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Autophagosome biogenesis requires a localized perturbation of lipid membrane dynamics and a unique protein-lipid conjugate. Autophagy-related (ATG) proteins catalyze this biogenesis on cellular membranes, but the underlying molecular mechanism remains unclear. Focusing on the final step of the protein-lipid conjugation reaction, ATG8/LC3 lipidation, we show how membrane association of the conjugation machinery is organized and fine-tuned at the atomistic level. Amphipathic α-helices in ATG3 proteins (AHATG3) are found to have low hydrophobicity and to be less bulky. Molecular dynamics simulations reveal that AHATG3 regulates the dynamics and accessibility of the thioester bond of the ATG3∼LC3 conjugate to lipids, allowing covalent lipidation of LC3. Live cell imaging shows that the transient membrane association of ATG3 with autophagic membranes is governed by the less bulky- hydrophobic feature of AHATG3. Collectively, the unique properties of AHATG3 facilitate protein- lipid bilayer association leading to the remodeling of the lipid bilayer required for the formation of autophagosomes.
It is currently not known how distributed neuronal responses in early visual areas carry stimulus-related information. We made multielectrode recordings from cat primary visual cortex and applied methods from machine learning in order to analyze the temporal evolution of stimulus-related information in the spiking activity of large ensembles of around 100 neurons. We used sequences of up to three different visual stimuli (letters of the alphabet) presented for 100 ms and with intervals of 100 ms or larger. Most of the information about visual stimuli extractable by sophisticated methods of machine learning, i.e., support vector machines with nonlinear kernel functions, was also extractable by simple linear classification such as can be achieved by individual neurons. New stimuli did not erase information about previous stimuli. The responses to the most recent stimulus contained about equal amounts of information about both this and the preceding stimulus. This information was encoded both in the discharge rates (response amplitudes) of the ensemble of neurons and, when using short time constants for integration (e.g., 20 ms), in the precise timing of individual spikes (<= ~20 ms), and persisted for several 100 ms beyond the offset of stimuli. The results indicate that the network from which we recorded is endowed with fading memory and is capable of performing online computations utilizing information about temporally sequential stimuli. This result challenges models assuming frame-by-frame analyses of sequential inputs.
We study odd parity J=1/2 and J=3/2 Ξc resonances using a unitarized coupled-channel framework based on a SU(6)lsf×HQSS-extended Weinberg–Tomozawa baryon–meson interaction, while paying a special attention to the renormalization procedure. We predict a large molecular ΛcK¯ component for the Ξc(2790) with a dominant 0− light-degree-of-freedom spin configuration. We discuss the differences between the 3/2− Λc(2625) and Ξc(2815) states, and conclude that they cannot be SU(3) siblings, whereas we predict the existence of other Ξc-states, one of them related to the two-pole structure of the Λc(2595). It is of particular interest a pair of J=1/2 and J=3/2 poles, which form a HQSS doublet and that we tentatively assign to the Ξc(2930) and Ξc(2970), respectively. Within this picture, the Ξc(2930) would be part of a SU(3) sextet, containing either the Ωc(3090) or the Ωc(3119), and that would be completed by the Σc(2800). Moreover, we identify a J=1/2 sextet with the Ξb(6227) state and the recently discovered Σb(6097). Assuming the equal spacing rule and to complete this multiplet, we predict the existence of a J=1/2 Ωb odd parity state, with a mass of 6360 MeV and that should be seen in the ΞbK¯ channel.
In this letter we present some stringy corrections to black hole spacetimes emerging from string T-duality. As a first step, we derive the static Newtonian potential by exploiting the relation between the T-duality and the path integral duality. We show that the intrinsic non-perturbative nature of stringy corrections introduces an ultraviolet cutoff known as zero-point length in the path integral duality literature. As a result, the static potential is found to be regular. We use this result to derive a consistent black hole metric for the spherically symmetric, electrically neutral case. It turns out that the new spacetime is regular and is formally equivalent to the Bardeen metric, apart from a different ultraviolet regulator. On the thermodynamics side, the Hawking temperature admits a maximum before a cooling down phase towards a thermodynamically stable end of the black hole evaporation process. The findings support the idea of universality of quantum black holes.
In this Letter, we propose a new scenario emerging from the conjectured presence of a minimal length ℓ in the spacetime fabric, on the one side, and the existence of a new scale invariant, continuous mass spectrum, of un-particles on the other side. We introduce the concept of un-spectral dimension DU of a d-dimensional, euclidean (quantum) spacetime, as the spectral dimension measured by an “un-particle” probe. We find a general expression for the un-spectral dimension DU labelling different spacetime phases: a semi-classical phase, where ordinary spectral dimension gets contribution from the scaling dimension dU of the un-particle probe; a critical “Planckian phase”, where four-dimensional spacetime can be effectively considered two-dimensional when dU=1; a “Trans-Planckian phase”, which is accessible to un-particle probes only, where spacetime as we currently understand it looses its physical meaning.
This paper studies the geometry and the thermodynamics of a holographic screen in the framework of the ultraviolet self-complete quantum gravity. To achieve this goal we construct a new static, neutral, nonrotating black hole metric, whose outer (event) horizon coincides with the surface of the screen. The spacetime admits an extremal configuration corresponding to the minimal holographic screen and having both mass and radius equalling the Planck units. We identify this object as the spacetime fundamental building block, whose interior is physically unaccessible and cannot be probed even during the Hawking evaporation terminal phase. In agreement with the holographic principle, relevant processes take place on the screen surface. The area quantization leads to a discrete mass spectrum. An analysis of the entropy shows that the minimal holographic screen can store only one byte of information, while in the thermodynamic limit the area law is corrected by a logarithmic term.
In this paper we discuss to what extent one can infer details of the interior structure of a black hole based on its horizon. Recalling that black hole thermal properties are connected to the non-classical nature of gravity, we circumvent the restrictions of the no-hair theorem by postulating that the black hole interior is singularity free due to violations of the usual energy conditions. Further these conditions allow one to establish a one-to-one, holographic projection between Planckian areal “bits” on the horizon and “voxels”, representing the gravitational degrees of freedom in the black hole interior. We illustrate the repercussions of this idea by discussing an example of the black hole interior consisting of a de Sitter core postulated to arise from the local graviton quantum vacuum energy. It is shown that the black hole entropy can emerge as the statistical entropy of a gas of voxels.
In this Letter we study the radiation measured by an accelerated detector, coupled to a scalar field, in the presence of a fundamental minimal length. The latter is implemented by means of a modified momentum space Green's function. After calibrating the detector, we find that the net flux of field quanta is negligible, and that there is no Planckian spectrum. We discuss possible interpretations of this result, and we comment on experimental implications in heavy ion collisions and atomic systems.
In the presence of a minimal length, physical objects cannot collapse to an infinite density, singular, matter point. In this paper, we consider the possible final stage of the gravitational collapse of "thick" matter layers. The energy momentum tensor we choose to model these shell-like objects is a proper modification of the source for "noncommutative geometry inspired," regular black holes. By using higher momenta of Gaussian distribution to localize matter at finite distance from the origin, we obtain new solutions of the Einstein equation which smoothly interpolates between Minkowski's geometry near the center of the shell and Schwarzschild’s spacetime far away from the matter layer. The metric is curvature singularity free. Black hole type solutions exist only for "heavy" shells; that is, M >= Me, where Me is the mass of the extremal configuration. We determine the Hawking temperature and a modified area law taking into account the extended nature of the source.
The Karl Schwarzschild Meeting 2017 (KSM2017) has been the third instalment of the conference dedicated to the great Frankfurter scientist, who derived the first black hole solution of Einstein's equations about 100 years ago.
The event has been a 5 day meeting in the field of black holes, AdS/CFT correspondence and gravitational physics. Like the two previous instalments, the conference continued to attract a stellar ensemble of participants from the world's most renowned institutions. The core of the meeting has been a series of invited talks from eminent experts (keynote speakers) as well as the presence of plenary research talks by students and junior speakers.
List of Conference photo and poster, Sponsors and funding acknowledgments, Committees and List of participants are available in this PDF.
We present an analysis of the role of the charge within the self-complete quantum gravity paradigm. By studying the classicalization of generic ultraviolet improved charged black hole solutions around the Planck scale, we showed that the charge introduces important differences with respect to the neutral case. First, there exists a family of black hole parameters fulfilling the particle-black hole condition. Second, there is no extremal particle-black hole solution but quasi extremal charged particle-black holes at the best. We showed that the Hawking emission disrupts the condition of particle-black hole. By analyzing the Schwinger pair production mechanism, the charge is quickly shed and the particle-black hole condition can ultimately be restored in a cooling down phase towards a zero temperature configuration, provided non-classical effects are taken into account.
In this paper, we present an overview of some of the existing issues of the research in quantum gravity. We also introduce the basic ideas that led Padmanabhan to consider a duality property in path integrals. Such a duality is consistent with the T-duality in string theory. More importantly, the path integral duality discloses a universal feature of any quantum geometry, namely the existence of a zero point length L0. We also comment about recent developments aiming to expose effects of the zero point length in strong electrodynamics and black holes. There are reasons to believe that the main characters of the phenomenology of quantum gravity may be described by means of a single parameter like L0.
From August to November 2017, Madagascar endured an outbreak of plague. A total of 2417 cases of plague were confirmed, causing a death toll of 209. Public health intervention efforts were introduced and successfully stopped the epidemic at the end of November. The plague, however, is endemic in the region and occurs annually, posing the risk of future outbreaks. To understand the plague transmission, we collected real-time data from official reports, described the outbreak's characteristics, and estimated transmission parameters using statistical and mathematical models. The pneumonic plague epidemic curve exhibited multiple peaks, coinciding with sporadic introductions of new bubonic cases. Optimal climate conditions for rat flea to flourish were observed during the epidemic. Estimate of the plague basic reproduction number during the large wave of the epidemic was high, ranging from 5 to 7 depending on model assumptions. The incubation and infection periods for bubonic and pneumonic plague were 4.3 and 3.4 days and 3.8 and 2.9 days, respectively. Parameter estimation suggested that even with a small fraction of the population exposed to infected rat fleas (1/10,000) and a small probability of transition from a bubonic case to a secondary pneumonic case (3%), the high human-to-human transmission rate can still generate a large outbreak. Controlling rodent and fleas can prevent new index cases, but managing human-to-human transmission is key to prevent large-scale outbreaks.
Background: Recent epidemics have entailed global discussions on revamping epidemic control and prevention approaches. A general consensus is that all sources of data should be embraced to improve epidemic preparedness. As a disease transmission is inherently governed by individual-level responses, pathogen dynamics within infected hosts posit high potentials to inform population-level phenomena. We propose a multiscale approach showing that individual dynamics were able to reproduce population-level observations.
Methods: Using experimental data, we formulated mathematical models of pathogen infection dynamics from which we simulated mechanistically its transmission parameters. The models were then embedded in our implementation of an age-specific contact network that allows to express individual differences relevant to the transmission processes. This approach is illustrated with an example of Ebola virus (EBOV).
Results: The results showed that a within-host infection model can reproduce EBOV’s transmission parameters obtained from population data. At the same time, population age-structure, contact distribution and patterns can be expressed using network generating algorithm. This framework opens a vast opportunity to investigate individual roles of factors involved in the epidemic processes. Estimating EBOV’s reproduction number revealed a heterogeneous pattern among age-groups, prompting cautions on estimates unadjusted for contact pattern. Assessments of mass vaccination strategies showed that vaccination conducted in a time window from five months before to one week after the start of an epidemic appeared to strongly reduce epidemic size. Noticeably, compared to a non-intervention scenario, a low critical vaccination coverage of 33% cannot ensure epidemic extinction but could reduce the number of cases by ten to hundred times as well as lessen the case-fatality rate.
Conclusions: Experimental data on the within-host infection have been able to capture upfront key transmission parameters of a pathogen; the applications of this approach will give us more time to prepare for potential epidemics. The population of interest in epidemic assessments could be modelled with an age-specific contact network without exhaustive amount of data. Further assessments and adaptations for different pathogens and scenarios to explore multilevel aspects in infectious diseases epidemics are underway.
Ebola virus (EBOV) infection causes a high death toll, killing a high proportion of EBOV-infected patients within 7 days. Comprehensive data on EBOV infection are fragmented, hampering efforts in developing therapeutics and vaccines against EBOV. Under this circumstance, mathematical models become valuable resources to explore potential controlling strategies. In this paper, we employed experimental data of EBOV-infected nonhuman primates (NHPs) to construct a mathematical framework for determining windows of opportunity for treatment and vaccination. Considering a prophylactic vaccine based on recombinant vesicular stomatitis virus expressing the EBOV glycoprotein (rVSV-EBOV), vaccination could be protective if a subject is vaccinated during a period from one week to four months before infection. For the case of a therapeutic vaccine based on monoclonal antibodies (mAbs), a single dose might resolve the invasive EBOV replication even if it was administrated as late as four days after infection. Our mathematical models can be used as building blocks for evaluating therapeutic and vaccine modalities as well as for evaluating public health intervention strategies in outbreaks. Future laborator experiments will help to validate and refine the estimates of the windows of opportunity proposed here.
Driven by the loss of energy, isolated rotating neutron stars (pulsars) are gradually slowing down to lower frequencies, which increases the tremendous compression of the matter inside of them. This increase in compression changes both the global properties of rotating neutron stars as well as their hadronic core compositions. Both effects may register themselves observationally in the thermal evolution of such stars, as demonstrated in this Letter. The rotation-driven particle process which we consider here is the direct Urca (DU) process, which is known to become operative in neutron stars if the number of protons in the stellar core exceeds a critical limit of around 11% to 15%. We find that neutron stars spinning down from moderately high rotation rates of a few hundred Hertz may be creating just the right conditions where the DU process becomes operative, leading to an observable effect (enhanced cooling) in the temperature evolution of such neutron stars. As it turns out, the rotation-driven DU process could explain the unusual temperature evolution observed for the neutron star in Cas A, provided the mass of this neutron star lies in the range of 1.5 to 1.9M⊙ and its rotational frequency at birth was between 40 (400 Hz) and 70% (800 Hz) of the Kepler (mass shedding) frequency, respectively.
Background: After induction of DNA double strand breaks (DSBs), the DNA damage response (DDR) is activated. One of the earliest events in DDR is the phosphorylation of serine 139 on the histone variant H2AX (gH2AX) catalyzed by phosphatidylinositol 3-kinases-related kinases. Despite being extensively studied, H2AX distribution[1] across the genome and gH2AX spreading around DSBs sites[2] in the context of different chromatin compaction states or transcription are yet to be fully elucidated.
Materials and methods: gH2AX was induced in human hepatocellular carcinoma cells (HepG2) by exposure to 10 Gy X-rays (250 kV, 16 mA). Samples were incubated 0.5, 3 or 24 hours post irradiation to investigate early, intermediate and late stages of DDR, respectively. Chromatin immunoprecipitation was performed to select H2AX, H3 and gH2AX-enriched chromatin fractions. Chromatin-associated DNA was then sequenced by Illumina ChIP-Seq platform. HepG2 gene expression and histone modification (H3K36me3, H3K9me3) ChIP-Seq profiles were retrieved from Gene Expression Omnibus (accession numbers GSE30240 and GSE26386, respectively).
Results: First, we combined G/C usage, gene content, gene expression or histone modification profiles (H3K36me3, H3K9me3) to define genomic compartments characterized by different chromatin compaction states or transcriptional activity. Next, we investigated H3, H2AX and gH2AX distributions in such defined compartments before and after exposure to ionizing radiation (IR) to study DNA repair kinetics during DDR. Our sequencing results indicate that H2AX distribution followed H3 occupancy and, thus, the nucleosome pattern. The highest H2AX and H3 enrichment was observed in transcriptionally active compartments (euchromatin) while the lowest was found in low G/C and gene-poor compartments (heterochromatin). Under physiological conditions, the body of highly and moderately transcribed genes was devoid of gH2AX, despite presenting high H2AX levels. gH2AX accumulation was observed in 5’ or 3’ flanking regions, instead. The same genes showed a prompt gH2AX accumulation during the early stage of DDR which then decreased over time as DDR proceeded.
Finally, during the late stage of DDR the residual gH2AX signal was entirely retained in heterochromatic compartments. At this stage, euchromatic compartments were completely devoid of gH2AX despite presenting high levels of non-phosphorylated H2AX.
Conclusions: We show that gH2AX distribution ultimately depends on H2AX occupancy, the latter following H3 occupancy and, thus, nucleosome pattern. Both H2AX and H3 levels were higher in actively transcribed compartments. However, gH2AX levels were remarkably low over the body of actively transcribed genes suggesting that transcription levels antagonize gH2AX spreading. Moreover, repair processes did not take place uniformly across the genome; rather, DNA repair was affected by genomic location and transcriptional activity. We propose that higher H2AX density in euchromaticcompartments results in high relative gH2AXconcentration soon after the activation of DDR, thus favoring the recruitment of the DNA repair machinery to those compartments. When the damage is repaired and gH2AX is removed, its residual fraction is retained in the heterochromatic compartments which are then targeted and repaired at later times.
We present the current status of hybrid approaches to describe heavy ion collisions and their future challenges and perspectives. First we present a hybrid model combining a Boltzmann transport model of hadronic degrees of freedom in the initial and final state with an optional hydrodynamic evolution during the dense and hot phase. Second, we present a recent extension of the hydrodynamical model to include fluctuations near the phase transition by coupling a chiral field to the hydrodynamic evolution.
Background: In this interdisciplinary project, the biological effects of heavy ions are compared to those of X-rays using tissue slice culture preparations from rodents and humans. Advantages of this biological model are the conservation of an organotypic environment and the independency from genetic immortalization strategies used to generate cell lines. Its open access allows easy treatment and observation via live-imaging microscopy. Materials and methods: Rat brains and human brain tumor tissue are cut into 300 micro m thick tissue slices. These slices are cultivated using a membrane-based culture system and kept in an incubator at 37°C until treatment. The slices are treated with X-rays at the radiation facility of the University Hospital in Frankfurt at doses of up to 40 Gy. The heavy ion irradiations were performed at the UNILAC facility at GSI with different ions of 11.4 A MeV and fluences ranging from 0.5–10 x 106 particles/cm². Using 3D-confocal microscopy, cell-death and immune cell activation of the irradiated slices are analyzed. Planning of the irradiation experiments is done with simulation programs developed at GSI and FIAS. Results: After receiving a single application of either X-rays or heavy ions, slices were kept in culture for up to 9d post irradiation. DNA damage was visualized using gamma H2AXstaining. Here, a dose-dependent increase and time-dependent decrease could clearly be observed for the X-ray irradiation. Slices irradiated with heavy ions showed less gamma H2AX-positive cells distributed evenly throughout the slice, even though particles were calculated to penetrate only 90–100 micro m into the slice. Conclusions: Single irradiations of brain tissue, even at high doses of 40 Gy, will result neither in tissue damage visible on a macroscopic level nor necrosis. This is in line with the view that the brain is highly radio-resistant. However, DNA damage can be detected very well in tissue slices using gamma H2AX-immuno staining. Thus, slice cultures are an excellent tool to study radiation-induced damage and repair mechanisms in living tissues.
A considerable effort has been dedicated recently to the construction of generic equations of state (EOSs) for matter in neutron stars. The advantage of these approaches is that they can provide model-independent information on the interior structure and global properties of neutron stars. Making use of more than 106 generic EOSs, we assess the validity of quasi-universal relations of neutron-star properties for a broad range of rotation rates, from slow rotation up to the mass-shedding limit. In this way, we are able to determine with unprecedented accuracy the quasi-universal maximum-mass ratio between rotating and nonrotating stars and reveal the existence of a new relation for the surface oblateness, i.e., the ratio between the polar and equatorial proper radii. We discuss the impact that our findings have on the imminent detection of new binary neutron-star mergers and how they can be used to set new and more stringent limits on the maximum mass of nonrotating neutron stars, as well as to improve the modeling of the X-ray emission from the surface of rotating stars.