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We analysed our experimental recent findings of the dipole response of the odd-mass stable nucleus 205Tl within the quasi-particle phonon model. Using the phonon basis constructed for the neighbouring 204Hg and wave function configurations for 205Tl consisting of a mixture of quasiparticle ⊗ N-phonon configurations (N=0,1,2), only one group of fragmented dipole excited states has been reproduced at 5.5 MeV in comparison to the experimental distribution which shows a second group at about 5 MeV. The computed dipole transition strengths are mainly of E1 character which could be associated to the pygmy dipole resonance.
Age-related memory decline is associated with changes in neural functioning but little is known about how aging affects the quality of information representation in the brain. Whereas a long-standing hypothesis of the aging literature links cognitive impairments to less distinct neural representations in old age, memory studies have shown that high similarity between activity patterns benefits memory performance for the respective stimuli. Here, we addressed this apparent conflict by investigating between-item representational similarity in 50 younger (19–27 years old) and 63 older (63–75 years old) human adults (male and female) who studied scene-word associations using a mnemonic imagery strategy while electroencephalography was recorded. We compared the similarity of spatiotemporal frequency patterns elicited during encoding of items with different subsequent memory fate. Compared to younger adults, older adults’ memory representations were more similar to each other but items that elicited the most similar activity patterns early in the encoding trial were those that were best remembered by older adults. In contrast, young adults’ memory performance benefited from decreased similarity between earlier and later periods in the encoding trials, which might reflect their better success in forming unique memorable mental images of the joint picture–word pair. Our results advance the understanding of the representational properties that give rise to memory quality as well as how these properties change in the course of aging.
We have identified a mistake in how Fig. 1 is referenced in the text of the article Eur. Phys. J. C 77 (2017) no. 8, 569 which affected three paragraphs of the results section. The corrected three paragraphs as well as the unmodified accompanying figure are reproduced in this document with the correct labeling.
In addition, an editing issue led to a missing acknowledgements section. The missing section is reproduced at the end of this document in the manner in which it should have appeared in the published article.
Stroke is a major public health issue worldwide. The prevalence of stroke in 2010 was 33 million, with 16.9 million people having a first stroke.1 Stroke was the second‐leading cause of death behind heart disease globally, accounting for over 10% of total deaths worldwide.
Stroke is a heterogeneous condition that can be due to rupture of a blood vessel (hemorrhagic) or to blockage of a vessel (ischemic). About 85% of strokes are ischemic in origin and these are often classified by mechanism. This should be distinguished from risk factors such as hypertension, diabetes, smoking, etc. Risk factors increase the risk of stroke but do not necessarily explain the mechanism of a particular stroke. About 25% of ischemic strokes have a radiographic appearance similar to that seen in patients with cardioembolic sources (such as atrial fibrillation [AF], prosthetic valves, valvular prolapse, or mitral valve regurgitation), but no embolic source is found. These "cryptogenic strokes" (CS; also called embolic strokes of undetermined source) pose a particular clinical challenge in that the optimal antithrombotic therapy to reduce recurrence is uncertain. Since there are currently no data to support long‐term oral anticoagulation (OAC) in CS, but also no specific trials that have addressed this question, guidelines recommend antiplatelet therapy. Identification of AF in these patients changes the most likely mechanism to cardioembolism, and thus changes the recommended antithrombotic therapy to OAC, which is extremely effective in preventing stroke in patients with AF.
This report is based on discussions held at The Diagnostics and Monitoring Stroke Focus Group, a meeting held on January 15 to 17, 2015. The meeting focused on CS as a healthcare issue, and the utility of extended cardiac monitoring for AF in patients with strokes of unknown origin. The objectives of the meeting were to review existing information on the subject, define areas where knowledge was lacking or limited, and discuss study designs by which information gaps might be filled.
The recent approval by the US Food and Drug Administration of ocriplasmin for the treatment of symptomatic vitreomacular adhesion (VMA), often associated with vitreomacular traction (VMT) and macular hole (MH), has brought new attention to the field of pharmacologic vitreolysis. The need for an enzyme to split the vitreomacular interface, which is formed by a strong adhesive interaction between the posterior vitreous cortex and the internal limiting membrane, historically stems from pediatric eye surgery. This review summarizes the different anatomic classifications of posterior vitreous detachment or anomalous posterior vitreous detachment and puts these in the context of clinical pathologies commonly observed in clinical practice of the vitreoretinal specialist, such as MH, VMT, age-related macular degeneration, and diabetic macular edema. We revisit the outcome of the Phase II studies that indicated ocriplasmin was a safe and effective treatment for selected cases of symptomatic VMA and MH. Release of VMA at day 28 was achieved by 26.5% of patients in the ocriplasmin group versus 10.1% in the placebo group (P<0.001). Interestingly, for MHs, the numbers were more remarkable. Predictive factors for successful ocriplasmin treatment were identified for VMT (VMA diameter smaller than 1,500 µm) and MH (smaller than 250 µm). In comparison with the highly predictable outcome after vitrectomy, the general success rate of ocriplasmin not under clinical trial conditions has not fully met expectations and needs to be proven in real-world clinical settings. The ocriplasmin data will be compared in the future with observational data on spontaneous VMA release, will help retina specialists make more accurate predictions, and will improve outcome rates.
The transverse momentum distributions of the strange and double-strange hyperon resonances (Σ(1385)±, Ξ(1530)0) produced in p–Pb collisions at sNN−−−√=5.02 TeV were measured in the rapidity range −0.5<yCMS<0 for event classes corresponding to different charged-particle multiplicity densities, ⟨dNch/dηlab⟩. The mean transverse momentum values are presented as a function of ⟨dNch/dηlab⟩, as well as a function of the particle masses and compared with previous results on hyperon production. The integrated yield ratios of excited to ground-state hyperons are constant as a function of ⟨dNch/dηlab⟩. The equivalent ratios to pions exhibit an increase with ⟨dNch/dηlab⟩, depending on their strangeness content.
The tyrosine kinase inhibitor sunitinib is used as first‐line therapy in patients with metastasized renal cell carcinoma (mRCC), given in fixed‐dose regimens despite its high variability in pharmacokinetics (PKs). Interindividual variability of drug exposure may be responsible for differences in response. Therefore, dosing strategies based on pharmacokinetic/pharmacodynamic (PK/PD) models may be useful to optimize treatment. Plasma concentrations of sunitinib, its active metabolite SU12662, and the soluble vascular endothelial growth factor receptors sVEGFR‐2 and sVEGFR‐3, were measured in 26 patients with mRCC within the EuroTARGET project and 21 patients with metastasized colorectal cancer (mCRC) from the C‐II‐005 study. Based on these observations, PK/PD models with potential influence of genetic predictors were developed and linked to time‐to‐event (TTE) models. Baseline sVEGFR‐2 levels were associated with clinical outcome in patients with mRCC, whereas active drug PKs seemed to be more predictive in patients with mCRC. The models provide the basis of PK/PD‐guided strategies for the individualization of anti‐angiogenic therapies.
The multi-strange baryon yields in Pb--Pb collisions have been shown to exhibit an enhancement relative to pp reactions. In this work, Ξ and Ω production rates have been measured with the ALICE experiment as a function of transverse momentum, pT, in p-Pb collisions at a centre-of-mass energy of sNN−−−√ = 5.02 TeV. The results cover the kinematic ranges 0.6 GeV/c<pT<7.2 GeV/c and 0.8 GeV/c<pT< 5 GeV/c, for Ξ and Ω respectively, in the common rapidity interval -0.5 <yCMS< 0. Multi-strange baryons have been identified by reconstructing their weak decays into charged particles. The pT spectra are analysed as a function of event charged-particle multiplicity, which in p-Pb collisions ranges over one order of magnitude and lies between those observed in pp and Pb-Pb collisions. The measured pT distributions are compared to the expectations from a Blast-Wave model. The parameters which describe the production of lighter hadron species also describe the hyperon spectra in high multiplicity p-Pb. The yield of hyperons relative to charged pions is studied and compared with results from pp and Pb-Pb collisions. A statistical model is employed, which describes the change in the ratios with volume using a canonical suppression mechanism, in which the small volume causes a species-dependent relative reduction of hadron production. The calculations, in which the magnitude of the effect depends on the strangeness content, show good qualitative agreement with the data.
Evolution of nematic fluctuations in CaK(Fe1−xNix)4As4 with spin-vortex crystal magnetic order
(2020)
The CaK(Fe1−xNix)4As4 superconductors resemble the archetypal 122-type iron-based materials but have a crystal structure with distinctly lower symmetry. This family hosts one of the few examples of the so-called spin-vortex crystal magnetic order, a non-collinear magnetic configuration that preserves tetragonal symmetry, in contrast to the orthorhombic collinear stripe-type magnetic configuration common to the 122-type systems. Thus, nematic order is completely absent from its phase diagram. To investigate the evolution of nematic fluctuations in such a case, we present elastoresistance and elastic modulus measurements in CaK(Fe1−xNix)4As4 (x=0−0.05) combined with phenomenological modeling and density functional theory. We find clear experimental signatures of considerable nematic fluctuations, including softening of the Young's modulus Y[110] and a Curie-Weiss type divergence of the B2g elastoresistance coefficient in CaK(Fe0.951Ni0.049)4As4. Overall, nematic fluctuations within this series bear strong similarities to the hole-doped Ba1−xKxFe2As2 series, including a substitution-induced sign change. Our theoretical analysis addresses the effect of the specific crystal symmetry of the 1144-type structure in determining its magnetic ground state and on the nematic fluctuations.
Structure and regulatory interactions of the cytoplasmic terminal domains of serotonin transporter
(2014)
Uptake of neurotransmitters by sodium-coupled monoamine transporters of the NSS family is required for termination of synaptic transmission. Transport is tightly regulated by protein–protein interactions involving the small cytoplasmic segments at the amino- and carboxy-terminal ends of the transporter. Although structures of homologues provide information about the transmembrane regions of these transporters, the structural arrangement of the terminal domains remains largely unknown. Here, we combined molecular modeling, biochemical, and biophysical approaches in an iterative manner to investigate the structure of the 82-residue N-terminal and 30-residue C-terminal domains of human serotonin transporter (SERT). Several secondary structures were predicted in these domains, and structural models were built using the Rosetta fragment-based methodology. One-dimensional 1H nuclear magnetic resonance and circular dichroism spectroscopy supported the presence of helical elements in the isolated SERT N-terminal domain. Moreover, introducing helix-breaking residues within those elements altered the fluorescence resonance energy transfer signal between terminal cyan fluorescent protein and yellow fluorescent protein tags attached to full-length SERT, consistent with the notion that the fold of the terminal domains is relatively well-defined. Full-length models of SERT that are consistent with these and published experimental data were generated. The resultant models predict confined loci for the terminal domains and predict that they move apart during the transport-related conformational cycle, as predicted by structures of homologues and by the “rocking bundle” hypothesis, which is consistent with spectroscopic measurements. The models also suggest the nature of binding to regulatory interaction partners. This study provides a structural context for functional and regulatory mechanisms involving SERT terminal domains.
Ubiquitin (Ub)-mediated regulation of plasmalemmal ion channel activity canonically occurs via stimulation of endocytosis. Whether ubiquitination can modulate channel activity by alternative mechanisms remains unknown. Here, we show that the transient receptor potential vanilloid 4 (TRPV4) cation channel is multiubiquitinated within its cytosolic N-terminal and C-terminal intrinsically disordered regions (IDRs). Mutagenizing select lysine residues to block ubiquitination of the N-terminal but not C-terminal IDR resulted in a marked elevation of TRPV4-mediated intracellular calcium influx, without increasing cell surface expression levels. Conversely, enhancing TRPV4 ubiquitination via expression of an E3 Ub ligase reduced TRPV4 channel activity but did not decrease plasma membrane abundance. These results demonstrate Ub-dependent regulation of TRPV4 channel function independent of effects on plasma membrane localization. Consistent with ubiquitination playing a key negative modulatory role of the channel, gain-of-function neuropathy-causing mutations in the TRPV4 gene led to reduced channel ubiquitination in both cellular and Drosophila models of TRPV4 neuropathy, whereas increasing mutant TRPV4 ubiquitination partially suppressed channel overactivity. Together, these data reveal a novel mechanism via which ubiquitination of an intracellular flexible IDR domain modulates ion channel function independently of endocytic trafficking and identify a contributory role for this pathway in the dysregulation of TRPV4 channel activity by neuropathy-causing mutations.
Particle identification is an important feature of the ALICE detector at the LHC. In particular, for particle identification via the time-of-flight technique, the precise determination of the event collision time represents an important ingredient of the quality of the measurement. In this paper, the different methods used for such a measurement in ALICE by means of the T0 and the TOF detectors are reviewed. Efficiencies, resolution and the improvement of the particle identification separation power of the methods used are presented for the different LHC colliding systems (pp , p-Pb and Pb-Pb) during the first period of data taking of LHC (Run 1).
Neural pattern similarity differentially relates to memory performance in younger and older adults
(2019)
Age-related memory decline is associated with changes in neural functioning, but little is known about how aging affects the quality of information representation in the brain. Whereas a long-standing hypothesis of the aging literature links cognitive impairments to less distinct neural representations in old age (“neural dedifferentiation”), memory studies have shown that overlapping neural representations of different studied items are beneficial for memory performance. In an electroencephalography (EEG) study, we addressed the question whether distinctiveness or similarity between patterns of neural activity supports memory differentially in younger and older adults. We analyzed between-item neural pattern similarity in 50 younger (19–27 years old) and 63 older (63–75 years old) male and female human adults who repeatedly studied and recalled scene–word associations using a mnemonic imagery strategy. We compared the similarity of spatiotemporal EEG frequency patterns during initial encoding in relation to subsequent recall performance. The within-person association between memory success and pattern similarity differed between age groups: For older adults, better memory performance was linked to higher similarity early in the encoding trials, whereas young adults benefited from lower similarity between earlier and later periods during encoding, which might reflect their better success in forming unique memorable mental images of the joint picture–word pairs. Our results advance the understanding of the representational properties that give rise to subsequent memory, as well as how these properties may change in the course of aging.
TRIANNI mice carry an entire set of human immunoglobulin V region gene segments and are a powerful tool to rapidly isolate human monoclonal antibodies. After immunizing these mice with DNA encoding the spike protein of SARS-CoV-2 and boosting with spike protein, we identified 29 hybridoma antibodies that reacted with the SARS-CoV-2 spike protein. Nine antibodies neutralize SARS-CoV-2 infection at IC50 values in the subnanomolar range. ELISA-binding studies and DNA sequence analyses revealed one cluster of three clonally related neutralizing antibodies that target the receptor-binding domain and compete with the cellular receptor hACE2. A second cluster of six clonally related neutralizing antibodies bind to the N-terminal domain of the spike protein without competing with the binding of hACE2 or cluster 1 antibodies. SARS-CoV-2 mutants selected for resistance to an antibody from one cluster are still neutralized by an antibody from the other cluster. Antibodies from both clusters markedly reduced viral spread in mice transgenic for human ACE2 and protected the animals from SARS-CoV-2-induced weight loss. The two clusters of potent noncompeting SARS-CoV-2 neutralizing antibodies provide potential candidates for therapy and prophylaxis of COVID-19. The study further supports transgenic animals with a human immunoglobulin gene repertoire as a powerful platform in pandemic preparedness initiatives.
Background: In the context of the investigation of the quark gluon plasma produced in heavy-ion collisions, hadrons containing heavy (charm or beauty) quarks play a special role for the characterization of the hot and dense medium created in the interaction. The measurement of the production of charm and beauty hadrons in proton–proton collisions, besides providing the necessary reference for the studies in heavy-ion reactions, constitutes an important test of perturbative quantum chromodynamics (pQCD) calculations. Heavy-flavor production in proton–nucleus collisions is sensitive to the various effects related to the presence of nuclei in the colliding system, commonly denoted cold-nuclear-matter effects. Most of these effects are expected to modify open-charm production at low transverse momenta (pT) and, so far, no measurement of D-meson production down to zero transverse momentum was available at mid-rapidity at the energies attained at the CERN Large Hadron Collider (LHC).
Purpose: The measurements of the production cross sections of promptly produced charmed mesons in p-Pb collisions at the LHC down to pT=0 and the comparison to the results from pp interactions are aimed at the assessment of cold-nuclear-matter effects on open-charm production, which is crucial for the interpretation of the results from Pb-Pb collisions.
Methods: The prompt charmed mesons D0,D+,D*+, and D+s were measured at mid-rapidity in p-Pb collisions at a center-of-mass energy per nucleon pair √sNN=5.02 TeV with the ALICE detector at the LHC. D mesons were reconstructed from their decays D0→K−π+,D+→K−π+π+, D*+→D0π+,D+s→ϕπ+→K−K+π+, and their charge conjugates, using an analysis method based on the selection of decay topologies displaced from the interaction vertex. In addition, the prompt D0 production cross section was measured in pp collisions at √s=7 TeV and p-Pb collisions at √sNN=5.02 TeV down to pT=0 using an analysis technique that is based on the estimation and subtraction of the combinatorial background, without reconstruction of the D0 decay vertex.
Results: The production cross section in pp collisions is described within uncertainties by different implementations of pQCD calculations down to pT=0. This allowed also a determination of the total c¯c production cross section in pp collisions, which is more precise than previous ALICE measurements because it is not affected by uncertainties owing to the extrapolation to pT=0. The nuclear modification factor RpPb(pT), defined as the ratio of the pT-differential D meson cross section in p-Pb collisions and that in pp collisions scaled by the mass number of the Pb nucleus, was calculated for the four D-meson species and found to be compatible with unity within uncertainties. The results are compared to theoretical calculations that include cold-nuclear-matter effects and to transport model calculations incorporating the interactions of charm quarks with an expanding deconfined medium.
Conclusions: These measurements add experimental evidence that the modification of the D-meson transverse momentum distributions observed in Pb–Pb collisions with respect to pp interactions is due to strong final-state effects induced by the interactions of the charm quarks with the hot and dense partonic medium created in ultrarelativistic heavy-ion collisions. The current precision of the measurement does not allow us to draw conclusions on the role of the different cold-nuclear-matter effects and on the possible presence of additional hot-medium effects in p-Pb collisions. However, the analysis technique without decay-vertex reconstruction, applied on future larger data samples, should provide access to the physics-rich range down to pT=0.
The production cross sections of the prompt charmed mesons D0, D+, D∗+ and Ds were measured at mid-rapidity in p-Pb collisions at a centre-of-mass energy per nucleon pair sNN−−−√=5.02 TeV with the ALICE detector at the LHC. D mesons were reconstructed from their decays D0→K−π+, D+→K−π+π+, D∗+→D0π+, D+s→ϕπ+→K−K+π+, and their charge conjugates. The pT-differential production cross sections were measured at mid-rapidity in the interval 1<pT<24 GeV/c for D0, D+ and D∗+ mesons and in 2<pT<12 GeV/c for Ds mesons, using an analysis method based on the selection of decay topologies displaced from the interaction vertex. The production cross sections of the D0, D+ and D∗+ mesons were also measured in three pT intervals as a function of the rapidity ycms in the centre-of-mass system in −1.26<ycms<0.34. In addition, the prompt D0 cross section was measured in pp collisions at s√=7 TeV and p-Pb collisions at sNN−−−√=5.02 TeV down to pT=0 using an analysis technique that is based on the estimation and subtraction of the combinatorial background, without reconstruction of the D0 decay vertex. The nuclear modification factor RpPb(pT), defined as the ratio of the pT-differential D-meson cross section in p-Pb collisions and that in pp collisions scaled by the mass number of the Pb nucleus, was calculated for the four D-meson species and found to be compatible with unity within experimental uncertainties. The results are compared to theoretical calculations that include cold-nuclear-matter effects and to transport model calculations incorporating the interactions of charm quarks with an expanding deconfined medium.
The production cross sections of the prompt charmed mesons D0, D+, D∗+ and Ds were measured at mid-rapidity in p-Pb collisions at a centre-of-mass energy per nucleon pair sNN−−−√=5.02 TeV with the ALICE detector at the LHC. D mesons were reconstructed from their decays D0→K−π+, D+→K−π+π+, D∗+→D0π+, D+s→ϕπ+→K−K+π+, and their charge conjugates. The pT-differential production cross sections were measured at mid-rapidity in the interval 1<pT<24 GeV/c for D0, D+ and D∗+ mesons and in 2<pT<12 GeV/c for Ds mesons, using an analysis method based on the selection of decay topologies displaced from the interaction vertex. The production cross sections of the D0, D+ and D∗+ mesons were also measured in three pT intervals as a function of the rapidity ycms in the centre-of-mass system in −1.26<ycms<0.34. In addition, the prompt D0 cross section was measured in pp collisions at s√=7 TeV and p-Pb collisions at sNN−−−√=5.02 TeV down to pT=0 using an analysis technique that is based on the estimation and subtraction of the combinatorial background, without reconstruction of the D0 decay vertex. The nuclear modification factor RpPb(pT), defined as the ratio of the pT-differential D-meson cross section in p-Pb collisions and that in pp collisions scaled by the mass number of the Pb nucleus, was calculated for the four D-meson species and found to be compatible with unity within experimental uncertainties. The results are compared to theoretical calculations that include cold-nuclear-matter effects and to transport model calculations incorporating the interactions of charm quarks with an expanding deconfined medium.
The measurement of prompt D-meson production as a function of multiplicity in p-Pb collisions at sNN−−−√=5.02 TeV with the ALICE detector at the LHC is reported. D0, D+ and D∗+ mesons are reconstructed via their hadronic decay channels in the centre-of-mass rapidity range −0.96<ycms<0.04 and transverse momentum interval 1<pT<24 GeV/c. The multiplicity dependence of D-meson production is examined by either comparing yields in p-Pb collisions in different event classes, selected based on the multiplicity of produced particles or zero-degree energy, with those in pp collisions, scaled by the number of binary nucleon-nucleon collisions (nuclear modification factor); as well as by evaluating the per-event yields in p-Pb collisions in different multiplicity intervals normalised to the multiplicity-integrated ones (relative yields). The nuclear modification factors for D0, D+ and D∗+ are consistent with one another. The D-meson nuclear modification factors as a function of the zero-degree energy are consistent with unity within uncertainties in the measured pT regions and event classes. The relative D-meson yields, calculated in various pT intervals, increase as a function of the charged-particle multiplicity. The results are compared with the equivalent pp measurements at s√=7 TeV as well as with EPOS~3 calculations.