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A decisive experimental test of the Chiral Magnetic Effect (CME) is considered one of the major scientific goals at the Relativistic Heavy-Ion Collider (RHIC) towards understanding the nontrivial topological fluctuations of the Quantum Chromodynamics vacuum. In heavy-ion collisions, the CME is expected to result in a charge separation phenomenon across the reaction plane, whose strength could be strongly energy dependent. The previous CME searches have been focused on top RHIC energy collisions. In this Letter, we present a low energy search for the CME in Au+Au collisions at sNN−−−√=27 GeV. We measure elliptic flow scaled charge-dependent correlators relative to the event planes that are defined at both mid-rapidity |η|<1.0 and at forward rapidity 2.1<|η|<5.1. We compare the results based on the directed flow plane (Ψ1) at forward rapidity and the elliptic flow plane (Ψ2) at both central and forward rapidity. The CME scenario is expected to result in a larger correlation relative to Ψ1 than to Ψ2, while a flow driven background scenario would lead to a consistent result for both event planes. In 10-50\% centrality, results using three different event planes are found to be consistent within experimental uncertainties, suggesting a flow driven background scenario dominating the measurement. We obtain an upper limit on the deviation from a flow driven background scenario at the 95\% confidence level. This work opens up a possible road map towards future CME search with the high statistics data from the RHIC Beam Energy Scan Phase-II.
The chiral magnetic effect (CME) is predicted to occur as a consequence of a local violation of P and CP symmetries of the strong interaction amidst a strong electro-magnetic field generated in relativistic heavy-ion collisions. Experimental manifestation of the CME involves a separation of positively and negatively charged hadrons along the direction of the magnetic field. Previous measurements of the CME-sensitive charge-separation observables remain inconclusive because of large background contributions. In order to better control the influence of signal and backgrounds, the STAR Collaboration performed a blind analysis of a large data sample of approximately 3.8 billion isobar collisions of 9644Ru+9644Ru and 9640Zr+9640Zr at sNN−−−√=200 GeV. Prior to the blind analysis, the CME signatures are predefined as a significant excess of the CME-sensitive observables in Ru+Ru collisions over those in Zr+Zr collisions, owing to a larger magnetic field in the former. A precision down to 0.4% is achieved, as anticipated, in the relative magnitudes of the pertinent observables between the two isobar systems. Observed differences in the multiplicity and flow harmonics at the matching centrality indicate that the magnitude of the CME background is different between the two species. No CME signature that satisfies the predefined criteria has been observed in isobar collisions in this blind analysis.
The chiral magnetic wave (CMW) has been theorized to propagate in the deconfined nuclear medium formed in high-energy heavy-ion collisions, and to cause a difference in elliptic flow (v2) between negatively and positively charged hadrons. Experimental data consistent with the CMW have been reported by the STAR Collaboration at the Relativistic Heavy Ion Collider (RHIC), based on the charge asymmetry dependence of the pion v2 from Au+Au collisions at sNN−−−√ = 27 to 200 GeV. In this comprehensive study, we present the STAR measurements of elliptic flow and triangular flow of charged pions, along with the v2 of charged kaons and protons, as a function of charge asymmetry in Au+Au collisions at sNN−−−√ = 27, 39, 62.4 and 200 GeV. The slope parameters extracted from the linear dependence of the v2 difference on charge asymmetry for different particle species are reported and compared in different centrality intervals. In addition, the slopes of v2 for charged pions in small systems, \textit{i.e.}, p+Au and d+Au at sNN−−−√ = 200 GeV, are also presented and compared with those in large systems, \textit{i.e.}, Au+Au at sNN−−−√ = 200 GeV and U+U at 193 GeV. Our results provide new insights for the possible existence of the CMW, and further constrain the background contributions in heavy-ion collisions at RHIC energies.
Based on 368.5 pb−1 of 𝑒+𝑒− collision data collected at center-of-mass energies 4.914 and 4.946 GeV by the BESIII detector, the 𝑒+𝑒−→𝜙𝜒𝑐1(3872) process is searched for the first time. No significant signal is observed and the upper limits at the 90% confidence level on the product of the Born cross section 𝜎(𝑒+𝑒−→𝜙𝜒𝑐1(3872)) and the branching fraction ℬ[𝜒𝑐1(3872)→𝜋+𝜋−𝐽/𝜓] at 4.914 and 4.946 GeV are set to be 0.85 and 0.96 pb, respectively. These measurements provide useful information for the production of the 𝜒𝑐1(3872) at 𝑒+𝑒− colliders and deepen our understanding about the nature of this particle.
Using 9.0 fb−1 of e+e− collision data collected at center-of-mass energies from 4.178 to 4.278 GeV with the BESIII detector at the BEPCII collider, we perform the first search for the radiative transition χc1(3872)→γψ2(3823). No χc1(3872)→γψ2(3823) signal is observed. The upper limit on the ratio of branching fractions B(χc1(3872)→γψ2(3823),ψ2(3823)→γχc1)/B(χc1(3872)→π+π−J/ψ) is set as 0.075 at the 90\% confidence level. Our result contradicts theoretical predictions under the assumption that the χc1(3872) is the pure charmonium state χc1(2P).
Using 7.33~fb−1 of e+e− collision data collected by the BESIII detector at center-of-mass energies in the range of s√=4.128−4.226~GeV, we search for the rare decays D+s→h+(h0)e+e−, where h represents a kaon or pion. By requiring the e+e− invariant mass to be consistent with a ϕ(1020), 0.98<M(e+e−)<1.04 ~GeV/c2, the decay D+s→π+ϕ,ϕ→e+e− is observed with a statistical significance of 7.8σ, and evidence for the decay D+s→ρ+ϕ,ϕ→e+e− is found for the first time with a statistical significance of 4.4σ. The decay branching fractions are measured to be B(D+s→π+ϕ,ϕ→e+e−)=(1.17+0.23−0.21±0.03)×10−5, and B(D+s→ρ+ϕ,ϕ→e+e−)=(2.44+0.67−0.62±0.16)×10−5, where the first uncertainties are statistical and the second systematic. No significant signal for the three four-body decays of D+s→π+π0e+e−, D+s→K+π0e+e−, and D+s→K0Sπ+e+e− is observed. For D+s→π+π0e+e−, the ϕ mass region is vetoed to minimize the long-distance effects. The 90% confidence level upper limits set on the branching fractions of these decays are in the range of (7.0−8.1)×10−5.
Using (448.1±2.9)×106 ψ(3686) events collected with the BESIII detector, we perform the first search for the weak baryonic decay ψ(3686)→Λ+cΣ¯−+c.c.. The analysis procedure is optimized using a blinded method. No significant signal is observed, and the upper limit on the branching fraction (B) of ψ(3686)→Λ+cΣ¯−+c.c. is set to be 1.4×10−5 at the 90\% confidence level.
Using (448.1±2.9)×106 ψ(3686) events collected with the BESIII detector, we perform the first search for the weak baryonic decay ψ(3686)→Λ+cΣ¯−+c.c.. The analysis procedure is optimized using a blinded method. No significant signal is observed, and the upper limit on the branching fraction (B) of ψ(3686)→Λ+cΣ¯−+c.c. is set to be 1.4×10−5 at the 90\% confidence level.
The Cabibbo-allowed weak radiative decay Λ+c→Σ+γ has been searched for in a sample of Λ+cΛ¯−c pairs produced in e+e− annihilations, corresponding to an integrated luminosity of 4.5fb−1 collected with the BESIII detector at center-of-mass energies between 4.60 and 4.70 GeV. No excess of signal above background is observed, and we set an upper limit on the branching fraction of this decay to be B(Λ+c→Σ+γ)<4.4×10−4 at a confidence level of 90\%, which is in agreement with Standard Model expectations.
The Cabibbo-allowed weak radiative decay Λ+c→Σ+γ has been searched for in a sample of Λ+cΛ¯−c pairs produced in e+e− annihilations, corresponding to an integrated luminosity of 4.5fb−1 collected with the BESIII detector at center-of-mass energies between 4.60 and 4.70 GeV. No excess of signal above background is observed, and we set an upper limit on the branching fraction of this decay to be B(Λ+c→Σ+γ)<4.4×10−4 at a confidence level of 90\%, which is in agreement with Standard Model expectations.
We present results of a search for two hypothetical strange dibaryon states, i.e. the H-dibaryon and the possible Λn¯ bound state. The search is performed with the ALICE detector in central (0-10%) Pb-Pb collisions at sNN−−−√=2.76 TeV, by invariant mass analysis in the decay modes Λn¯→d¯π+ and H-dibaryon →Λpπ−. No evidence for these bound states is observed. Upper limits are determined at 99% confidence level for a wide range of lifetimes and for the full range of branching ratios. The results are compared to thermal, coalescence and hybrid UrQMD model expectations, which describe correctly the production of other loosely bound states, like the deuteron and the hypertriton.
We present results of a search for two hypothetical strange dibaryon states, i.e. the H-dibaryon and the possible Λn¯¯¯¯¯¯ bound state. The search is performed with the ALICE detector in central (0-10%) Pb-Pb collisions at sNN−−−√=2.76 TeV, by invariant mass analysis in the decay modes Λn¯¯¯¯¯¯→d¯¯¯π+ and H-dibaryon →Λpπ−. No evidence for these bound states is observed. Upper limits are determined at 99% confidence level for a wide range of lifetimes and for the full range of branching ratios. The results are compared to thermal, coalescence and hybrid UrQMD model expectations, which describe correctly the production of other loosely bound states, like the deuteron and the hypertriton.
Search for X(3872)→π⁰π⁰χc₁,₂
(2024)
Using 10.1 fb−1 of e+e− collision data collected by the BESIII detector with center-of-mass energies between 4.15 GeV and 4.30 GeV, we search for the decays X(3872)→π0π0χc1,2, where the X(3872) is produced in e+e−→γX(3872). No evidence above 3σ is found for either decay. Upper limits at the 90% C.L. on the branching fractions of X(3872)→π0π0χc1,2 normalized to the branching fraction of X(3872)→π+π−J/ψ are set to be B(X(3872)→π0π0χc1)/B(X(3872)→π+π−J/ψ)<1.1 and B(X(3872)→π0π0χc2)/B(X(3872)→π+π−J/ψ)<0.5, taking into account both statistical and systematic uncertainties.
Using (2.712±0.014)×109 ψ(3686) events collected with the BESIII detector operating at the BEPCII, we find an evidence of the ηc(2S)→K+K−η′ decay with a statistical significance of 3.1σ. Its decay branching fraction is measured to be (12.24±4.60(stat.)±2.37(syst.)±4.68(extr.))×10−4, where the first uncertainty is statistical, the second is systematic, and the third uncertainty is from the branching fraction of the ψ(3686)→γηc(2S) decay. The upper limit on the product branching fraction B[ψ(3686)→γηc(2S)]× B[ηc(2S)→K+K−η′] is set to be 1.14×10−6 at 90% confidence level. In addition, the branching fractions of χc1→K+K−η′ and χc2→K+K−η′ are updated to be (8.47±0.09(stat.)±0.47(syst.))×10−4 and (1.53±0.04(stat.)±0.08(syst.))×10−4, respectively. The precision is improved by twofold.
Using (2712±14) × 106 ψ(2S) events collected with the BESIII detector at the BEPCII collider, we search for the decays ηc(2S)→ωω and ηc(2S)→ωϕ via the process ψ(2S)→γηc(2S). Evidence of ηc(2S)→ωω is found with a statistical significance of 3.2σ. The branching fraction is measured to be B(ηc(2S)→ωω)=(5.65±3.77(stat.)±5.32(syst.))×10−4. No statistically significant signal is observed for the decay ηc(2S)→ωϕ. The upper limit of the branching fraction at the 90\% confidence level is determined to be B(ψ(2S)→γηc(2S),ηc(2S)→ωϕ)<2.24×10−7. We also update the branching fractions of χcJ→ωω and χcJ→ωϕ decays via the ψ(2S)→γχcJ transition. The branching fractions are determined to be B(χc0→ωω)=(10.63±0.11±0.46)×10−4, B(χc1→ωω)=(6.39±0.07±0.29)×10−4, B(χc2→ωω)=(8.50±0.08±0.38)×10−4, B(χc0→ωϕ)=(1.18±0.03±0.05)×10−4, B(χc1→ωϕ)=(2.03±0.15±0.12)×10−5, and B(χc2→ωϕ)=(9.37±1.07±0.59)×10−6, where the first uncertainties are statistical and the second are systematic.
The measurement of azimuthal correlations of charged particles is presented for Pb-Pb collisions at sNN−−−√= 2.76 TeV and p-Pb collisions at sNN−−−√= 5.02 TeV with the ALICE detector at the CERN Large Hadron Collider. These correlations are measured for the second, third and fourth order flow vector in the pseudorapidity region |η|<0.8 as a function of centrality and transverse momentum pT using two observables, to search for evidence of pT-dependent flow vector fluctuations. For Pb-Pb collisions at 2.76 TeV, the measurements indicate that pT-dependent fluctuations are only present for the second order flow vector. Similar results have been found for p-Pb collisions at 5.02 TeV. These measurements are compared to hydrodynamic model calculations with event-by-event geometry fluctuations in the initial state to constrain the initial conditions and transport properties of the matter created in Pb-Pb and p-Pb collisions.
The measurement of azimuthal correlations of charged particles is presented for Pb-Pb collisions at sNN−−−√= 2.76 TeV and p-Pb collisions at sNN−−−√= 5.02 TeV with the ALICE detector at the CERN Large Hadron Collider. These correlations are measured for the second, third and fourth order flow vector in the pseudorapidity region |η|<0.8 as a function of centrality and transverse momentum pT using two observables, to search for evidence of pT-dependent flow vector fluctuations. For Pb-Pb collisions at 2.76 TeV, the measurements indicate that pT-dependent fluctuations are only present for the second order flow vector. Similar results have been found for p-Pb collisions at 5.02 TeV. These measurements are compared to hydrodynamic model calculations with event-by-event geometry fluctuations in the initial state to constrain the initial conditions and transport properties of the matter created in Pb-Pb and p-Pb collisions.
The quantum mechanical formula for Mayer s second cluster integral for the gas of relativistic particles with hard-core interaction is derived. The proper pion volume calculated with quantum mechanical formula is found to be an order of magnitude larger than its classical evaluation. The second cluster integral for the pion gas is calculated in quantum mechanical approach with account for both attractive and hard-core repulsive interactions. It is shown that, in the second cluster approximation, the repulsive -interactions as well as the finite width of resonances give important but almost canceling contributions. In contrast, an appreciable deviation from the ideal gas of pions and pion resonances is observed beyond the second clus- ter approximation in the framework of the Van der Waals excluded-volume model.
Job creation schemes (JCS) have been one important programme of active labour market policy in Germany aiming at the re-integration of hard-to-place unemployed individuals into regular employment. In ontrast to earlier evaluation studies of these programmes based on survey data, we use administrative data containing more than 11,000 participants for our analysis and hence, can take effect heterogeneity explicitly into account. We focus on effect heterogeneity caused by differences in the implementation of programmes (economic sector, types of support and implementing institutions). The results are rather discouraging and show that in general, JCS are unable to improve the re-integration chances of participants into regular employment.
Assuming a cryptographically strong cyclic group G of prime order q and a random hash function H, we show that ElGamal encryption with an added Schnorr signature is secure against the adaptive chosen ciphertext attack, in which an attacker can freely use a decryption oracle except for the target ciphertext. We also prove security against the novel one-more-decyption attack. Our security proofs are in a new model, corresponding to a combination of two previously introduced models, the Random Oracle model and the Generic model. The security extends to the distributed threshold version of the scheme. Moreover, we propose a very practical scheme for private information retrieval that is based on blind decryption of ElGamal ciphertexts.
Background Overweight and decreased physical fitness are highly prevalent in schizophrenia, represent a major risk factor for cardio-vascular diseases and decrease the patients’ life expectancies. It is thus important to understand the underlying mechanisms that link psychopathology and weight gain. We hypothesize that the dopaminergic reward system plays an important role in this.
Methods: We analyzed the seed-based functional connectivity (FC) of the ventral tegmental area (VTA) in a group of schizophrenic patients (n = 32) and age- as well as gender matched healthy controls (n = 27). We then correlated the resting-state results with physical fitness parameters, obtained in a fitness test, and psychopathology.
Results: The seed-based connectivity analysis revealed decreased functional connections between the VTA and the anterior cingulate cortex (ACC), as well as the dorsolateral prefrontal cortex and increased functional connectivity between the VTA and the middle temporal gyrus in patients compared to healthy controls. The decreased FC between the VTA and the ACC of the patient group could further be associated with increased body fat and negatively correlated with the overall physical fitness. We found no significant correlations with psychopathology.
Conclusion: Although we did not find significant correlations with psychopathology, we could link decreased physical fitness and high body fat with dysconnectivity between the VTA and the ACC in schizophrenia. These findings demonstrate that a dysregulated reward system is not just responsible for symptomatology in schizophrenia but is also involved in comorbidities and could pave the way for future lifestyle therapy interventions.
Music, like language, is characterized by hierarchically organized structure that unfolds over time. Music listening therefore requires not only the tracking of notes and beats but also internally constructing high-level musical structures or phrases and anticipating incoming contents. Unlike for language, mechanistic evidence for online musical segmentation and prediction at a structural level is sparse. We recorded neurophysiological data from participants listening to music in its original forms as well as in manipulated versions with locally or globally reversed harmonic structures. We discovered a low-frequency neural component that modulated the neural rhythms of beat tracking and reliably parsed musical phrases. We next identified phrasal phase precession, suggesting that listeners established structural predictions from ongoing listening experience to track phrasal boundaries. The data point to brain mechanisms that listeners use to segment continuous music at the phrasal level and to predict abstract structural features of music.
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.
Selective attention implements preferential routing of attended stimuli, likely through increasing the influence of the respective synaptic inputs on higher-area neurons. As the inputs of competing stimuli converge onto postsynaptic neurons, presynaptic circuits might offer the best target for attentional top-down influences. If those influences enabled presynaptic circuits to selectively entrain postsynaptic neurons, this might lead to selective routing. Indeed, when two visual stimuli induce two gamma rhythms in V1, only the gamma induced by the attended stimulus entrains gamma in V4. Here, we modeled this selective entrainment with a Dynamic Causal Model for Cross-Spectral Densities and found that it can be explained by attentional modulation of intrinsic V1 connections. Specifically, local inhibition was decreased in the granular input layer and increased in the supragranular output layer of the V1 circuit that processed the attended stimulus. Thus, presynaptic attentional influences and ensuing entrainment were sufficient to mediate selective routing.
We derive the self-consistent relativistic quantum transport equation for the pion distribution function based on an effective Lagrangian of the QHD-II model. The closed time-path Green's function technique, the semi-classical, quasi-particle and Born approximation are employed in the derivation. Both the mean field and collision term are derived from the same Lagrangian and presented analytically. The dynamical equation for the pions is consistent with that for the nucleons and deltas which we developed before. Thus, we obtain a self-consistent relativistic transport model which describes the hadronic matter with N, Delta and pi degrees of freedom simultaneously. Within this approach, we investigate the medium effects on the pion dispersion relation as well as the pion absorption and pion production channels in cold nuclear matter. In contrast to the results of the non-relativistic model, the pion dispersion relation becomes harder at low momenta and softer at high momenta as compared to the free one. The theoretically predicted free pi N to Delta cross section is in agreement with the experimental data. Medium effects on the pi N to Delta cross section and momentum-dependent Delta-decay width are shown to be substantial.
Objects that are congruent with a scene are recognised more efficiently than objects that are incongruent. Further, semantic integration of incongruent objects elicits a stronger N300/N400 EEG component. Yet, the time course and mechanisms of how contextual information supports access to semantic object information is unclear. We used computational modelling and EEG to test how context influences semantic object processing. Using representational similarity analysis, we established that EEG patterns dissociated between objects in congruent or incongruent scenes from around 300 ms. By modelling semantic processing of objects using independently normed properties, we confirm that the onset of semantic processing of both congruent and incongruent objects is similar (∼150 ms). Critically, after ∼275 ms, we discover a difference in the duration of semantic integration, lasting longer for incongruent compared to congruent objects. These results constrain our understanding of how contextual information supports access to semantic object information.
Objects that are congruent with a scene are recognised more efficiently than objects that are incongruent. Further, semantic integration of incongruent objects elicits a stronger N300/N400 EEG component. Yet, the time course and mechanisms of how contextual information supports access to semantic object information is unclear. We used computational modelling and EEG to test how context influences semantic object processing. Using representational similarity analysis, we established that EEG patterns dissociated between objects in congruent or incongruent scenes from around 300 ms. By modelling semantic processing of objects using independently normed properties, we confirm that the onset of semantic processing of both congruent and incongruent objects is similar (∼150 ms). Critically, after ∼275 ms, we discover a difference in the duration of semantic integration, lasting longer for incongruent compared to congruent objects. These results constrain our understanding of how contextual information supports access to semantic object information.
The STAR experiment at RHIC reports new measurements of jet quenching based on the semi-inclusive distribution of charged-particle jets recoiling from direct photon (γdir) and neutral pion (π0) triggers in p+p and central Au+Au collisions at √sNN=200 GeV, for triggers in the range 9<EtrigT<20 GeV. The datasets have integrated luminosities of 3.9 nb−1 for Au+Au and 23 pb−1 for p+p collisions. Jets are reconstructed using the anti-kT algorithm with resolution parameters R=0.2 and 0.5. The large uncorrelated jet background in central Au+Au collisions is corrected using a mixed-event approach, which enables precise charged-particle jet measurements at low transverse momentum pchT,jet and large R. Recoil-jet distributions are reported in the range pchT,jet<25 GeV. Comparison of the distributions measured in p+p and Au+Au collisions reveals strong medium-induced jet yield suppression for R=0.2, with markedly less suppression for R=0.5. These data provide new insight into the mechanisms underlying jet quenching, and the angular dependence of medium-induced jet-energy transport.
Signal transfer of visual stimuli to V4 occurs in gamma-rhythmic, pulsed information packages
(2020)
Summary Selective visual attention allows the brain to focus on behaviorally relevant information while ignoring irrelevant signals. As a possible mechanism, routing by synchronization was proposed: neural populations sending attended signals align their gamma-rhythmic activities with receiving populations, such that spikes from the senders arrive at excitability peaks of the receivers, enhancing signal transfer. Conversely, the non-attended signals arrive unaligned to the receiver’s oscillation, reducing signal transfer. Therefore, visual signals should be transferred through periodically pulsed information packages, resulting in a modulation of the stimulus content within the receiver’s activity by its gamma phase and amplitude. To test this prediction, we quantified gamma phase-specific stimulus content within neural activity from area V4 of macaques performing a visual attention task. For the attended stimulus we find enhanced stimulus content reaching its maximum near excitability peaks, with effect magnitude increasing with oscillation amplitude, establishing a functional link between selective processing and gamma activity.
The concept of Large Extra Dimensions (LED) provides a way of solving the Hierarchy Problem which concerns the weakness of gravity compared with the strong and electro-weak forces. A consequence of LED is that miniature Black Holes (mini-BHs) may be produced at the Large Hadron Collider in p+p collisions. The present work uses the CHARYBDIS mini-BH generator code to simulate the hadronic signal which might be expected in a mid-rapidity particle tracking detector from the decay of these exotic objects if indeed they are produced. An estimate is also given for Pb+Pb collisions.
String theory suggests the existence of a minimum length scale. An exciting quantum mechanical implication of this feature is a modification of the uncertainty principle. In contrast to the conventional approach, this generalised uncertainty principle does not allow to resolve space time distances below the Planck length. In models with extra dimensions, which are also motivated by string theory, the Planck scale can be lowered to values accessible by ultra high energetic cosmic rays (UHECRs) and by future colliders, i.e. M f approximately equal to 1 TeV. It is demonstrated that in this novel scenario, short distance physics below 1/M f is completely cloaked by the uncertainty principle. Therefore, Planckian effects could be the final physics discovery at future colliders and in UHECRs. As an application, we predict the modifications to the e+ e- to f+ f- cross-sections.
We discuss modifications of the gyromagnetic moment of electrons and muons due to a minimal length scale combined with a modified fundamental scaleMf . First-order deviations from the theoretical standard model value for g-2 due to these String Theory-motivated e ects are derived. Constraints for the new fundamental scale Mf are given.
String theory suggests modifications of our spacetime such as extra dimensions and the existence of a mininal length scale. In models with addidional dimensions, the Planck scale can be lowered to values accessible by future colliders. Effective theories which extend beyond the standart-model by including extra dimensions and a minimal length allow computation of observables and can be used to make testable predictions. Expected effects that arise within these models are the production of gravitons and black holes. Furthermore, the Planck-length is a lower bound to the possible resolution of spacetime which might be reached soon.
Signatures of quark gluon plasma formation in high-energy heavy ion collisions : a critical review
(1998)
Ultra-relativistic heavy ion collisions offer the unique opportunity to probe highly excited dense nuclear matter under controlled laboratory conditions. The compelling driving force for such studies is the expectation that an entirely new form of matter may be created from such reactions. That form of matter, called the Quark Gluon Plasma (QGP), is the QCD analogue of the plasma phase of ordinary atomic matter. However, unlike such ordinary plasmas, the deconfined quanta of a QGP are not directly observable because of the fundamental confining property of the physical QCD vacuum. What is observable are hadronic and leptonic residues of the transient QGP state. There is a large variety of such individual probes.
Disordered proteins and nucleic acids can condense into droplets that resemble the membraneless organelles observed in living cells. MD simulations offer a unique tool to characterize the molecular interactions governing the formation of these biomolecular condensates, their physico-chemical properties, and the factors controlling their composition and size. However, biopolymer condensation depends sensitively on the balance between different energetic and entropic contributions. Here, we develop a general strategy to fine-tune the potential energy function for molecular dynamics simulations of biopolymer phase separation. We rebalance protein-protein interactions against solvation and entropic contributions to match the excess free energy of transferring proteins between dilute solution and condensate. We illustrate this formalism by simulating liquid droplet formation of the FUS low complexity domain (LCD) with a rebalanced MARTINI model. By scaling the strength of the nonbonded interactions in the coarse-grained MARTINI potential energy function, we map out a phase diagram in the plane of protein concentration and interaction strength. Above a critical scaling factor of αc ≈ 0.6, FUS LCD condensation is observed, where α = 1 and 0 correspond to full and repulsive interactions in the MARTINI model, respectively. For a scaling factor α = 0.65, we recover the experimental densities of the dilute and dense phases, and thus the excess protein transfer free energy into the droplet and the saturation concentration where FUS LCD condenses. In the region of phase separation, we simulate FUS LCD droplets of four different sizes in stable equilibrium with the dilute phase and slabs of condensed FUS LCD for tens of microseconds, and over one millisecond in aggregate. We determine surface tensions in the range of 0.01 to 0.4mN/m from the fluctuations of the droplet shape and from the capillary-wave-like broadening of the interface between the two phases. From the dynamics of the protein end-to-end distance, we estimate shear viscosities from 0.001 to 0.02Pas for the FUS LCD droplets with scaling factors α in the range of 0.625 to 0.75, where we observe liquid droplets. Significant hydration of the interior of the droplets keeps the proteins mobile and the droplets fluid.
The epitranscriptome embodies many new and largely unexplored functions of RNA. A major roadblock in the epitranscriptomics field is the lack of transcriptome-wide methods to detect more than a single RNA modification type at a time, identify RNA modifications in individual molecules, and estimate modification stoichiometry accurately. We address these issues with CHEUI (CH3 (methylation) Estimation Using Ionic current), a new method that concurrently detects N6-methyladenosine (m6A) and 5-methylcytidine (m5C) in individual RNA molecules from the same sample, as well as differential methylation between any two conditions. CHEUI processes observed and expected nanopore direct RNA sequencing signals with convolutional neural networks to achieve high single-molecule accuracy and outperforms other methods in detecting m6A and m5C sites and quantifying their stoichiometry. CHEUI’s unique capability to identify two modification types in the same sample reveals a non-random co-occurrence of m6A and m5C in mRNA transcripts in cell lines and tissues. CHEUI unlocks an unprecedented potential to study RNA modification configurations and discover new epitranscriptome functions.
The epitranscriptome embodies many new and largely unexplored functions of RNA. A major roadblock in the epitranscriptomics field is the lack of transcriptome-wide methods to detect more than a single RNA modification type at a time, identify RNA modifications in individual molecules, and estimate modification stoichiometry accurately. We address these issues with CHEUI (CH3 (methylation) Estimation Using Ionic current), a new method that concurrently detects N6-methyladenosine (m6A) and 5-methylcytidine (m5C) in individual RNA molecules from the same sample, as well as differential methylation between any two conditions. CHEUI processes observed and expected nanopore direct RNA sequencing signals with convolutional neural networks to achieve high single-molecule accuracy and outperforms other methods in detecting m6A and m5C sites and quantifying their stoichiometry. CHEUI’s unique capability to identify two modification types in the same sample reveals a non-random co-occurrence of m6A and m5C in mRNA transcripts in cell lines and tissues. CHEUI unlocks an unprecedented potential to study RNA modification configurations and discover new epitranscriptome functions.
The epitranscriptome embodies many new and largely unexplored functions of RNA. A major roadblock in the epitranscriptomics field is the lack of transcriptome-wide methods to detect more than a single RNA modification type at a time, identify RNA modifications in individual molecules, and estimate modification stoichiometry accurately. We address these issues with CHEUI (CH3 (methylation) Estimation Using Ionic current), a new method that concurrently detects N6-methyladenosine (m6A) and 5-methylcytidine (m5C) in individual RNA molecules from the same sample, as well as differential methylation between any two conditions. CHEUI processes observed and expected nanopore direct RNA sequencing signals with convolutional neural networks to achieve high single-molecule accuracy and outperforms other methods in detecting m6A and m5C sites and quantifying their stoichiometry. CHEUI’s unique capability to identify two modification types in the same sample reveals a non-random co-occurrence of m6A and m5C in mRNA transcripts in cell lines and tissues. CHEUI unlocks an unprecedented potential to study RNA modification configurations and discover new epitranscriptome functions.
The epitranscriptome embodies many new and largely unexplored functions of RNA. A major roadblock in the epitranscriptomics field is the lack of transcriptome-wide methods to detect more than a single RNA modification type at a time, identify RNA modifications in individual molecules, and estimate modification stoichiometry accurately. We address these issues with CHEUI (CH3 (methylation) Estimation Using Ionic current), a new method that concurrently detects N6-methyladenosine (m6A) and 5-methylcytidine (m5C) in individual RNA molecules from the same sample, as well as differential methylation between any two conditions. CHEUI processes observed and expected nanopore direct RNA sequencing signals with convolutional neural networks to achieve high single-molecule accuracy and outperforms other methods in detecting m6A and m5C sites and quantifying their stoichiometry. CHEUI’s unique capability to identify two modification types in the same sample reveals a non-random co-occurrence of m6A and m5C in mRNA transcripts in cell lines and tissues. CHEUI unlocks an unprecedented potential to study RNA modification configurations and discover new epitranscriptome functions.
The epitranscriptome embodies many new and largely unexplored functions of RNA. A major roadblock in the epitranscriptomics field is the lack of transcriptome-wide methods to detect more than a single RNA modification type at a time, identify RNA modifications in individual molecules, and estimate modification stoichiometry accurately. We address these issues with CHEUI (CH3 (methylation) Estimation Using Ionic current), a new method that concurrently detects N6-methyladenosine (m6A) and 5-methylcytidine (m5C) in individual RNA molecules from the same sample, as well as differential methylation between any two conditions, using signals from nanopore direct RNA sequencing. CHEUI processes observed and expected signals with convolutional neural networks to achieve high single-molecule accuracy and outperform other methods in detecting m6A and m5C sites and quantifying their stoichiometry. CHEUI’s unique capability to identify two modification types in the same sample reveals a non-random co-occurrence of m6A and m5C in mRNA transcripts in cell lines and tissues. CHEUI unlocks an unprecedented potential to study RNA modification configurations and discover new epitranscriptome functions.
The human growth factor receptor MET is a receptor tyrosine kinase involved in cell proliferation, migration, and survival. MET is also hijacked by the intracellular pathogen Listeria monocytogenes. Its invasion protein, internalin B (InlB), binds to MET and promotes the formation of a signaling dimer that triggers the internalization of the pathogen. Here, we use a combination of structural biology, modeling, molecular dynamics simulations, and in situ single-molecule Förster resonance energy transfer (smFRET) experiments to elucidate the early events in MET activation by Listeria. Simulations show that InlB binding stabilizes MET in a conformation that promotes dimer formation. smFRET identifies the organization of the in situ signaling dimer. Further MD simulations of the dimer model are in quantitative agreement with smFRET. We accurately describe the structural dynamics underpinning an important cellular event and introduce a powerful methodological pipeline applicable to studying the activation of other plasma membrane receptors.
Dendritic spines are crucial for excitatory synaptic transmission as the size of a spine head correlates with the strength of its synapse. The distribution of spine head sizes follows a lognormal-like distribution with more small spines than large ones. We analysed the impact of synaptic activity and plasticity on the spine size distribution in adult-born hippocampal granule cells from rats with induced homo- and heterosynaptic long-term plasticity in vivo and CA1 pyramidal cells from Munc-13-1-Munc13-2 knockout mice with completely blocked synaptic transmission. Neither induction of extrinsic synaptic plasticity nor the blockage of presynaptic activity degrades the lognormal-like distribution but changes its mean, variance and skewness. The skewed distribution develops early in the life of the neuron. Our findings and their computational modelling support the idea that intrinsic synaptic plasticity is sufficient for the generation, while a combination of intrinsic and extrinsic synaptic plasticity maintains lognormal like distribution of spines.
The first measurements of skewness and kurtosis of mean transverse momentum (⟨pT⟩) fluctuations are reported in Pb−Pb collisions at sNN−−−√ = 5.02 TeV, Xe−Xe collisions at sNN−−−√ = 5.44 TeV and pp collisions at s√=5.02 TeV using the ALICE detector. The measurements are carried out as a function of system size ⟨dNch/dη⟩1/3|η|<0.5, using charged particles with transverse momentum (pT) and pseudorapidity (η), in the range 0.2<pT<3.0 GeV/c and |η|<0.8, respectively. In Pb−Pb and Xe−Xe collisions, positive skewness is observed in the fluctuations of ⟨pT⟩ for all centralities, which is significantly larger than what would be expected in the scenario of independent particle emission. This positive skewness is considered a crucial consequence of the hydrodynamic evolution of the hot and dense nuclear matter created in heavy-ion collisions. Furthermore, similar observations of positive skewness for minimum bias pp collisions are also reported here. Kurtosis of ⟨pT⟩ fluctuations is found to be in good agreement with the kurtosis of Gaussian distribution, for most central Pb−Pb collisions. Hydrodynamic model calculations with MUSIC using Monte Carlo Glauber initial conditions are able to explain the measurements of both skewness and kurtosis qualitatively from semicentral to central collisions in Pb--Pb system. Color reconnection mechanism in PYTHIA8 model seems to play a pivotal role in capturing the qualitative behavior of the same measurements in pp collisions.
The MICOS complex subunit MIC13 is essential for mitochondrial cristae organization. Mutations in MIC13 cause severe mitochondrial hepato-encephalopathy displaying defective cristae morphology and loss of the MIC10-subcomplex. Here we identified SLP2 as a novel interacting partner of MIC13 and decipher a critical role of SLP2 for MICOS assembly at distinct steps. SLP2 provides a large interaction hub for MICOS subunits and loss of SLP2 imparted YME1L-mediated proteolysis of MIC26 and drastic alterations in cristae morphology. We further identified a MIC13-specific role in stabilizing the MIC10-subcomplex via a MIC13-YME1L axis. SLP2 together with the stabilized MIC10-subcomplex promotes efficient assembly of the MIC60-subcomplex forming the MICOS-MIB complex. Consistently, super-resolution nanoscopy showed a dispersed distribution of the MIC60 in cells lacking SLP2 and MIC13. Our study reveals converging and interdependent assembly pathways for the MIC10- and MIC60-subcomplexes which are controlled in two ways, the MIC13-YME1L and the SLP2-YME1L axes, revealing mechanistic insights of these factors in cristae morphogenesis. These results will be helpful in understanding the human pathophysiology linked to mutations in MIC13 or its interaction partners.
Snapshots of acetyl-CoA synthesis, the final step of CO₂ fixation in the Wood-Ljungdahl pathway
(2024)
In the ancient microbial Wood-Ljungdahl pathway, CO2 is fixed in a multi-step process with acetyl-CoA synthesis at the bifunctional carbon monoxide dehydrogenase/acetyl-CoA synthase complex (CODH/ACS). Here, we present catalytic snapshots of the CODH/ACS from the gas-converting acetogen Clostridium autoethanogenum, characterizing the molecular choreography of the overall reaction including electron transfer to the CODH for CO2 reduction, methyl transfer from the corrinoid iron-sulfur protein (CoFeSP) partner to the ACS active site and acetyl-CoA production. Unlike CODH, the multidomain ACS undergoes large conformational changes to form an internal connection to the CODH active site, accommodate the CoFeSP for methyl transfer and protect the reaction intermediates. Altogether, the structures allow us to draw a detailed reaction mechanism of this enzyme crucial for CO2 fixation in anaerobic organisms.
A measurement of dielectron production in proton-proton (pp) collisions at s√=13 TeV, recorded with the ALICE detector at the CERN LHC, is presented in this Letter. The data set was recorded with a reduced magnetic solenoid field. This enables the investigation of a kinematic domain at low dielectron invariant mass mee and pair transverse momentum pT,ee that was previously inaccessible at the LHC. The cross section for dielectron production is studied as a function of mee, pT,ee, and event multiplicity dNch/dη. The expected dielectron rate from hadron decays, called hadronic cocktail, utilizes a parametrization of the measured η/π0 ratio in pp and proton-nucleus (p-A) collisions, assuming that this ratio shows no strong dependence on collision energy at low transverse momentum. Comparison of the measured dielectron yield to the hadronic cocktail at 0.15<mee<0.6 GeV/c2 and for pT,ee<0.4 GeV/c indicates an enhancement of soft dielectrons, reminiscent of the 'anomalous' soft-photon and -dilepton excess in hadron-hadron collisions reported by several experiments under different experimental conditions. The enhancement factor over the hadronic cocktail amounts to 1.61±0.13(stat.)±0.17(syst.,data)±0.34(syst.,cocktail) in the ALICE acceptance. Acceptance-corrected excess spectra in mee and pT,ee are extracted and compared with calculations of dielectron production from hadronic bremsstrahlung and thermal radiation within a hadronic many-body approach.
A measurement of dielectron production in proton-proton (pp) collisions at s√=13 TeV, recorded with the ALICE detector at the CERN LHC, is presented in this Letter. The data set was recorded with a reduced magnetic solenoid field. This enables the investigation of a kinematic domain at low dielectron invariant mass mee and pair transverse momentum pT,ee that was previously inaccessible at the LHC. The cross section for dielectron production is studied as a function of mee, pT,ee, and event multiplicity dNch/dη. The expected dielectron rate from hadron decays, called hadronic cocktail, utilizes a parametrization of the measured η/π0 ratio in pp and proton-nucleus (p-A) collisions, assuming that this ratio shows no strong dependence on collision energy at low transverse momentum. Comparison of the measured dielectron yield to the hadronic cocktail at 0.15<mee<0.6 GeV/c2 and for pT,ee<0.4 GeV/c indicates an enhancement of soft dielectrons, reminiscent of the 'anomalous' soft-photon and -dilepton excess in hadron-hadron collisions reported by several experiments under different experimental conditions. The enhancement factor over the hadronic cocktail amounts to 1.61±0.13(stat.)±0.17(syst.,data)±0.34(syst.,cocktail) in the ALICE acceptance. Acceptance-corrected excess spectra in mee and pT,ee are extracted and compared with calculations of dielectron production from hadronic bremsstrahlung and thermal radiation within a hadronic many-body approach.
A measurement of dielectron production in proton-proton (pp) collisions at s√=13 TeV, recorded with the ALICE detector at the CERN LHC, is presented in this Letter. The data set was recorded with a reduced magnetic solenoid field. This enables the investigation of a kinematic domain at low dielectron invariant mass mee and pair transverse momentum pT,ee that was previously inaccessible at the LHC. The cross section for dielectron production is studied as a function of mee, pT,ee, and event multiplicity dNch/dη. The expected dielectron rate from hadron decays, called hadronic cocktail, utilizes a parametrization of the measured η/π0 ratio in pp and proton-nucleus (p-A) collisions, assuming that this ratio shows no strong dependence on collision energy at low transverse momentum. Comparison of the measured dielectron yield to the hadronic cocktail at 0.15<mee<0.6 GeV/c2 and for pT,ee<0.4 GeV/c indicates an enhancement of soft dielectrons, reminiscent of the 'anomalous' soft-photon and -dilepton excess in hadron-hadron collisions reported by several experiments under different experimental conditions. The enhancement factor over the hadronic cocktail amounts to 1.69±0.14(stat.)±0.18(syst.,data)±0.36(syst.,cocktail) in the ALICE acceptance. Acceptance-corrected excess spectra in mee and pT,ee are extracted and compared with calculations of dielectron production from hadronic bremsstrahlung and thermal radiation within a hadronic many-body approach.
Some pitfalls of measuring representational similarity using Representational Similarity Analysis
(2022)
A core challenge in cognitive and brain sciences is to assess whether different biological systems represent the world in a similar manner. Representational Similarity Analysis (RSA) is an innovative approach that addresses this problem by looking for a second-order isomorphisim in neural activation patterns. This innovation makes it easy to compare latent representations across individuals, species and computational models, and accounts for its popularity across disciplines ranging from artificial intelligence to computational neuroscience. Despite these successes, using RSA has led to difficult-to-reconcile and contradictory findings, particularly when comparing primate visual representations with deep neural networks (DNNs): even though DNNs have been shown to learn and behave in vastly different ways to humans, comparisons based on RSA have shown striking similarities in some studies. Here, we demonstrate some pitfalls of using RSA and explain how contradictory findings can arise due to false inferences about representational similarity based on RSA-scores. In a series of studies that capture increasingly plausible training and testing scenarios, we compare neural representations in computational models, primate cortex and human cortex. These studies reveal two problematic phenomena that are ubiquitous in current research: a “mimic effect”, where confounds in stimuli can lead to high RSA-scores between provably dissimilar systems, and a “modulation effect”, where RSA-scores become dependent on stimuli used for testing. Since our results bear on a number of influential findings, such as comparisons made between human visual representations and those of primates and DNNs, we provide recommendations to avoid these pitfalls and sketch a way forward to a more solid science of representation in cognitive systems.
Recent approaches to Word Sense Disambiguation (WSD) generally fall into two classes: (1) information-intensive approaches and (2) information-poor approaches. Our hypothesis is that for memory-based learning (MBL), a reduced amount of data is more beneficial than the full range of features used in the past. Our experiments show that MBL combined with a restricted set of features and a feature selection method that minimizes the feature set leads to competitive results, outperforming all systems that participated in the SENSEVAL-3 competition on the Romanian data. Thus, with this specific method, a tightly controlled feature set improves the accuracy of the classifier, reaching 74.0% in the fine-grained and 78.7% in the coarse-grained evaluation.
The space-time dynamics and pion-HBT radii in central heavy ion-collisions at CERN-SPS and BNL-RHIC are investigated within a hydrodynamic simulation. The dependence of the dynamics and the HBT-parameters on the EoS is studied with different parametrizations of a chiral SU(3) sigma omega model. The selfconsistent collective expansion includes the e ects of e ective hadron masses, generated by the nonstrange and strange scalar condensates. Different chiral EoS show di erent types of phase transitions and even a crossover. The influence of the order of the phase transition and of the latent heat on the space-time dynamics and pion-HBT radii is studied. A small latent heat, i.e. a weak first-order chiral phase transition, or a smooth crossover lead to distinctly di erent HBT predictions than a strong first order phase transition. A quantitative description of the data, both at SPS energies as well as at RHIC energies, appears di cult to achieve within the ideal hydrodynamic approach using the SU(3) chiral EoS. A strong first-order quasi-adiabatic chiral phase transition seems to be disfavored by the pion-HBT data from CERN-SPS and BNL-RHIC.
n this paper we study invasion probabilities and invasion times of cooperative parasites spreading in spatially structured host populations. The spatial structure of the host population is given by a random geometric graph on [0,1]n, n∈N, with a Poisson(N)-distributed number of vertices and in which vertices are connected over an edge when they have a distance of at most rN∈Θ(Nβ−1n) for some 0<β<1 and N→∞. At a host infection many parasites are generated and parasites move along edges to neighbouring hosts. We assume that parasites have to cooperate to infect hosts, in the sense that at least two parasites need to attack a host simultaneously. We find lower and upper bounds on the invasion probability of the parasites in terms of survival probabilities of branching processes with cooperation. Furthermore, we characterize the asymptotic invasion time.
An important ingredient of the proofs is a comparison with infection dynamics of cooperative parasites in host populations structured according to a complete graph, i.e. in well-mixed host populations. For these infection processes we can show that invasion probabilities are asymptotically equal to survival probabilities of branching processes with cooperation.
Furthermore, we build in the proofs on techniques developed in [BP22], where an analogous invasion process has been studied for host populations structured according to a configuration model.
We substantiate our results with simulations.
The hippocampal formation is linked to spatial navigation, but there is little corroboration from freely-moving primates with concurrent monitoring of three-dimensional head and gaze stances. We recorded neurons and local field potentials across hippocampal regions in rhesus macaques during free foraging in an open environment while tracking their head and eye. Theta band activity was intermittently present at movement onset and modulated by saccades. Many cells were phase-locked to theta, with few showing theta phase precession. Most hippocampal neurons encoded a mixture of spatial variables beyond place fields and a negligible number showed prominent grid tuning. Spatial representations were dominated by facing location and allocentric direction, mostly in head, rather than gaze, coordinates. Importantly, eye movements strongly modulated neural activity in all regions. These findings reveal that the macaque hippocampal formation represents three-dimensional space using a multiplexed code, with head orientation and eye movement properties dominating over simple place and grid coding during free exploration.
Resting state fMRI has been employed to identify alterations in functional connectivity within or between brain regions following acute and chronic exposure to Δ9-tetrahydrocannabinol (THC), the psychoactive component in cannabis. Most studies focused a priori on a limited number of local brain areas or circuits, without considering the impact of cannabis on wholebrain network organization. The present study attempted to identify changes in the wholebrain human functional connectome as assessed with ultra-high field (7T) resting state scans of occasional (N=12) and chronic cannabis users (N=14) during placebo and following vaporization of cannabis. Two distinct data-driven methodologies, i.e. network-based statistics (NBS) and connICA, were used to identify changes in functional connectomes associated with acute cannabis intoxication and chronic cannabis use. Both methodologies revealed a broad state of hyperconnectivity within the entire range of major brain networks in chronic cannabis users compared to occasional cannabis users, which might be reflective of an adaptive network reorganization following prolonged cannabis exposure. The connICA methodology also extracted a distinct spatial connectivity pattern of hypoconnectivity involving the dorsal attention, limbic, subcortical and cerebellum networks and of hyperconnectivity between the default mode and ventral attention network, that was associated with the feeling of subjective high during THC intoxication across both user groups. Whole-brain network approaches identified spatial patterns in functional brain connectomes that distinguished acute from chronic cannabis use, and offer an important utility for probing the interplay between short and long-term alterations in functional brain dynamics when progressing from occasional to chronic use of cannabis.
Human language relies on hierarchically structured syntax to facilitate efficient and robust communication. The correct processing of syntactic information is essential for successful communication between speakers. As an abstract level of language, syntax has often been studied separately from the physical form of the speech signal, thus often masking the interactions that can promote better syntactic processing in the human brain. We analyzed a MEG dataset to investigate how acoustic cues, specifically prosody, interact with syntactic operations. We examined whether prosody enhances the cortical encoding of syntactic representations. We decoded left-sided dependencies directly from brain activity and evaluated possible modulations of the decoding by the presence of prosodic boundaries. Our findings demonstrate that prosodic boundary presence improves the representation of left-sided dependencies, indicating the facilitative role of prosodic cues in processing abstract linguistic features. This study gives neurobiological evidence for the boosting of syntactic processing via interaction with prosody.
SpikeShip: a method for fast, unsupervised discovery of high-dimensional neural spiking patterns
(2023)
Neural coding and memory formation depend on temporal spiking sequences that span high-dimensional neural ensembles. The unsupervised discovery and characterization of these spiking sequences requires a suitable dissimilarity measure to spiking patterns, which can then be used for clustering and decoding. Here, we present a new dissimilarity measure based on optimal transport theory called SpikeShip, which compares multi-neuron spiking patterns based on all the relative spike-timing relationships among neurons. SpikeShip computes the optimal transport cost to make all the relative spike timing relationships (across neurons) identical between two spiking patterns. We show that this transport cost can be decomposed into a temporal rigid translation term, which captures global latency shifts, and a vector of neuron-specific transport flows, which reflect inter-neuronal spike timing differences. SpikeShip can be effectively computed for high-dimensional neuronal ensembles, has a low (linear) computational cost that has the same order as the spike count, and is sensitive to higher-order correlations. Furthermore SpikeShip is binless, can handle any form of spike time distributions, is not affected by firing rate fluctuations, can detect patterns with a low signal-to-noise ratio, and can be effectively combined with a sliding window approach. We compare the advantages and differences between SpikeShip and other measures like SPIKE and Victor-P urpura distance. We applied SpikeShip to large-scale Neuropixel recordings during spontaneous activity and visual encoding. We show that high-dimensional spiking sequences detected via SpikeShip reliably distinguish between different natural images and different behavioral states. These spiking sequences carried complementary information to conventional firing rate codes. SpikeShip opens new avenues for studying neural coding and memory consolidation by rapid and unsupervised detection of temporal spiking patterns in high-dimensional neural ensembles.
Die drei Bereiche, die hier verglichen werden sollen, entsprechen in etwa der überkommenen Trias von Literatur, Musik und bildender Kunst, einer Gliederung, die im Medienzeitalters mit Videos, CDs, Installationen oder Happenings eigentlich obsolet ist. Allerdings geht es hier nur um die Eigenart der Zeichensysteme, auf denen die verschiedenen Bereiche beruhen, nicht um die Werke, die dadurch möglich werden, obgleich natürlich auch die Kunstwerke im emphatischen Sinn, die bedeutenden und die banalen, die großen und die misslungenen Gestaltungen nur möglich und verstehbar sind aufgrund der Zeichen, auf denen sie beruhen.
Im vorliegenden Artikel geht es um sprachliche Elemente, die in einer Sprache bereits vorhanden sind, als Nonstandard gelten bzw. nicht in anerkannter verbindlicher Weise standardisiert sind und nun in verändertem Gebrauch differenzierend genutzt werden. Der neue Gebrauch hat ein oder mehrere initiale Ereignisse, die – systemorientiert formuliert – an einer oder mehreren Stellen eines Sprachraums auftreten und in einer evolutionären Drift häufiger werden oder verschwinden, bzw. – handlungsorientiert formuliert – von unterschiedlichen Sprechern übernommen, mit neuen Semantiken versehen werden oder unbeachtet bleiben.
Bern, bis ins 18. Jh. Zentrum der regionalen Großmacht, heute mit nicht ganz 130.000 Einwohnern die viertgrößte Stadt der Schweiz und seit 1848 die Hauptstadt der Schweiz. Auf Grund dieser Ausgangslage würde man erwarten, dass Bern wie andere Städte eine sprachliche Strahlungskraft in die unmittelbare Umgebung aufweist. Entgegen der allgemeinen Vorstellung zeigt sich jedoch in den Karten des Sprachatlas der deutschen Schweiz (SDS) kaum eine der für die Umgebung von Städten typischen sprachgeographische Verbreitungsbilder. So finden sich viele Isoglossen in unmittelbarer Nähe der Stadt Bern: trichter-, keil- oder gar kreisförmige Bündelungen von Isoglossen, die auf eine sprachliche Wirkung der Stadt hindeuten würde, lassen sich kaum nachweisen.
Die Sprachsituation der deutschen Schweiz, wo die Mundarten den großen Teil der gesprochenen Sprachrealität darstellen, bietet ein weites Feld für Erforschung der gesprochenen Sprache. Die starke Position der Mundarten und die weitgehend mündliche Überlieferung machen sie für die Sprachwandelforschung interessant. Nachdem die Erforschung von Sprachwandel lange auf der Rekonstruktion gesprochener Sprache aus Schriftzeugnissen beschränkt war, kann seit dem wissenschaftlich reflektierten Festhalten gesprochener Sprache in Transkripten und seit der Möglichkeit zur Tonarchivierung auf historische Zeugnisse gesprochener Sprache zurückgegriffen werden. So kann die primäre Sprachform berücksichtigt werden. Denn obwohl Lautwandel lange der zentrale Bereich der Sprachgeschichtsschreibung war und die Sprachgeschichtsschreibung weitgehend vom "Primat des Sprechens" (Sonderegger 1979, 11) ausgegangen war, musste sie sich lange mit Schriftzeugnissen abfinden, die nur Reflexe gesprochener Sprache darstellten.
In this work, inhomogeneous chiral phases are studied in a variety of Four-Fermion and Yukawa models in 2+1 dimensions at zero and non-zero temperature and chemical potentials. Employing the mean-field approximation, we do not find indications for an inhomogeneous phase in any of the studied models. We show that the homogeneous phases are stable against inhomogeneous perturbations. At zero temperature, full analytic results are presented.
The production of Large Extra Dimension (LXD) Black Holes (BHs), with a new, fundamental mass scale of M_f = 1 TeV, has been predicted to occur at the Large Hadron Collider, LHC, with the formidable rate of 10^8 per year in p-p collisions at full energy, 14 TeV, and at full luminosity. We show that such LXD-BH formation will be experimentally observable at the LHC by the complete disappearance of all very high p_t (> 500 GeV) back-to-back correlated Di-Jets of total mass M > M_f = 1 TeV. We suggest to complement this clear cut-off signal at M > 2*500 GeV in the di-jet-correlation function by detecting the subsequent, Hawking-decay products of the LXD-BHs, namely either multiple high energy (> 100 GeV) SM Mono-Jets (i.e. away-side jet missing), sprayed off the evaporating BHs isentropically into all directions or the thermalization of the multiple overlapping Hawking-radiation in a eckler-Kapusta-Plasma. Microcanonical quantum statistical calculations of the Hawking evaporation process for these LXD-BHs show that cold black hole remnants (BHRs) of Mass sim M_f remain leftover as the ashes of these spectacular Di-Jet-suppressed events. Strong Di-Jet suppression is also expected with Heavy Ion beams at the LHC, due to Quark-Gluon-Plasma induced jet attenuation at medium to low jet energies, p_t < 200 GeV. The (Mono-)Jets in these events can be used to trigger for Tsunami-emission of secondary compressed QCD-matter at well defined Mach-angles, both at the trigger side and at the awayside (missing) jet. The Machshock-angles allow for a direct measurement of both the equation of state EoS and the speed of sound c_s via supersonic bang in the "big bang" matter. We discuss the importance of the underlying strong collective flow - the gluon storm - of the QCD- matter for the formation and evolution of these Machshock cones. We predict a significant deformation of Mach shocks from the gluon storm in central Au+Au collisions at RHIC and LHC energies, as compared to the case of weakly coupled jets propagating through a static medium. A possible complete stopping of pt > 50 GeV jets at the LHC in 2-3 fm yields nonlinear high density Mach shocks in he quark gluon plasma, which can be studied in the complex emission and disintegration pattern of the possibly supercooled matter. We report on first full 3-dimensional fluid dynamical studies of the strong effects of a first order phase transition on the evolution and the Tsunami-like Mach shock emission of the QCD matter.
Motivation: The topic of this paper is the estimation of alignments and mutation rates based on stochastic sequence-evolution models that allow insertions and deletions of subsequences ("fragments") and not just single bases. The model we propose is a variant of a model introduced by Thorne, Kishino, and Felsenstein (1992). The computational tractability of the model depends on certain restrictions in the insertion/deletion process; possible effects we discuss.
Results: The process of fragment insertion and deletion in the sequence-evolution model induces a hidden Markov structure at the level of alignments and thus makes possible efficient statistical alignment algorithms. As an example we apply a sampling procedure to assess the variability in alignment and mutation parameter estimates for HVR1 sequences of human and orangutan, improving results of previous work. Simulation studies give evidence that estimation methods based on the proposed model also give satisfactory results when applied to data for which the restrictions in the insertion/deletion process do not hold.
Availability: The source code of the software for sampling alignments and mutation rates for a pair of DNA sequences according to the fragment insertion and deletion model is freely available from www.math.uni-frankfurt.de/~stoch/software/mcmcsalut under the terms of the GNU public license (GPL, 2000).
Statistical coalescence model analysis of J / psi production in Pb + Pb collisions at 158 A GeV
(2001)
Production of J/psi mesons in heavy ion collisions is considered within the statistical coalescence model. The model is in agreement with the experi- mental data of the NA50 Collaboration for Pb+Pb collisions at 158 A·GeV in a wide centrality range, including the so called anomalous suppression domain. The model description of the J/ psi data requires, however, strong enhancement of the open charm production in central Pb+Pb collisions. This model prediction may be checked in the future SPS runs.
The statistical coalescence model for the production of open and hidden charm is considered within the canonical ensemble formulation. The data for the J/psi multiplicity in Pb+Pb collisions at 158 A·GeV are used for the model prediction of the open charm yield which has not yet been measured in these reactions.
A microscopic model of deconfined matter based on color interactions between semi-classical quarks is studied. A hadronization mechanism is imposed to examine the properties and the disassembly of a thermalized quark plasma and to investigate the possible existence of a phase transition from quark matter to hadron matter.
In Arabidopsis thaliana, the stem cell niche (SCN) within the root apical meristem (RAM) is maintained by an intricate regulatory network that ensures optimal growth and high developmental plasticity. Yet, many aspects of this regulatory network of stem cell quiescence and replenishment are still not fully understood. Here, we investigate the interplay of the key transcription factors (TFs) BRASSINOSTEROID AT VASCULAR AND ORGANIZING CENTRE (BRAVO), PLETHORA 3 (PLT3) and WUSCHEL-RELATED HOMEOBOX 5 (WOX5) involved in SCN maintenance. Phenotypical analysis of mutants involving these TFs uncover their combinatorial regulation of cell fates and divisions in the SCN. Moreover, interaction studies employing fluorescence resonance energy transfer fluorescence lifetime imaging microscopy (FRET-FLIM) in combination with novel analysis methods, allowed us to quantify protein-protein interaction (PPI) affinities as well as higher-order complex formation of these TFs. We integrated our experimental results into a computational model, suggesting that cell type specific profiles of protein complexes and characteristic complex formation, that is also dependent on prion-like domains in PLT3, contribute to the intricate regulation of the SCN. We propose that these unique protein complex ‘signatures’ could serve as a read-out for cell specificity thereby adding another layer to the sophisticated regulatory network that balances stem cell maintenance and replenishment in the Arabidopsis root.
Spike count correlations (SCCs) are ubiquitous in sensory cortices, are characterized by rich structure and arise from structured internal interactions. Yet, most theories of visual perception focus exclusively on the mean responses of individual neurons. Here, we argue that feedback interactions in primary visual cortex (V1) establish the context in which individual neurons process complex stimuli and that changes in visual context give rise to stimulus-dependent SCCs. Measuring V1 population responses to natural scenes in behaving macaques, we show that the fine structure of SCCs is stimulus-specific and variations in response correlations across-stimuli are independent of variations in response means. Moreover, we demonstrate that stimulus-specificity of SCCs in V1 can be directly manipulated by controlling the high-order structure of synthetic stimuli. We propose that stimulus-specificity of SCCs is a natural consequence of hierarchical inference where inferences on the presence of high-level image features modulate inferences on the presence of low-level features.
A growing body of psychophysical research reports theta (3-8 Hz) rhythmic fluctuations in visual perception that are often attributed to an attentional sampling mechanism arising from theta rhythmic neural activity in mid- to high-level cortical association areas. However, it remains unclear to what extent such neuronal theta oscillations might already emerge at early sensory cortex like the primary visual cortex (V1), e.g. from the stimulus filter properties of neurons. To address this question, we recorded multi-unit neural activity from V1 of two macaque monkeys viewing a static visual stimulus with variable sizes, orientations and contrasts. We found that among the visually responsive electrode sites, more than 50 % showed a spectral peak at theta frequencies. Theta power varied with varying basic stimulus properties. Within each of these stimulus property domains (e.g. size), there was usually a single stimulus value that induced the strongest theta activity. In addition to these variations in theta power, the peak frequency of theta oscillations increased with increasing stimulus size and also changed depending on the stimulus position in the visual field. Further analysis confirmed that this neural theta rhythm was indeed stimulus-induced and did not arise from small fixational eye movements (microsaccades). When the monkeys performed a detection task of a target embedded in a theta-generating visual stimulus, reaction times also tended to fluctuate at the same theta frequency as the one observed in the neural activity. The present study shows that a highly stimulus-dependent neuronal theta oscillation can be elicited in V1 that appears to influence the temporal dynamics of visual perception.
Intrinsic covariation of brain activity has been studied across many levels of brain organization. Between visual areas, neuronal activity covaries primarily among portions with similar retinotopic selectivity. We hypothesized that spontaneous inter-areal co-activation is subserved by neuronal synchronization. We performed simultaneous high-density electrocorticographic recordings across several visual areas in awake monkeys to investigate spatial patterns of local and inter-areal synchronization. We show that stimulation-induced patterns of inter-areal co-activation were reactivated in the absence of stimulation. Reactivation occurred through both, inter-areal co-fluctuation of local activity and inter-areal phase synchronization. Furthermore, the trial-by-trial covariance of the induced responses recapitulated the pattern of inter-areal coupling observed during stimulation, i.e. the signal correlation. Reactivation-related synchronization showed distinct peaks in the theta, alpha and gamma frequency bands. During passive states, this rhythmic reactivation was augmented by specific patterns of arrhythmic correspondence. These results suggest that networks of intrinsic covariation observed at multiple levels and with several recording techniques are related to synchronization and that behavioral state may affect the structure of intrinsic dynamics.
Under natural conditions, the visual system often sees a given input repeatedly. This provides an opportunity to optimize processing of the repeated stimuli. Stimulus repetition has been shown to strongly modulate neuronal-gamma band synchronization, yet crucial questions remained open. Here we used magnetoencephalography in 30 human subjects and find that gamma decreases across ~10 repetitions and then increases across further repetitions, revealing plastic changes of the activated neuronal circuits. Crucially, changes induced by one stimulus did not affect responses to other stimuli, demonstrating stimulus specificity. Changes partially persisted when the inducing stimulus was repeated after 25 minutes of intervening stimuli. They were strongest in early visual cortex and increased interareal feedforward influences. Our results suggest that early visual cortex gamma synchronization enables adaptive neuronal processing of recurring stimuli. These and previously reported changes might be due to an interaction of oscillatory dynamics with established synaptic plasticity mechanisms.
When a visual stimulus is repeated, average neuronal responses typically decrease, yet they might maintain or even increase their impact through increased synchronization. Previous work has found that many repetitions of a grating lead to increasing gamma-band synchronization. Here we show in awake macaque area V1 that both, repetition-related reductions in firing rate and increases in gamma are specific to the repeated stimulus. These effects showed some persistence on the timescale of minutes. Further, gamma increases were specific to the presented stimulus location. Importantly, repetition effects on gamma and on firing rates generalized to natural images. These findings suggest that gamma-band synchronization subserves the adaptive processing of repeated stimulus encounters, both for generating efficient stimulus responses and possibly for memory formation.
Topological semimetal antiferromagnets provide a rich source of exotic topological states which can be controlled by manipulating the orientation of the Néel vector, or by modulating the lattice parameters through strain. We investigate via ab initio density functional theory calculations, the effects of shear strain on the bulk and surface states n two antiferromagnetic EuCd2As2 phases with out-of-plane and in-plane spin configurations. When magnetic moments are along the c-axis, a 3% longitudinal or diagonal shear strain can tune the Dirac semimetal phase to an axion insulator phase, characterized by the parity-based invariant η4I=2. For an in-plane magnetic order, the axion insulator phase remains robust under all shear strains. We further find that for both magnetic orders, the bulk gap increases and a surface gap opens on the (001) surface up to 16 meV. Because of a nonzero η4I index and gapped states on the (001) surface, hinge modes are expected to happen on the side surface states between those gapped surface states. This result can provide a valuable insight in the realization of the long-sought axion states.
Equation of state of baryon rich quark matter is studied within the SU(3) Nambu Jona-Lasinio model with flavour mixing interaction. Possible bound states (strangelets) and chiral phase transitions in this matter are investigated at various values of strangeness fraction rs. The model predictions are very sensitive to the ratio of vector and scalar coupling constants, ¾ = GV /GS. At ¾ = 0.5 and zero temperature the maximum binding energy (about 15 MeV per baryon) takes place at rs C 0.4. Such strangelets are negatively charged and have typical life times < 10 7 s. The calculations are carried out also at finite temperatures. They show that bound states exist up to temperatures of about 15 MeV. The model predicts a first order chiral phase transition at finite baryon densities. The parameters of this phase transition are calculated as a function of rs.
We investigate the properties of charge neutral equilibrium cold quark matter within the Nambu Jona-Lasinio model. The calculations are carried out for di erent ratios of coupling constants characterizing the vector and scalar 4 fermion interaction, xi = GV /GS. It is shown that for xi < 0.4 matter is self bound and for xi < 0.65 it has a first order phase transition of the liquid gas type. The Gibbs conditions in the mixed phase are applied for the case of two chemical potentials associated with the baryon number and electric charge. The characteristics of the quark stars are calculated for xi = 0, 0.5 and 1. It is found that the phase transition leads to a strong density variation at the surface of these stars. For xi = 1 the properties of quark stars show behaviors typical for neutron stars. At >< 0.4 the stars near to the maximum mass have a large admixture of strange quarks in their interiors. PACS number: 14.65.-q, 26.60.+c, 97.10.-q
In ultra-relativistic heavy ion collisions, early stage multiple scatterings may lead to an increase of the color electric field strength. Consequently, particle production - especially heavy quark (and di-quark) production - is greatly enhanced according to the Schwinger mechanism. We test this idea via the Ultra-relativistic Quantum Molecular Dynamics model (UrQMD) for Au+Au collisions at the full RHIC energy (ps = 200 AGeV). Relative to p+p collisions, a factor of 60, 20 and 7 enhancement respectively, for (sss), (ss), and , (s) is predicted for a model with increased color electric field strength.
The centrality dependence of (multi-)strange hadron abundances is studied for Pb(158 AGeV)Pb reactions and compared to p(158 GeV)Pb collisions. The microscopic transport model UrQMD is used for this analysis. The predicted Lambda/pi-, Xi-/pi- and Omega-/pi- ratios are enhanced due to rescattering in central Pb-Pb collisions as compared to peripheral Pb-Pb or p-Pb collisions. A reduction of the constituent quark masses to the current quark masses m_s \sim 230 MeV, m_q \sim 10 MeV, as motivated by chiral symmetry restoration, enhances the hyperon yields to the experimentally observed high values. Similar results are obtained by an ad hoc overall increase of the color electric field strength (effective string tension of kappa=3 GeV/fm). The enhancement depends strongly on the kinematical cuts. The maximum enhancement is predicted around midrapidity. For Lambda's, strangeness suppression is predicted at projectile/target rapidity. For Omega's, the predicted enhancement can be as large as one order of magnitude. Comparisons of Pb-Pb data to proton induced asymmetric (p-A) collisions are hampered due to the predicted strong asymmetry in the various rapidity distributions of the different (strange) particle species. In p-Pb collisions, strangeness is locally (in rapidity) not conserved. The present comparison to the data of the WA97 and NA49 collaborations clearly supports the suggestion that conventional (free) hadronic scenarios are unable to describe the observed high (anti-)hyperon yields in central collisions. The doubling of the strangeness to nonstrange suppression factor, gamma_s \approx 0.65, might be interpreted as a signal of a phase of nearly massless particles.
New results from the energy scan programme of NA49, in particular kaon production at 30 AGeV and phi production at 40 and 80 AGeV are presented. The K+/pi+ ratio shows a pronounced maximum at 30 AGeV; the kaon slope parameters are constant at SPS energies. Both findings support the scenario of a phase transition at about 30 AGeV beam energy. The phi/pi ratio increases smoothly with beam energy, showing an energy dependence similar to K-/pi-. The measured particle yields can be reproduced by a hadron gas model, with chemical freeze-out parameters on a smooth curve in the T-muB plane. The transverse spectra can be understood as resulting from a rapidly expanding, locally equilibrated source. No evidence for an earlier kinetic decoupling of heavy hyperons is found.
We report multi-differential measurements of strange hadron production ranging from mid- to target-rapidity in Au+Au collisions at a center-of-momentum energy per nucleon pair of sNN−−−√=3 GeV with the STAR experiment at RHIC. K0S meson and Λ hyperon yields are measured via their weak decay channels. Collision centrality and rapidity dependences of the transverse momentum spectra and particle ratios are presented. Particle mass and centrality dependence of the average transverse momenta of Λ and K0S are compared with other strange particles, providing evidence of the development of hadronic rescattering in such collisions. The 4π yields of each of these strange hadrons show a consistent centrality dependence. Discussions on radial flow, the strange hadron production mechanism, and properties of the medium created in such collisions are presented together with results from hadronic transport and thermal model calculations.
Während der wissenschaftliche Nachwuchs im Forschungsbereich strategisch und wissenschaftlich fundiert samt diversen Prüfungen (Bachelor, Master, Promotion, ggf. auch Habilitation) ausgebildet wird, existiert im Bereich der Lehre nichts auch nur annährend Vergleichbares. Die übliche „Qualifizierung“ des Nachwuchslehrenden findet meist nur „On-the-job“ (vgl. Conradi, 1983) statt, d.h. durch eigenes Ausprobieren nach Beobachtung anderer Lehrender während des eigenen Studiums. Unter guten Bedingungen hat der Lehrende vorab oder begleitend Weiterbildungen zu guter Lehre besucht. Eine strategische Einbettung dieser Personalentwicklungsmaßnahmen, wie es seitens der Forschung intendiert wird, ist nicht vorhanden. Dieser Beitrag stellt mögliche Formen vor und führt exemplarisch eine darunter näher aus.
We use holography to study the dynamics of a strongly-coupled gauge theory in four-dimensional de Sitter space with Hubble rate H. The gauge theory is non-conformal with a characteristic mass scale M. We solve Einstein’s equations numerically and determine the time evolution of homogeneous gauge theory states. If their initial energy density is high compared with H4 then the early-time evolution is well described by viscous hydrodynamics with a non-zero bulk viscosity. At late times the dynamics is always far from equilibrium. The asymptotic late-time state preserves the full de Sitter symmetry group and its dual geometry is a domain-wall in AdS5. The approach to this state is characterised by an emergent relation of the form P = w E that is different from the equilibrium equation of state in flat space. The constant w does not depend on the initial conditions but only on H/M and is negative if the ratio H/M is close to unity. The event and the apparent horizons of the late-time solution do not coincide with one another, reflecting its non-equilibrium nature. In between them lies an “entanglement horizon” that cannot be penetrated by extremal surfaces anchored at the boundary, which we use to compute the entanglement entropy of boundary regions. If the entangling region equals the observable universe then the extremal surface coincides with a bulk cosmological horizon that just touches the event horizon, while for larger regions the extremal surface probes behind the event horizon.
Candida boidinii NAD+-dependent formate dehydrogenase (CbFDH) has gained significant attention for its potential applications in the production of biofuels and various industrial chemicals from inorganic carbon dioxide. The present study reports the atomic X-ray crystal structures of the wild-type CbFDH at cryogenic and ambient temperatures as well as Val120Thr mutant at cryogenic temperature determined at the Turkish Light Source "Turkish DeLight". The structures reveal new hydrogen bonds between Thr120 and water molecules in the mutant CbFDH's active site, suggesting increased stability of the active site and more efficient electron transfer during the reaction. Further experimental data is needed to test these hypotheses. Collectively, our findings provide invaluable insights into future protein engineering efforts that could potentially enhance the efficiency and effectiveness of CbFDH.
Candida boidinii NAD+-dependent formate dehydrogenase (CbFDH) has gained significant attention for its potential applications in the production of biofuels and various industrial chemicals from inorganic carbon dioxide. The present study reports the atomic X-ray crystal structures of the wild-type CbFDH at cryogenic and ambient temperatures as well as Val120Thr mutant at cryogenic temperature determined at the Turkish Light Source "Turkish DeLight". The structures reveal new hydrogen bonds between Thr120 and water molecules in the mutant CbFDH's active site, suggesting increased stability of the active site and more efficient electron transfer during the reaction. Further experimental data is needed to test these hypotheses. Collectively, our findings provide invaluable insights into future protein engineering efforts that could potentially enhance the efficiency and effectiveness of CbFDH.
Human feline leukemia virus subgroup C receptor-related proteins 1 and 2 (FLVCR1 and 2) are members of the major facilitator superfamily1. Their dysfunction is linked to several clinical disorders, including PCARP, HSAN, and Fowler syndrome2–7. Earlier studies concluded that FLVCR1 may function as a putative heme exporter8–12, while FLVCR2 was suggested to act as a heme importer13, yet conclusive biochemical and detailed molecular evidence remained elusive for the function of both transporters14–17. Here, we show that FLVCR1 and FLVCR2 facilitate the transport of choline and ethanolamine across human plasma membranes, utilizing a concentration-driven substrate translocation process. Through structural and computational analyses, we have identified distinct conformational states of FLVCRs and unraveled the coordination chemistry underlying their substrate interactions. Within the binding pocket of both transporters, we identify fully conserved tryptophan and tyrosine residues holding a central role in the formation of cation-π interactions, essential for choline and ethanolamine selectivity. Our findings not only clarify the mechanisms of choline and ethanolamine transport by FLVCR1 and FLVCR2, enhancing our comprehension of disease-associated mutations that interfere with these vital processes, but also shed light on the conformational dynamics of these MFS-type proteins during the transport cycle.
Human feline leukaemia virus subgroup C receptor-related proteins 1 and 2 (FLVCR1 and 2) are major facilitator superfamily transporters from the solute carrier family 49. Dysregulation of these ubiquitous transporters has been linked to various haematological and neurological disorders. While both FLVCRs were initially proposed to hold a physiological function in heme transport, subsequent studies questioned this notion. Here, we used structural, computational and biochemical methods and conclude that these two FLVCRs function as human choline transporters. We present cryo-electron microscopy structures of FLVCRs in different inward- and outward-facing conformations, captured in the apo state or in complex with choline in their translocation pathways. Our findings provide insights into the molecular framework of choline coordination and transport, largely mediated by conserved cation-π interactions, and further illuminate the conformational dynamics of the transport cycle. Moreover, we identified a heme binding site on the protein surface of the FLVCR2 N-domain, and observed that heme actively drives the conformational transitions of the protein. This auxiliary binding site might indicate a potential regulatory role of heme in the FLVCR2 transport mechanisms. Our work resolves the contested substrate specificity of the FLVCRs, and sheds light on the process of maintaining cellular choline homeostasis at the molecular level.
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.
The heterotetrameric human transfer RNA (tRNA) splicing endonuclease (TSEN) catalyzes the excision of intronic sequences from precursor tRNAs (pre-tRNAs)1. Mutations in TSEN and its associated RNA kinase CLP1 are linked to the neurodegenerative disease pontocerebellar hypoplasia (PCH)2–8. The three-dimensional (3D) assembly of TSEN/CLP1, the mechanism of substrate recognition, and the molecular details of PCH-associated mutations are not fully understood. Here, we present cryo-electron microscopy structures of human TSEN with intron-containing pre-tRNATyrgta and pre-tRNAArgtct. TSEN exhibits broad structural homology to archaeal endonucleases9 but has evolved additional regulatory elements that are involved in handling and positioning substrate RNA. Essential catalytic residues of subunit TSEN34 are organized for the 3’ splice site which emerges from a bulge-helix configuration. The triple-nucleotide bulge at the intron/3’-exon boundary is stabilized by an arginine tweezer motif of TSEN2 and an interaction with the proximal minor groove of the helix. TSEN34 and TSEN54 define the 3’ splice site by holding the tRNA body in place. TSEN54 adapts a bipartite fold with a flexible central region required for CLP1 binding. PCH-associated mutations are located far from pre-tRNA binding interfaces explaining their negative impact on structural integrity of TSEN without abrogating its catalytic activity in vitro10. Our work defines the molecular framework of pre-tRNA recognition and cleavage by TSEN and provides a structural basis to better understand PCH in the future.
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 nsP3 macrodomain is a conserved protein interaction module that plays essential regulatory roles in host immune response by recognizing and removing posttranslational ADP-ribosylation sites during SARS-CoV-2 infection. Thus, targeting this protein domain may offer a therapeutic strategy to combat the current and future virus pandemics. To assist inhibitor development efforts, we report here a comprehensive set of macrodomain crystal structures complexed with diverse naturally-occurring nucleotides, small molecules as well as nucleotide analogues including GS-441524 and its phosphorylated analogue, active metabolites of remdesivir. The presented data strengthen our understanding of the SARS-CoV-2 macrodomain structural plasticity and it provides chemical starting points for future inhibitor development.
In response to pathogen infection, gasdermin (GSDM) proteins form membrane pores that induce a host cell death process called pyroptosis1–3. Studies of human and mouse GSDM pores reveal the functions and architectures of 24–33 protomers assemblies4–9, but the mechanism and evolutionary origin of membrane targeting and GSDM pore formation remain unknown. Here we determine a structure of a bacterial GSDM (bGSDM) pore and define a conserved mechanism of pore assembly. Engineering a panel of bGSDMs for site-specific proteolytic activation, we demonstrate that diverse bGSDMs form distinct pore sizes that range from smaller mammalian-like assemblies to exceptionally large pores containing >50 protomers. We determine a 3.3 Å cryo-EM structure of a Vitiosangium bGSDM in an active slinky-like oligomeric conformation and analyze bGSDM pores in a native lipid environment to create an atomic-level model of a full 52-mer bGSDM pore. Combining our structural analysis with molecular dynamics simulations and cellular assays, we define a stepwise model of GSDM pore assembly and demonstrate that pore formation is driven by local unfolding of membrane-spanning β-strand regions and pre-insertion of a covalently bound palmitoyl into the target membrane. These results yield insights into the diversity of GSDM pores found in nature and the function of an ancient post-translational modification in enabling a programmed host cell death process.
Dysfunction of YEATS-domain-containing MLLT1, an acetyl/acyl-lysine dependent epigenetic reader domain, has been implicated in the development of aggressive cancers. Mutations in the YEATS domain have been recently reported as a cause of MLLT1 aberrant reader function. However, structural basis for the reported alterations in affinity for acetyled/acylated histone has remained elusive. Here, we report the crystal structures of both insertion and substitution present in cancer, revealing significant conformational changes of the YEATS-domain loop 8. Structural comparison demonstrates that such alteration not only altered the binding interface for acetylated/acylated histones, but the sequence alterations in the T1 loop may enable dimeric assembly consistent inducing self-association behavior. Nevertheless, we show that also the MLLT1 mutants can be targeted by developed acetyllysine mimetic inhibitors with affinities similarly to wild type. Our report provides a structural basis for the altered behaviors and potential strategy for targeting oncogenic MLLT1 mutants.
Zinc finger (ZnF) domains appear in a pool of structural contexts and despite their small size achieve varying target specificities, covering single-stranded and double-stranded DNA and RNA as well as proteins. Combined with other RNA-binding domains, ZnFs enhance affinity and specificity of RNA-binding proteins (RBPs). The ZnF-containing immunoregulatory RBP Roquin initiates mRNA decay, thereby controlling the adaptive immune system. Its unique ROQ domain shape-specifically recognizes stem-looped cis-elements in mRNA 3’-untranslated regions (UTR). The N-terminus of Roquin contains a RING domain for protein-protein interactions and a ZnF, which was suggested to play an essential role in RNA decay by Roquin. The ZnF domain boundaries, its RNA motif preference and its interplay with the ROQ domain have remained elusive, also driven by the lack of high-resolution data of the challenging protein. We provide the solution structure of the Roquin-1 ZnF and use an RBNS-NMR pipeline to show that the ZnF recognizes AU-rich elements (ARE). We systematically refine the contributions of adenines in a poly(U)-background to specific complex formation. With the simultaneous binding of ROQ and ZnF to a natural target transcript of Roquin, our study for the first time suggests how Roquin integrates RNA shape and sequence specificity through the ROQ-ZnF tandem.
Rhodesain is the lysosomal cathepsin L-like cysteine protease of T. brucei rhodesiense, the causative agent of Human African Trypanosomiasis. The enzyme is essential for the proliferation and pathogenicity of the parasite as well as its ability to overcome the blood-brain barrier of the host. Lysosomal cathepsins are expressed as zymogens with an inactivating pro-domain that is cleaved under acidic conditions. A structure of the uncleaved maturation intermediate from a trypanosomal cathepsin L-like protease is currently not available. We thus established the heterologous expression of T. brucei rhodesiense pro-rhodesain in E. coli and determined its crystal structure. The trypanosomal pro-domain differs from non-parasitic pro-cathepsins by a unique, extended α-helix that blocks the active site and whose interactions resemble that of the antiprotozoal inhibitor K11777. Interdomain dynamics between pro- and core protease domain as observed by photoinduced electron transfer fluorescence correlation spectroscopy increase at low pH, where pro-rhodesain also undergoes autocleavage. Using the crystal structure, molecular dynamics simulations and mutagenesis, we identify a conserved interdomain salt bridge that prevents premature intramolecular cleavage at higher pH values and may thus present a control switch for the observed pH-sensitivity of pro-enzyme cleavage in (trypanosomal) CathL-like proteases.
Salt-inducible kinases (SIKs) are key metabolic regulators. Imbalance of SIK function is associated with the development of diverse cancers, including breast, gastric and ovarian cancer. Chemical tools to clarify the roles of SIK in different diseases are, however, sparse and are generally characterized by poor kinome-wide selectivity. Here, we have adapted the pyrido[2,3-d]pyrimidin-7-one-based PAK inhibitor G-5555 for the targeting of SIK, by exploiting differences in the back-pocket region of these kinases. Optimization was supported by high-resolution crystal structures of G-5555 bound to the known off-targets MST3 and MST4, leading to a chemical probe, MRIA9, with dual SIK/PAK activity and excellent selectivity over other kinases. Furthermore, we show that MRIA9 sensitizes ovarian cancer cells to treatment with the mitotic agent paclitaxel, confirming earlier data from genetic knockdown studies and suggesting a combination therapy with SIK inhibitors and paclitaxel for the treatment of paclitaxel-resistant ovarian cancer.
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.