, highly homologous to human FAS, with octanoyl moieties covalently bound to the transferase (MAT) and the condensation (KS) domain. The MAT domain binds the octanoyl moiety in a novel (unique) conformation, which reflects the pronounced conformational dynamics of the substrate binding site responsible for the MAT substrate promiscuity. In contrast, the KS binding pocket just subtly adapts to the octanoyl moiety upon substrate binding. Besides the rigid domain structure, we found a positive cooperative effect in the substrate binding of the KS domain by a comprehensive enzyme kinetic study. These structural and mechanistic findings contribute significantly to our understanding of the mode of action of FAS and may guide future rational inhibitor designs.
This article reports measurements characterizing the Underlying Event (UE) associated with hard scatterings at midrapidity (|η|<0.8) in pp collisions at s√ = 13 TeV. The hard scatterings are identified by the leading particle, the charged particle with the highest transverse momentum (pleadingT) in the event. Charged-particle numbers and summed transverse-momentum densities are measured in different azimuthal regions defined with respect to the leading particle direction: Toward, Transverse, and Away. The Toward and Away regions contain the fragmentation products of the hard scatterings in addition to the UE contribution, whereas particles in the Transverse region are expected to originate predominantly from the UE. The study is performed as a function of pleadingT with three different pT thresholds for the associated particles, ptrackT> 0.15, 0.5, and 1.0 GeV/c. The charged-particle density in the Transverse region rises steeply for low values of pleadingT and reaches a plateau. The results confirm the trend observed at lower collision energies that the charged-particle density in the Transverse region shows a stronger increase with s√ than the inclusive charged-particle density at midrapidity. The plateau in the Transverse region (5<pleadingT<40 GeV/c) is further characterized by the probability distribution of its charged-particle multiplicity normalized to its average value (relative transverse activity, RT) and the mean transverse momentum as a function of RT. Experimental results are compared to model calculations obtained using PYTHIA 8 and EPOS LHC. The overall agreement between models and data is within 30%. These measurements provide new insights on the interplay between hard scatterings and the associated UE in pp collisions.
During animal development, it is crucial that cells can sense and adapt to mechanical forces from their environment. Ultimately, these forces are transduced through the actomyosin cortex. How the cortex can simultaneously respond to and create forces during cytokinesis is not well understood. Here we show that under mechanical stress, cortical actomyosin flow switches its polarization during cytokinesis in the C. elegans embryo. In unstressed embryos, longitudinal cortical flows contribute to contractile ring formation, while rotational cortical flow is additionally induced in uniaxially loaded embryos. Rotational cortical flow is required for the redistribution of the actomyosin cortex in loaded embryos. Rupture of longitudinally aligned cortical fibers during cortex rotation releases tension, initiates orthogonal longitudinal flow and thereby contributes to furrowing in loaded embryos. A targeted screen for factors required for rotational flow revealed that actomyosin regulators involved in RhoA regulation, cortical polarity and chirality are all required for rotational flow and become essential for cytokinesis under mechanical stress. In sum, our findings extend the current framework of mechanical stress response during cell division and show scaling of orthogonal cortical flows to the amount of mechanical stress.