Refine
Year of publication
- 2021 (208) (remove)
Document Type
- Preprint (208) (remove)
Language
- English (208)
Has Fulltext
- yes (208) (remove)
Is part of the Bibliography
- no (208)
Keywords
- 26 LncRNA (1)
- Acinetobacter baumannii (1)
- Amblyopia (1)
- BRAF (1)
- Bestattung (1)
- Binocular Rivalry (1)
- Brauchtum (1)
- Browsertool (1)
- Buparlisib (1)
- COVID-19 (1)
Institute
- Physik (135)
- Frankfurt Institute for Advanced Studies (FIAS) (102)
- Informatik (98)
- Medizin (32)
- Ernst Strüngmann Institut (7)
- Psychologie (7)
- Senckenbergische Naturforschende Gesellschaft (6)
- Buchmann Institut für Molekulare Lebenswissenschaften (BMLS) (5)
- Institut für Ökologie, Evolution und Diversität (5)
- MPI für Hirnforschung (5)
The production of ϕ mesons has been studied in pp collisions at LHC energies with the ALICE detector via the dimuon decay channel in the rapidity region 2.5<y<4. Measurements of the differential cross section d2σ/dydpT are presented as a function of the transverse momentum (pT) at the center-of-mass energies s√=5.02, 8 and 13 TeV and compared with the ALICE results at midrapidity. The differential cross sections at s√=5.02 and 13 TeV are also studied in several rapidity intervals as a function of pT, and as a function of rapidity in three pT intervals. A hardening of the pT-differential cross section with the collision energy is observed, while, for a given energy, pT spectra soften with increasing rapidity and, conversely, rapidity distributions get slightly narrower at increasing pT. The new results, complementing the published measurements at s√=2.76 and 7 TeV, allow one to establish the energy dependence of ϕ meson production and to compare the measured cross sections with phenomenological models. None of the considered models manages to describe the evolution of the cross section with pT and rapidity at all the energies.
A measurement of the inclusive b-jet production cross section is presented in pp and p-Pb collisions at sNN−−−√=5.02 TeV, using data collected with the ALICE detector at the LHC. The jets were reconstructed in the central rapidity region |η|<0.5 from charged particles using the anti-kT algorithm with resolution parameter R=0.4. Identification of b jets exploits the long lifetime of b-hadrons, using the properties of secondary vertices and impact parameter distributions. The pT-differential inclusive production cross section of b jets, as well as the corresponding inclusive b-jet fraction, are reported for pp and p-Pb collisions in the jet transverse momentum range 10≤pT, ch jet≤100 GeV/c, together with the nuclear modification factor, Rb-jetpPb. The analysis thus extends the lower pT limit of b-jet measurements at the LHC. The nuclear modification factor is found to be consistent with unity, indicating that the production of b jets in p--Pb at sNN−−−√=5.02 TeV is not affected by cold nuclear matter effects within the current precision. The measurements are well reproduced by POWHEG NLO pQCD calculations with PYTHIA fragmentation.
The study of nuclei and antinuclei production has proven to be a powerful tool to investigate the formation mechanism of loosely bound states in high-energy hadronic collisions. The first measurement of the production of 3ΛH in p-Pb collisions at sNN−−−√ = 5.02 TeV is presented in this Letter. Its production yield measured in the rapidity interval −1<y<0 for the 40% highest multiplicity p-Pb collisions is dN/dy=[6.3±1.8(stat.)±1.2(syst.)]×10−7. The measurement is compared with the expectations of statistical hadronisation and coalescence models, which describe the nucleosynthesis in hadronic collisions. These two models predict very different yields of the hypertriton in small collision systems such as p-Pb and therefore the measurement of dN/dy is crucial to distinguish between them. The precision of this measurement leads to the exclusion with a significance larger than 6σ of some configurations of the statistical hadronisation, thus constraining the production mechanism of loosely bound states.
Femtoscopic correlations with the particle pair combinations K0SK0S and K0SK± are studied in pp collisions at s√=5.02 and 13 TeV by the ALICE experiment. At both energies, boson source parameters are extracted for both pair combinations, by fitting models based on Gaussian size distributions of the sources, to the measured two-particle correlation functions. The interaction model used for the K0SK0S analysis includes quantum statistics and strong final-state interactions through the f0(980) and a0(980) resonances. The model used for the K0SK± analysis includes only the final-state interaction through the a0 resonance. Source parameters extracted in the present work are compared with published values from pp collisions at s√= 7 TeV and the different pair combinations are found to be consistent. From the finding that the strength of the K0SK0S correlations is significantly greater than the strength of the K0SK± correlations, the new results are compatible with the a0 resonance being a tetraquark state of the form (q1,q2¯¯¯¯¯,s,s¯¯¯), where q1 and q2 are u or d quarks.
Angular correlations of heavy-flavour and charged particles in high-energy proton-proton collisions are sensitive to the production mechanisms of heavy quarks and to their fragmentation as well as hadronisation processes. The measurement of the azimuthal-correlation function of prompt D mesons with charged particles in proton-proton collisions at a centre-of-mass energy of s√=13 TeV with the ALICE detector is reported, considering D0, D+, and D∗+ mesons in the transverse-momentum interval 3<pT<36 GeV/c at midrapidity (|y|<0.5), and charged particles with pT>0.3 GeV/c and pseudorapidity |η|<0.8. This measurement has an improved precision and provides an extended transverse-momentum coverage compared to previous ALICE measurements at lower energies. The study is also performed as a function of the charged-particle multiplicity, showing no modifications of the correlation function with multiplicity within uncertainties. The properties and the transverse-momentum evolution of the near- and away-side correlation peaks are studied and compared with predictions from various Monte Carlo event generators. The obtained results can provide constraints on the generators. Among those considered, PYTHIA8 and POWHEG+PYTHIA8 provide the best description of the measured observables.
This article presents groomed jet substructure measurements in pp and Pb−Pb collisions at sNN−−−√=5.02 TeV with the ALICE detector. The Soft Drop grooming algorithm provides access to the hard parton splittings inside a jet by removing soft wide-angle radiation. We report the groomed jet momentum splitting fraction, zg, and the (scaled) groomed jet radius, θg. Charged-particle jets are reconstructed at midrapidity using the anti-kT algorithm with resolution parameters R=0.2 and R=0.4. In heavy-ion collisions, the large underlying event poses a challenge for the reconstruction of groomed jet observables, since fluctuations in the background can cause groomed parton splittings to be misidentified. By using strong grooming conditions to reduce this background, we report these observables fully corrected for detector effects and background fluctuations for the first time. A narrowing of the θg distribution in Pb−Pb collisions compared to pp collisions is seen, which provides direct evidence of the modification of the angular structure of jets in the quark−gluon plasma. No significant modification of the zg distribution in Pb−Pb collisions compared to pp collisions is observed. These results are compared with a variety of theoretical models of jet quenching, and provide constraints on jet energy-loss mechanisms and coherence effects in the quark−gluon plasma.
Understanding the production mechanism of light (anti)nuclei is one of the key challenges of nuclear physics and has important consequences for astrophysics, since it provides an input for indirect darkmatter searches in space. In this paper, the latest results about the production of light (anti)nuclei in pp collisions at √ s = 13 TeV are presented, focusing on the comparison with the predictions of coalescence and thermal models. For the first time, the coalescence parameters B2 for deuterons and B3 for helions are compared with parameter-free theoretical predictions that are directly constrained by the femtoscopic measurement of the source radius in the same event class. A fair description of the data with a Gaussian wave function is observed for both deuteron and helion, supporting the coalescence mechanism for the production of light (anti)nuclei in pp collisions. This method paves the way for future investigations of the internal structure of more complex nuclear clusters, including the hypertriton.
We present the first measurement of event-by-event fluctuations in the kaon sector in Pb-Pb collisions at sNN−−−√= 2.76 TeV with the ALICE detector at the LHC. The robust fluctuation correlator νdyn is used to evaluate the magnitude of fluctuations of the relative yields of neutral and charged kaons, as well as the relative yields of charged kaons, as a function of collision centrality and selected kinematic ranges. While the correlator νdyn[K+,K−] exhibits a scaling approximately in inverse proportion of the charged particle multiplicity, νdyn[K0S,K±] features a significant deviation from such scaling. Within uncertainties, the value of νdyn[K0S,K±] is independent of the selected transverse momentum interval, while it exhibits a pseudorapidity dependence. The results are compared with HIJING, AMPT and EPOS-LHC predictions, and are further discussed in the context of the possible production of disoriented chiral condensates in central Pb-Pb collisions.
J/ψ production as a function of charged-particle multiplicity in p–Pb
collisions at √sNN = 8.16 TeV
(2021)
Inclusive J/ψ yields and average transverse momenta in p-Pb collisions at a center-of-mass energy per nucleon pair sNN−−−√ = 8.16 TeV are measured as a function of the charged-particle pseudorapidity density with ALICE. The J/ψ mesons are reconstructed at forward (2.03<ycms<3.53) and backward (−4.46<ycms<−2.96) center-of-mass rapidity in their dimuon decay channel while the charged-particle pseudorapidity density is measured around midrapidity. The J/ψ yields at forward and backward rapidity normalized to their respective average values increase with the normalized charged-particle pseudorapidity density, the former showing a weaker increase than the latter. The normalized average transverse momenta at forward and backward rapidity manifest a steady increase from low to high charged-particle pseudorapidity density with a saturation beyond the average value.
The pT-differential production cross sections of prompt and non-prompt (produced in beauty-hadron decays) D mesons were measured by the ALICE experiment at midrapidity (|y|<0.5) in proton--proton collisions at s√=5.02 TeV. The data sample used in the analysis corresponds to an integrated luminosity of (19.3±0.4) nb−1. D mesons were reconstructed from their decays D0→K−π+, D+→K−π+π+, and D+s→ϕπ+→K−K+π+ and their charge conjugates. Compared to previous measurements in the same rapidity region, the cross sections of prompt D+ and D+s mesons have an extended pT coverage and total uncertainties reduced by a factor ranging from 1.05 to 1.6, depending on pT, allowing for a more precise determination of their pT-integrated cross sections. The results are well described by perturbative QCD calculations. The fragmentation fraction of heavy quarks to strange mesons divided by the one to non-strange mesons, fs/(fu+fd), is compatible for charm and beauty quarks and with previous measurements at different centre-of-mass energies and collision systems. The bb¯¯¯ production cross section per rapidity unit at midrapidity, estimated from non-prompt D-meson measurements, is dσbb¯¯¯/dy||y|<0.5=34.5±2.4(stat.)+4.7−2.9(tot.syst.) μb. It is compatible with previous measurements at the same centre-of-mass energy and with the cross section predicted by perturbative QCD calculations.
The pT-differential production cross sections of prompt and non-prompt (produced in beauty-hadron decays) D mesons were measured by the ALICE experiment at midrapidity (|y|<0.5) in proton--proton collisions at s√=5.02 TeV. The data sample used in the analysis corresponds to an integrated luminosity of (19.3±0.4) nb−1. D mesons were reconstructed from their decays D0→K−π+, D+→K−π+π+, and D+s→ϕπ+→K−K+π+ and their charge conjugates. Compared to previous measurements in the same rapidity region, the cross sections of prompt D+ and D+s mesons have an extended pT coverage and total uncertainties reduced by a factor ranging from 1.05 to 1.6, depending on pT, allowing for a more precise determination of their pT-integrated cross sections. The results are well described by perturbative QCD calculations. The fragmentation fraction of heavy quarks to strange mesons divided by the one to non-strange mesons, fs/(fu+fd), is compatible for charm and beauty quarks and with previous measurements at different centre-of-mass energies and collision systems. The bb¯¯¯ production cross section per rapidity unit at midrapidity, estimated from non-prompt D-meson measurements, is dσbb¯¯¯/dy||y|<0.5=34.5±2.4(stat.)+4.7−2.9(tot.syst.) μb. It is compatible with previous measurements at the same centre-of-mass energy and with the cross section predicted by perturbative QCD calculations.
The Miocene is a key time in the evolution of African mammals and their ecosystems witnessing the origin of the African apes and the isolation of eastern coastal forests through an expanding biogeographic arid corridor. Until recently, however, Miocene sites from the southeastern regions of the continent were unknown. Here we report discovery of the first Miocene fossil teeth from the shoulders of the Urema Rift in Gorongosa National Park, Mozambique, at the southern East African Rift System. We provide the first 1) radiometric age determinations of the fossiliferous Mazamba Formation, 2) reconstructions of past vegetation in the region based on pedogenic carbonates and fossil wood, and 3) description of fossil teeth from the southern rift. Gorongosa is unique in the East African Rift System in combining marine invertebrates, marine vertebrates, terrestrial mammals, and fossil woods in coastal paleoenvironments. The Gorongosa fossil sites offer the first evidence of persistent woodlands and forests on the coastal margins of southeastern Africa during the Miocene, and an exceptional assemblage of fossil vertebrates including new species. Further work will allow the testing of hypotheses positing the formation of a northeast-southwest arid corridor isolating species on the eastern coastal forests from those elsewhere in Africa.
Brief The Miocene is a key time in the evolution of African mammals and their ecosystems encompassing hominine origins and the establishment of an arid corridor that isolated eastern Africa’s coastal forests. Until now, however, Miocene sites from southeastern Africa have been unknown. We report the discovery of the first Miocene fossil sites from Gorongosa National Park, Mozambique, and show that these sites formed in coastal settings. We provide radiometric ages for the fossiliferous sediments, reconstructions of past vegetation based on stable isotopes and fossil wood, and a description of the first fossil teeth from the region. Gorongosa is the only paleontological site in the East African Rift that combines fossil woods, marine invertebrates, marine vertebrates, and terrestrial mammals. Gorongosa offers the first evidence of persistent woodlands and forests on the coastal margins of southeastern Africa during the Miocene.
Adaptive threshold estimation procedures sample close to a subject’s perceptual threshold by dynamically adapting the stimulation based on the subject’s performance. Yet, perceptual thresholds not only depend on the observers’ sensory capabilities but also on any bias in terms of their expectations and response preferences, thus distorting the precision of the threshold estimates. Using the framework of signal detection theory (SDT), independent estimates of both, an observer’s sensitivity and internal processing bias can be delineated from threshold estimates. While this approach is commonly available for estimation procedures engaging the method of constant stimuli (MCS), correction procedures for adaptive methods (AM) are only scarcely applied. In this article, we introduce a new AM that takes individual biases into account, and that allows for a bias-corrected assessment of subjects’ sensitivity. This novel AM is validated with simulations and compared to a typical MCS-procedure, for which the implementation of bias correction has been previously demonstrated.
Comparing AM and MCS demonstrates the viability of the presented AM. Besides its feasibility, the results of the simulation reveal both, advantages, and limitations of the proposed AM. The procedure has considerable practical implications, in particular for the design of shaping procedures in sensory training experiments, in which task difficulty has to be constantly adapted to an observer’s performance, to improve training efficiency.
Bisphenols and phthalates, chemicals frequently used in plastic products, promote obesity in cell and animal models. However, these well-known metabolism disrupting chemicals (MDCs) represent only a minute fraction of all compounds found in plastics. To gain a comprehensive understanding of plastics as a source of exposure to MDCs, we characterized all chemicals present in 34 everyday products using nontarget high-resolution mass spectrometry and analyzed their joint adipogenic activities by high-content imaging. We detected 55,300 chemical features and tentatively identified 629 unique compounds, including 11 known MDCs. Importantly, chemicals that induced proliferation, growth, and triglyceride accumulation in 3T3-L1 adipocytes were found in one third of the products. Since the majority did not target peroxisome proliferator-activated receptor γ, the effects are likely to be caused by unknown MDCs. Our study demonstrates that daily-use plastics contain potent mixtures of MDCs and can, therefore, be a relevant yet underestimated environmental factor contributing to obesity.
Teaser Plastics contain a potent mixture of chemicals promoting adipogenesis, a key process in developing obesity.
Recently, a 15-valent (PCV15) and a 20-valent pneumococcal conjugate vaccine (PCV20) have been licensed by the US Food and Drug Administration and are under evaluation by the European Medicines Agency. PCV15 contains all serotypes of the 13-valent conjugate vaccine (PCV13) plus serotype 22F and 33F and PCV20 includes PCV13 serotypes plus serotypes 8, 10A, 11A, 12F, 15B, 22F, 33F. We investigated pneumococcal serotype distribution, secular trends and proportion of pneumonia caused by serotypes included in PCV13, PCV15, PCV20, and the 23-valent pneumococcal polysaccharide vaccine (PPV23) among adult patients with all-cause community-acquired pneumonia (CAP) between 2013 and 2019. We applied logistic mixed regression modelling to assess annual trends. Urine samples from adult patients with CAP treated in the community or hospital in Germany and included in the CAPNETZ study, a prospective multi-centre cohort study, were analysed by two serotype-specific multiplex urinary antigen detection assays (UAD1/UAD2) at Pfizer’s Vaccines Research and Development Laboratory. UAD1 detects serotypes in PCV13, UAD2 detects additional serotypes in PCV20 plus serotypes 2, 9N, 17F and 20. Out of 1,831 patients screened, urine samples with a valid UAD test result were available for 1,343 patients (73.3%). Among those patients, 829 patients (61.7%) were male, 792 patients (59.0%) were aged ≥60 years, 1038 patients (77.3%) had at least one comorbidity and 1,204 patients (89.7%) were treated in the hospital. The overall proportion of vaccine-type pneumonia among all-cause CAP for PCV13, PCV15, PCV20 and PPV23 was 7.7% (n=103), 9.1% (n=122), 12.3% (n=165) and 13.3% (n=178). Over the entire observation period, we did not observe evidence for significant annual trends in pneumococcal vaccine serotype coverage against pneumonia in adults (PCV13: OR 0.94, 95% CI 0.83-1.05; PCV15: OR 0.93, 95% CI 0.84-1.03; PCV20: OR 0.95, 95% CI 0.86-1.04; PPV23: OR 0.99, 95% CI 0.90-1.08). In conclusion, our data show that i) the infant vaccination program of PCV13, which started in Germany 2010 did not result in a relevant and sustained decrease of PCV13 serotypes in pneumonia in adults and ii) that the gap in the coverage between PCV20 and PPV23 was small and did not increase over the entire observation time.
Recently, a 15-valent (PCV15) and a 20-valent pneumococcal conjugate vaccine (PCV20) have been licensed by the US Food and Drug Administration and are under evaluation by the European Medicines Agency. PCV15 contains all serotypes of the 13-valent conjugate vaccine (PCV13) plus serotype 22F and 33F and PCV20 includes PCV13 serotypes plus serotypes 8, 10A, 11A, 12F, 15B, 22F, 33F. We investigated pneumococcal serotype distribution, secular trends and proportion of pneumonia caused by serotypes included in PCV13, PCV15, PCV20, and the 23-valent pneumococcal polysaccharide vaccine (PPV23) among adult patients with all-cause community-acquired pneumonia (CAP) between 2013 and 2019. We applied logistic mixed regression modelling to assess annual trends. Urine samples from adult patients with CAP treated in the community or hospital in Germany and included in the CAPNETZ study, a prospective multi-centre cohort study, were analysed by two serotype-specific multiplex urinary antigen detection assays (UAD1/UAD2) at Pfizer’s Vaccines Research and Development Laboratory. UAD1 detects serotypes in PCV13, UAD2 detects additional serotypes in PCV20 plus serotypes 2, 9N, 17F and 20. Out of 1,831 patients screened, urine samples with a valid UAD test result were available for 1,343 patients (73.3%). Among those patients, 829 patients (61.7%) were male, 792 patients (59.0%) were aged ≥60 years, 1038 patients (77.3%) had at least one comorbidity and 1,204 patients (89.7%) were treated in the hospital. The overall proportion of vaccine-type pneumonia among all-cause CAP for PCV13, PCV15, PCV20 and PPV23 was 7.7% (n=103), 9.1% (n=122), 12.3% (n=165) and 13.3% (n=178). Over the entire observation period, we did not observe evidence for significant annual trends in pneumococcal vaccine serotype coverage against pneumonia in adults (PCV13: OR 0.94, 95% CI 0.83-1.05; PCV15: OR 0.93, 95% CI 0.84-1.03; PCV20: OR 0.95, 95% CI 0.86-1.04; PPV23: OR 0.99, 95% CI 0.90-1.08). In conclusion, our data show i) no decline of PCV13 serotypes in all-cause CAP between 2013-2019 mainly due to a persistently high proportion of serotype 3 suggesting no meaningful effect of childhood PCV13 vaccination on PCV13 coverage in pneumonia in adults during this time period and ii) that the gap in the coverage between PCV20 and PPV23 was small and did not increase over the entire observation time.
Background: School attendance during the SARS-CoV-2 pandemic is intensely debated. Modelling studies suggest that school closures contribute to community transmission reduction. However, data among school-attending students and staff are scarce. In November 2020, we examined SARS-CoV-2 infections and seroreactivity in 24 randomly selected school classes and connected households in Berlin, Germany.
Methods: Students and school staff were examined, oro-nasopharyngeal swabs and blood samples collected, and SARS-CoV-2 infection and IgG antibodies detected by RT-PCR and ELISA. Household members performed self-swabs. Individual and institutional infection prevention and control measures were assessed. Classes with SARS-CoV-2 infection and connected household members were re-tested after one week.
Findings: 1119 participants were examined, including 177 primary and 175 secondary school students, 142 staff, and 625 household members. Participants reported mainly cold symptoms (19·4%). SARS-CoV-2 infection occurred in eight of 24 classes affecting each 1-2 individuals. Infection prevalence was 2·7% (95%CI; 1·2-5·0%; 9/338), 1·4% (0·2-5·1%; 2/140), and 2·3% (1·3-3·8%; 14/611) among students, staff and household members, respectively, including quarantined persons. Six of nine infected students were asymptomatic. Prevalence increased with inconsistent facemask use in school, way to school on foot, and case-contacts outside school. IgG antibodies were detected in 2·0% (0·8-4·1%; 7/347), 1·4% (0·2-5·0%; 2/141) and 1·4% (0·6-2·7%; 8/576), respectively. For three of nine households with infection(s) detected at cross-sectional assessment, origin in school seemed possible. After one week, no school-related, secondary infections appeared in affected classes; the attack rate in connected households was 1·1%.
Interpretation: These data suggest that school attendance under preventive measures is feasible, provided their rigorous implementation. In balancing threats and benefits of open versus closed schools during the pandemic, parents and society need to consider possible spill-overs into their households. Deeper insight is needed into the infection risks due to being a schoolchild as compared to attending school.
Pathophysiological models are urgently needed for personalized treatments of mental disorders. However, most potential neural markers for psychopathology are limited by low interpretability, prohibiting reverse inference from brain measures to clinical symptoms and traits. Neural signatures—i.e. multivariate brain-patterns trained to be both sensitive and specific to a construct of interest—might alleviate this problem, but are rarely applied to mental disorders. We tested whether previously developed neural signatures for negative affect and discrete emotions distinguish between healthy individuals and those with mental disorders characterized by emotion dysregulation, i.e. Borderline Personality Disorder (BPD) and complex Post-traumatic Stress Disorder (cPTSD). In three different fMRI studies, a total sample of 192 women (49 BPD, 62 cPTSD, 81 healthy controls) were shown pictures of scenes with negative or neutral content. Based on pathophysiological models, we hypothesized higher negative and lower positive reactivity of neural emotion signatures in participants with emotion dysregulation. The expression of neural signatures differed strongly between neutral and negative pictures (average Cohen’s d = 1.17). Nevertheless, a mega-analysis on individual participant data showed no differences in the reactivity of neural signatures between participants with and without emotion dysregulation. Confidence intervals ruled out even small effect sizes in the hypothesized direction and were further supported by Bayes factors. Overall, these results support the validity of neural signatures for emotional states during fMRI tasks, but raise important questions concerning their link to individual differences in emotion dysregulation.
The capacity of convalescent and vaccine-elicited sera and monoclonal antibodies (mAb) to neutralize SARS-CoV-2 variants is currently of high relevance to assess the protection against infections.
We performed a cell culture-based neutralization assay focusing on authentic SARS-CoV-2 variants B.1.617.1 (Kappa), B.1.617.2 (Delta), B.1.427/B.1.429 (Epsilon), all harboring the spike substitution L452R.
We found that authentic SARS-CoV-2 variants harboring L452R had reduced susceptibility to convalescent and vaccine-elicited sera and mAbs. Compared to B.1, Kappa and Delta showed a reduced neutralization by convalescent sera by a factor of 5.71 and 3.64, respectively, which constitutes a 2-fold greater reduction when compared to Epsilon. BNT2b2 and mRNA1273 vaccine-elicited sera were less effective against Kappa, Delta, and Epsilon compared to B.1. No difference was observed between Kappa and Delta towards vaccine-elicited sera, whereas convalescent sera were 1.6-fold less effective against Delta, respectively. Both B.1.617 variants Kappa (+E484Q) and Delta (+T478K) were less susceptible to either casirivimab or imdevimab.
In conclusion, in contrast to the parallel circulating Kappa variant, the neutralization efficiency of convalescent and vaccine-elicited sera against Delta was moderately reduced. Delta was resistant to imdevimab, which however, might be circumvented by a combination therapy with casirivimab together.
The coronavirus SARS-CoV-2 is the cause of the ongoing COVID-19 pandemic. Most SARS-CoV-2 infections are mild or even asymptomatic. However, a small fraction of infected individuals develops severe, life-threatening disease, which is caused by an uncontrolled immune response resulting in hyperinflammation. Antiviral interventions are only effective prior to the onset of hyperinflammation. Hence, biomarkers are needed for the early identification and treatment of high-risk patients. Here, we show in a range of model systems and data from post mortem samples that SARS-CoV-2 infection results in increased levels of CD47, which is known to mediate immune escape in cancer and virus-infected cells. Systematic literature searches also indicated that known risk factors such as older age and diabetes are associated with increased CD47 levels. High CD47 levels contribute to vascular disease, vasoconstriction, and hypertension, conditions which may predispose SARS-CoV-2-infected individuals to COVID-19-related complications such as pulmonary hypertension, lung fibrosis, myocardial injury, stroke, and acute kidney injury. Hence, CD47 is a candidate biomarker for severe COVID-19. Further research will have to show whether CD47 is a reliable diagnostic marker for the early identification of COVID-19 patients requiring antiviral therapy.
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.
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 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.
Reduced neutralization of SARS-CoV-2 Omicron variant by vaccine sera and monoclonal antibodies
(2021)
Due to numerous mutations in the spike protein, the SARS-CoV-2 variant of concern Omicron (B.1.1.529) raises serious concerns since it may significantly limit the antibody-mediated neutralization and increase the risk of reinfections. While a rapid increase in the number of cases is being reported worldwide, until now there has been uncertainty about the efficacy of vaccinations and monoclonal antibodies. Our in vitro findings using authentic SARS-CoV-2 variants indicate that in contrast to the currently circulating Delta variant, the neutralization efficacy of vaccine-elicited sera against Omicron was severely reduced highlighting T-cell mediated immunity as essential barrier to prevent severe COVID-19. Since SARS-CoV-2 Omicron was resistant to casirivimab and imdevimab, genotyping of SARS-CoV-2 may be needed before initiating mAb treatment. Variant-specific vaccines and mAb agents may be required to treat COVID-19 due to Omicron and other emerging variants of concern.
Reduced neutralization of SARS-CoV-2 Omicron variant by vaccine sera and monoclonal antibodies
(2021)
Due to numerous mutations in the spike protein, the SARS-CoV-2 variant of concern Omicron (B.1.1.529) raises serious concerns since it may significantly limit the antibody-mediated neutralization and increase the risk of reinfections. While a rapid increase in the number of cases is being reported worldwide, until now there has been uncertainty about the efficacy of vaccinations and monoclonal antibodies. Our in vitro findings using authentic SARS-CoV-2 variants indicate that in contrast to the currently circulating Delta variant, the neutralization efficacy of vaccine-elicited sera against Omicron was severely reduced highlighting T-cell mediated immunity as essential barrier to prevent severe COVID-19. Since SARS-CoV-2 Omicron was resistant to casirivimab and imdevimab, genotyping of SARS-CoV-2 may be needed before initiating mAb treatment. Variant-specific vaccines and mAb agents may be required to treat COVID-19 due to Omicron and other emerging variants of concern.
Our lives (and deaths) have been dominated for more than a year by COVID-19, a pandemic that has caused hundreds of millions of disease cases, millions of deaths, trillions in economic costs, and major restrictions on our freedom. We argue that much of this could have been avoided by repeated and systematic population-scale PCR-based testing and targeted quarantine. We describe key elements of the current implementations of such a system and demonstrate (with Germany as an example), that this strategy could have suppressed the pandemic within weeks, eliminating the vast majority of its overall impact in terms of deaths, economic costs and restrictions. It can, however, still play a major role in further reducing the worldwide impact of the current phase of the pandemic, and remain as a key protection against similar dangers in the future.
Abstract
The endoplasmic reticulum (ER) is a key organelle of membrane biogenesis and crucial for the folding of both membrane and secretory proteins. Sensors of the unfolded protein response (UPR) monitor the unfolded protein load in the ER and convey effector functions for maintaining ER homeostasis. Aberrant compositions of the ER membrane, referred to as lipid bilayer stress, are equally potent activators of the UPR. How the distinct signals from lipid bilayer stress and unfolded proteins are processed by the conserved UPR transducer Ire1 remains unknown. Here, we have generated a functional, cysteine-less variant of Ire1 and performed systematic cysteine crosslinking experiments in native membranes to establish its transmembrane architecture in signaling-active clusters. We show that the transmembrane helices of two neighboring Ire1 molecules adopt an X-shaped configuration independent of the primary cause for ER stress. This suggests that different forms of stress converge in a common, signaling-active transmembrane architecture of Ire1.
Summary
The endoplasmic reticulum (ER) is a hotspot of lipid biosynthesis and crucial for the folding of membrane and secretory proteins. The unfolded protein response (UPR) controls the size and folding capacity of the ER. The conserved UPR transducer Ire1 senses both unfolded proteins and aberrant lipid compositions to mount adaptive responses. Using a biochemical assay to study Ire1 in signaling-active clusters, Väth et al. provide evidence that the neighboring transmembrane helices of clustered Ire1 form an ‘X’ irrespectively of the primary cause of ER stress. Hence, different forms of ER stress converge in a common, signaling-active transmembrane architecture of Ire1.
The capacity of convalescent and vaccine-elicited sera and monoclonal antibodies (mAb) to neutralize SARS-CoV-2 variants is currently of high relevance to assess the protection against infections.
We performed a cell culture-based neutralization assay focusing on authentic SARS-CoV-2 variants B.1.617.1 (Kappa), B.1.617.2 (Delta), B.1.427/B.1.429 (Epsilon), all harboring the spike substitution L452R.
We found that authentic SARS-CoV-2 variants harboring L452R had reduced susceptibility to convalescent and vaccine-elicited sera and mAbs. Compared to B.1, Kappa and Delta showed a reduced neutralization by convalescent sera by a factor of 8.00 and 5.33, respectively, which constitutes a 2-fold greater reduction when compared to Epsilon. BNT2b2 and mRNA1273 vaccine-elicited sera were less effective against Kappa, Delta, and Epsilon compared to B.1. No difference was observed between Kappa and Delta towards vaccine-elicited sera, whereas convalescent sera were 1.5-fold less effective against Delta, respectively. Both B.1.617 variants Kappa (+E484Q) and Delta (+T478K) were less susceptible to either casirivimab or imdevimab.
In conclusion, in contrast to the parallel circulating Kappa variant, the neutralization efficiency of convalescent and vaccine-elicited sera against Delta was moderately reduced. Delta was resistant to imdevimab, which however, might be circumvented by a combination therapy with casirivimab together.
The European Beech is the dominant climax tree in most regions of Central Europe and valued for its ecological versatility and hardwood timber. Even though a draft genome has been published recently, higher resolution is required for studying aspects of genome architecture and recombination. Here we present a chromosome-level assembly of the more than 300 year-old reference individual, Bhaga, from the Kellerwald-Edersee National Park (Germany). Its nuclear genome of 541 Mb was resolved into 12 chromosomes varying in length between 28 Mb and 73 Mb. Multiple nuclear insertions of parts of the chloroplast genome were observed, with one region on chromosome 11 spanning more than 2 Mb of the genome in which fragments up to 54,784 bp long and covering the whole chloroplast genome were inserted randomly. Unlike in Arabidopsis thaliana, ribosomal cistrons are present in Fagus sylvatica only in four major regions, in line with FISH studies. On most assembled chromosomes, telomeric repeats were found at both ends, while centromeric repeats were found to be scattered throughout the genome apart from their main occurrence per chromosome. The genome- wide distribution of SNPs was evaluated using a second individual from Jamy Nature Reserve (Poland). SNPs, repeat elements and duplicated genes were unevenly distributed in the genomes, with one major anomaly on chromosome 4. The genome presented here adds to the available highly resolved plant genomes and we hope it will serve as a valuable basis for future research on genome architecture and for understanding the past and future of European Beech populations in a changing climate.
DNA points accumulation for imaging in nanoscale topography (DNA-PAINT) is a super-resolution technique with relatively easy-to-implement multi-target imaging. However, image acquisition is slow as sufficient statistical data has to be generated from spatio-temporally isolated single emitters. Here, we trained the neural network (NN) DeepSTORM to predict fluorophore positions from high emitter density DNA-PAINT data. This achieves image acquisition in one minute. We demonstrate multi-color super-resolution imaging of structure-conserved semi-thin neuronal tissue and imaging of large samples. This improvement can be integrated into any single-molecule microscope and enables fast single-molecule super-resolution microscopy.
Electrocardiograms (ECG) record the heart activity and are the most common and reliable method to detect cardiac arrhythmias, such as atrial fibrillation (AFib). Lately, many commercially available devices such as smartwatches are offering ECG monitoring. Therefore, there is increasing demand for designing deep learning models with the perspective to be physically implemented on these small portable devices with limited energy supply. In this paper, a workflow for the design of small, energy-efficient recurrent convolutional neural network (RCNN) architecture for AFib detection is proposed. However, the approach can be well generalized to every type of long time series. In contrast to previous studies, that demand thousands of additional network neurons and millions of extra model parameters, the logical steps for the generation of a CNN with only 114 trainable parameters are described. The model consists of a small segmented CNN in combination with an optimal energy classifier. The architectural decisions are made by using the energy consumption as a metric in an equally important way as the accuracy. The optimisation steps are focused on the software which can be embedded afterwards on a physical chip. Finally, a comparison with some previous relevant studies suggests that the widely used huge CNNs for similar tasks are mostly redundant and unessentially computationally expensive.
Many cross-sectional findings suggest that volumes of specific hippocampal subfields increase in middle childhood and early adolescence. In contrast, a small number of available longitudinal studies observed decreased volumes in most subfields over this age range. Further, it remains unknown whether structural changes in development are associated with corresponding gains in children’s memory. Here we report cross-sectional age differences in children’s hippocampal subfield volumes together with longitudinal developmental trajectories and their relationships with memory performance. In two waves, 109 healthy participants aged 6 to 10 years (wave 1: MAge=7.25, wave 2: MAge=9.27) underwent high-resolution magnetic resonance imaging to assess hippocampal subfield volumes, and completed cognitive tasks assessing hippocampus dependent memory processes. We found that cross-sectional age-associations and longitudinal developmental trends in hippocampal subfield volumes were highly discrepant, both by subfields and in direction. Further, volumetric changes were largely unrelated to changes in memory, with the exception that increase in subiculum volume was associated with gains in spatial memory. Importantly, the observed longitudinal patterns of brain-cognition coupling could not be inferred from cross-sectional findings. We discuss potential sources of these discrepancies. This study underscores that children’s structural brain development and its relationship to cognition cannot be inferred from cross-sectional age comparisons.
Highlights
The subiculum undergoes volumetric increase between 6-10 years of age
Change across two years in CA1-2 and DG-CA3 was not observed in this age window
Change across two years did not reflect age differences spanning two years
Cross-sectional and longitudinal slopes in stark contrast for hippocampal subfields
Longitudinal brain-cognition coupling cannot be inferred from cross-sectional data
The unicellular ciliate Paramecium contains a large vegetative macronucleus with several unusual characteristics including an extremely high coding density and high polyploidy. As macronculear chromatin is devoid of heterochromatin our study characterizes the functional epigenomic organisation necessary for gene regulation and proper PolII activity. Histone marks (H3K4me3, H3K9ac, H3K27me3) revealed no narrow peaks but broad domains along gene bodies, whereas intergenic regions were devoid of nucleosomes. Our data implicates H3K4me3 levels inside ORFs to be the main factor to associate with gene expression and H3K27me3 appears to occur as a bistable domain with H3K4me3 in plastic genes. Surprisingly, silent and lowly expressed genes show low nucleosome occupancy suggesting that gene inactivation does not involve increased nucleosome occupancy and chromatin condensation. Due to a high occupancy of Pol II along highly expressed ORFs, transcriptional elongation appears to be quite different to other species. This is supported by missing heptameric repeats in the C-terminal domain of Pol II and a divergent elongation system. Our data implies that unoccupied DNA is the default state, whereas gene activation requires nucleosome recruitment together with broad domains of H3K4me3. This could represent a buffer for paused Pol II along ORFs in absence of elongation factors of higher eukaryotes.
Biomolecular condensation underlies the biogenesis of an expanding array of membraneless assemblies, including stress granules (SGs) which form under a variety of cellular stresses. Advances have been made in understanding the molecular grammar that dictates the behavior of a few key scaffold proteins that make up these phases but how the partitioning of hundreds of other SG proteins is regulated remains largely unresolved. While investigating the rules that govern the condensation of ataxin-2, a SG protein implicated in neurodegenerative disease, we unexpectedly identified a short 14aa sequence that acts as an ataxin-2 condensation switch and is conserved across the eukaryote lineage. We identify poly(A)-binding proteins as unconventional RNA-dependent chaperones that control this regulatory switch. Our results uncover a hierarchy of cis and trans interactions that fine-tune ataxin-2 condensation and reveal a new molecular function for ancient poly(A)-binding proteins as emulsifiers of biomolecular condensate proteins. These findings may inspire novel approaches to therapeutically target aberrant phases in disease.
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.
Gender and attitudes toward welfare state reform: Are women really social investment promoters?
(2021)
This article contributes to the study of the demand side of welfare politics by investigating gender differences in social investment preferences systematically. Building on the different functions of social investment policies in creating, preserving, or mobilizing skills, we argue that women do not support social investment policies generally more strongly than men. Rather, women demand, in particular, policies to preserve their skills during career interruptions and help to mobilize their skills on the labour market. In a second analytical step, we examine women’s policy priorities if skill preservation and mobilization come at the expense of social compensation. We test our arguments for eight Western European countries with data from the INVEDUC survey. The confirmation of our arguments challenges a core assumption of the literatures on the social investment turn and women’s political realignment. We discuss the implication of our findings in the conclusions.
Background Stigma is one of the most significant constraints on people living with depression. There is a lack of validated scales in Portugal to measure depression stigma; therefore, validation of the Depression Stigma Scale (DSS) is an essential step to the depression stigma research in Portugal.
Methods We developed the adaptation process with the ITC Guidelines for Translation and Adapting Tests taken into consideration. We collected the sample as part of the OSPI program – Optimizing suicide prevention programs and their implementation in Europe, specifically within the application in Portugal, and included 1693 participants. Floor-ceiling effects and response ranges were analyzed, and we calculated Cronbach alphas, conducted a Principal Component Analysis and Confirmatory Analysis. Validity evidence was tested with two well-documented hypotheses, using data on gender and depression symptoms.
Results The sample was well comparable with the general Portuguese population, indicating its representativeness. We identified a three-factor structure in each subscale (personal and perceived stigma): weak-not-sick, discrimination, and dangerous/unpredictable. The Cronbach’s alphas were satisfactory, and validity was confirmed.
Conclusions This study established the validity and demonstrated good psychometric properties of the DSS in the Portuguese population. The validation of the DSS can be beneficial in exploring stigma predictors and evaluating the effectiveness of stigma reduction interventions.
The rapid spread and evolution of various strains of SARS-CoV-2, the virus responsible for COVID-19, continues to challenge the disease controlling measures globally. Alarming concern is, the number of second wave infections surpassed the first wave and the onset of severe symptoms manifesting rapidly. In this scenario, testing of maximum population in less time and minimum cost with existing diagnostic amenities is the only possible way to control the spread of the virus. The previously described RNA extraction-free methods using dry swab have been shown to be advantageous in these critical times by different studies. In this work, we show the temporal stability and performance of the dry swab viral detection method at two different temperatures. Contrived dry swabs holding serially diluted SARS-CoV-2 strains A2a and A3i at 25°C (room temperature; RT) and 4°C were subjected to direct RT-PCR and compared with standard VTM-RNA based method. The results clearly indicate that dry swab method of RNA detection is as efficient as VTM-RNA-based method in both strains, when checked for up to 72 hours. The lesser CT values of dry swab samples in comparison to that of the VTM-RNA samples suggest better sensitivity of the method within 48 hours of time. The results collectively suggest that dry swab samples are stable at RT for 24 hours and the detection of SARS-CoV-2 RNA by RT-PCR do not show variance from VTM-RNA. This extraction free, direct RT-PCR method holds phenomenal standing in the present life-threatening circumstances due to SARS-CoV-2.
Feeding exclusively on blood, vampire bats represent the only obligate sanguivorous lineage among mammals. To uncover genomic changes associated with adaptations to this unique dietary specialization, we generated a new haplotype-resolved reference-quality genome of the common vampire bat (Desmodus rotundus) and screened 26 bat species for genes that were specifically lost in the vampire bat lineage. We discovered previously-unknown gene losses that relate to metabolic and physiological changes, such as reduced insulin secretion (FFAR1, SLC30A8), limited glycogen stores (PPP1R3E), and a distinct gastric physiology (CTSE). Other gene losses likely reflect the biased nutrient composition (ERN2, CTRL) and distinct pathogen diversity of blood (RNASE7). Interestingly, the loss of REP15 likely helped vampire bats to adapt to high dietary iron levels by enhancing iron excretion and the loss of the 24S-hydroxycholesterol metabolizing enzyme CYP39A1 could contribute to their exceptional cognitive abilities. Finally, losses of key cone phototransduction genes (PDE6H, PDE6C) suggest that these strictly-nocturnal bats completely lack cone-based vision. These findings enhance our understanding of vampire bat biology and the genomic underpinnings of adaptations to sanguivory.
Incidence of an intracellular multiplication niche amongst Acinetobacter baumannii clinical isolates
(2021)
The spread of antibiotic resistant Acinetobacter baumannii poses a significant threat to public health worldwide. This nosocomial bacterial pathogen can be associated with life-threatening infections, particularly in intensive care units. A. baumannii is mainly described as an extracellular pathogen with restricted survival within cells. This study shows that a subset of A. baumannii clinical isolates extensively multiply within non-phagocytic immortalized and primary cells, without the induction of apoptosis, and with bacterial clusters visible up to 48 hours after infection. This phenotype was observed for the A. baumannii C4 strain associated with high mortality in a hospital outbreak, and the A. baumannii ABC141 strain which wasn’t isolated from an infection site but was found to be hyperinvasive. Intracellular multiplication of these A. baumannii strains occurred within spacious single membrane-bound vacuoles, labeled with the lysosomal associate membrane protein (LAMP1). However, these compartments excluded lysotracker, an indicator of acidic pH, suggesting that A. baumannii can divert its trafficking away from the lysosomal degradative pathway. These compartments were also devoid of autophagy features. A high-content microscopy screen of 43 additional A. baumannii clinical strains highlighted various phenotypes: (1) the majority of strains remained extracellular, (2) a significant proportion was capable of invasion and limited persistence, and (3) two strains efficiently multiplied within LAMP1-positive vacuoles, one of which was also hyperinvasive. These data identify an intracellular niche for specific A. baumannii clinical strains that enables extensive multiplication in an environment protected from host immune responses and out of reach from many antibiotics.
Importance Multidrug resistant Acinetobacter baumannii strains are associated with significant morbidity and mortality in hospitals world-wide. Understanding their pathogenicity is critical for improving therapeutics. Although A. baumannii can steadily adhere to surfaces and host cells, most bacteria remain extracellular. Recent studies have shown that a small proportion of bacteria can invade cells but present limited survival. We have found that some A. baumannii clinical isolates can establish a specialized intracellular niche that sustains extensive intracellular multiplication for a prolonged time without induction of cell death. We propose that this intracellular compartment allows A. baumannii to escape the cell’s normal degradative pathway, protecting bacteria from host immune responses and potentially hindering antibiotic accessibility. This may contribute to A. baumannii persistence, relapsing infections and enhanced mortality in susceptible patients. A high-content microscopy-based screen confirmed this pathogenicity trait is present in other clinical isolates. There is an urgent need for new antibiotics or alternative antimicrobial approaches, particularly to combat carbapenem-resistant A. baumannii. The discovery of an intracellular niche for this pathogen as well as hyperinvasive isolates may help guide the development of antimicrobial therapies and diagnostics in the future.
A key competence for open-ended learning is the formation of increasingly abstract representations useful for driving complex behavior. Abstract representations ignore specific details and facilitate generalization. Here we consider the learning of abstract representations in a multi-modal setting with two or more input modalities. We treat the problem as a lossy compression problem and show that generic lossy compression of multimodal sensory input naturally extracts abstract representations that tend to strip away modalitiy specific details and preferentially retain information that is shared across the different modalities. Furthermore, we propose an architecture to learn abstract representations by identifying and retaining only the information that is shared across multiple modalities while discarding any modality specific information.
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.
Mosquito species belonging to the genus Aedes have attracted the interest of scientists and public health officers for their invasive species traits and efficient capacity of transmitting viruses affecting humans. Some of these species were brought outside their native range by human activities such as trade and tourism, and colonised new regions thanks to a unique combination of eco-physiological traits.
Considering mosquito physiological and behavioural traits to understand and predict the spatial and temporal population dynamics is thus a crucial step to develop strategies to mitigate the local densities of invasive Aedes populations.
Here, we synthesised the life cycle of four invasive Aedes species (Ae. aegypti, Ae. albopictus, Ae. japonicus and Ae. koreicus) in a single multi-scale stochastic modelling framework which we coded in the R package dynamAedes. We designed a stage-based and time-discrete stochastic model driven by temperature, photo-period and inter-specific larval competition that can be applied to three different spatial scales: punctual, local and regional. These spatial scales consider different degrees of spatial complexity and data availability, by accounting for both active and passive dispersal of mosquito species as well as for the heterogeneity of the input temperature data.
Our overarching aim was to provide a flexible, open-source and user-friendly tool rooted in the most updated knowledge on species biology which could be applied to the management of invasive Aedes populations as well as for more theoretical ecological inquiries.
Vocal communication is essential to coordinate social interactions in mammals and it requires a fine discrimination of communication sounds. Auditory neurons can exhibit selectivity for specific calls, but how it is affected by preceding sounds is still debated. We tackled this using ethologically relevant vocalizations in a highly vocal mammalian species: Seba’s short-tailed bat. We show that cortical neurons present several degrees of selectivity for echolocation and distress calls. Embedding vocalizations within natural acoustic streams leads to stimulus-specific suppression of neuronal responses that changes sound selectivity in disparate manners: increases in neurons with poor discriminability in silence and decreases in neurons selective in silent settings. A computational model indicates that the observed effects arise from two forms of adaptation: presynaptic frequency specific adaptation acting in cortical inputs and stimulus unspecific postsynaptic adaptation. These results shed light into how acoustic context modulates natural sound discriminability in the mammalian cortex.
The development of super-resolution microscopy (SRM) has widened our understanding of biomolecular structure and function in biological materials. Imaging multiple targets within a single area would elucidate their spatial localization relative to the cell matrix and neighboring biomolecules, revealing multi-protein macromolecular structures and their functional co-dependencies. SRM methods are, however, limited to the number of suitable fluorophores that can be imaged during a single acquisition as well as the loss of antigens during antibody washing and restaining for organic dye multiplexing. We report the visualization of multiple protein targets within the pre- and postsynapse in 350-400 nm thick neuronal tissue sections using DNA-assisted single-molecule localization microscopy. Using antibodies labeled with short DNA oligonucleotides, multiple targets are visualized successively by sequential exchange of fluorophore-labeled complementary oligonucleotides present in the imaging buffer. The structural integrity of the tissue is maintained owing to only a single labelling step during sample preparation. Multiple targets are imaged using a single laser wavelength, minimizing chromatic aberration. This method proved robust for multi-target imaging in semi-thin tissue sections, paving the way towards structural cell biology with single-molecule super-resolution microscopy.
From loss to recovery: how to effectively assess chemosensory impairments during COVID-19 pandemic
(2021)
Chemosensory impairments have been established as a specific indicator of COVID-19. They affect most patients and may persist long past the resolution of respiratory symptoms, representing an unprecedented medical challenge. Since the SARS-CoV-2 pandemic started, we now know much more about smell, taste, and chemesthesis loss associated with COVID-19. However, the temporal dynamics and characteristics of recovery are still unknown. Here, capitalizing on data from the Global Consortium for Chemosensory Research (GCCR) crowdsourced survey, we assessed chemosensory abilities after the resolution of respiratory symptoms in participants diagnosed with COVID-19 during the first wave of the pandemic in Italy. This analysis led to the identification of two patterns of chemosensory recovery, limited (partial) and substantial, which were found to be associated with differential age, degrees of chemosensory loss, and regional patterns. Uncovering the self-reported phenomenology of recovery from smell, taste, and chemesthetic disorders is the first, yet essential step, to provide healthcare professionals with the tools to take purposeful and targeted action to address chemosensory disorders and its severe discomfort.
Mathematical modeling of the molecular switch of TNFR1-mediated signaling pathways using Petri nets
(2021)
The paper describes a mathematical model of the molecular switch of cell survival, apoptosis, and necroptosis in cellular signaling pathways initiated by tumor necrosis factor 1. Based on experimental findings in the current literature, we constructed a Petri net model in terms of detailed molecular reactions for the molecular players, protein complexes, post-translational modifications, and cross talk. The model comprises 118 biochemical entities, 130 reactions, and 299 connecting edges. Applying Petri net analysis techniques, we found 279 pathways describing complete signal flows from receptor activation to cellular response, representing the combinatorial diversity of functional pathways.120 pathways steered the cell to survival, whereas 58 and 35 pathways led to apoptosis and necroptosis, respectively. For 65 pathways, the triggered response was not deterministic, leading to multiple possible outcomes. Based on the Petri net, we investigated the detailed in silico knockout behavior and identified important checkpoints of the TNFR1 signaling pathway in terms of ubiquitination within complex I and the gene expression dependent on NF-κB, which controls the caspase activity in complex II and apoptosis induction.
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.
Analyzing non-invasive recordings of electroencephalography (EEG) and magnetoencephalography (MEG) directly in sensor space, using the signal from individual sensors, is a convenient and standard way of working with this type of data. However, volume conduction introduces considerable challenges for sensor space analysis. While the general idea of signal mixing due to volume conduction in EEG/MEG is recognized, the implications have not yet been clearly exemplified. Here, we illustrate how different types of activity overlap on the level of individual sensors. We show spatial mixing in the context of alpha rhythms, which are known to have generators in different areas of the brain. Using simulations with a realistic 3D head model and lead field and data analysis of a large resting-state EEG dataset, we show that electrode signals can be differentially affected by spatial mixing by computing a sensor complexity measure. While prominent occipital alpha rhythms result in less heterogeneous spatial mixing on posterior electrodes, central electrodes show a diversity of rhythms present. This makes the individual contributions, such as the sensorimotor mu-rhythm and temporal alpha rhythms, hard to disentangle from the dominant occipital alpha. Additionally, we show how strong occipital rhythms rhythms can contribute the majority of activity to frontal channels, potentially compromising analyses that are solely conducted in sensor space. We also outline specific consequences of signal mixing for frequently used assessment of power, power ratios and connectivity profiles in basic research and for neurofeedback application. With this work, we hope to illustrate the effects of volume conduction in a concrete way, such that the provided practical illustrations may be of use to EEG researchers to in order to evaluate whether sensor space is an appropriate choice for their topic of investigation.
In the course of global climate change, central Europe is experiencing more frequent and prolonged periods of drought. The drought years 2018 and 2019 affected European beeches (Fagus sylvatica L.) differently: even in the same stand, drought damaged trees neighboured healthy trees, suggesting that the genotype rather than the environment was responsible for this conspicuous pattern. We used this natural experiment to study the genomic basis of drought resistance with Pool-GWAS. Contrasting the extreme phenotypes identified 106 significantly associated SNPs throughout the genome. Most annotated genes with associated SNPs (>70%) were previously implicated in the drought reaction of plants. Non-synonymous substitutions led either to a functional amino acid exchange or premature termination. A SNP-assay with 70 loci allowed predicting drought phenotype in 98.6% of a validation sample of 92 trees. Drought resistance in European beech is a moderately polygenic trait that should respond well to natural selection, selective management, and breeding.