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Biological drug substance (DS) is often frozen to enhance storage stability, prolong shelf life, and increase flexibility during manufacturing. However, the freezing and thawing (F/T) of bulk DS at the manufacturing scale can impact product quality as a result of various critical conditions, including cryo-concentration during freezing, which are influenced, among other things, by product-independent process parameters (e.g., container type, fill level, F/T equipment, and protocols). In this article, we report the optimization of two major methodologies to study product-independent process parameters in DS bottles at the manufacturing scale, namely the recording of temperature profiles and liquid sampling after thawing to quantify the concentration gradients in the solution. We report experimentally justified measuring positions for temperature recordings, especially for the selection of the last point to freeze position, and highlight the implementation of camera-assisted inspection to determine the last point to thaw and the actual thawing time. In particular, we provide, for the first time, a detailed description of the technical implementation of these two measuring set-ups. Based on the reported case studies, we recommend choosing relevant measuring positions as a result of initial equipment characterization, resulting in a resource-conscious study set-up.
The small GTPases H, K, and NRAS are molecular switches indispensable for proper regulation of cellular proliferation and growth. Several mutations in the genes encoding members of this protein family are associated with cancer and result in aberrant activation of signaling processes caused by a deregulated recruitment of downstream effector proteins. In this study, we engineered variants of the Ras-binding domain (RBD) of the C-Raf proto-oncogene, Ser/Thr kinase (CRAF). These variants bound with high affinity with the effector-binding site of Ras in an active conformation. Structural characterization disclosed how the newly identified RBD mutations cooperate and thereby enhance affinity with the effector-binding site in Ras compared with WT RBD. The engineered RBD variants closely mimicked the interaction mode of naturally occurring Ras effectors and acted as dominant-negative affinity reagents that block Ras signal transduction. Experiments with cancer cells showed that expression of these RBD variants inhibits Ras signaling, reducing cell growth and inducing apoptosis. Using these optimized RBD variants, we stratified patient-derived colorectal cancer organoids with known Ras mutational status according to their response to Ras inhibition. These results revealed that the presence of Ras mutations was insufficient to predict sensitivity to Ras inhibition, suggesting that not all of these tumors required Ras signaling for proliferation. In summary, by engineering the Ras/Raf interface of the CRAF-RBD, we identified potent and selective inhibitors of Ras in its active conformation that outcompete binding of Ras-signaling effectors.
Highlights
• Executive functions contribute to problem-solving in six- to eight-year-olds.
• Working memory and cognitive flexibility contribute to problem-solving.
•Inhibition does not significantly contribute to problem-solving.
Abstract
Previous research has shown that executive functions can contribute to successful problem-solving in preschool and elementary school children. However, most studies did not simultaneously assess the role of different specific aspects of executive functions. Therefore, the aim of our study was to investigate the individual contribution of inhibition, working memory, and cognitive flexibility to science problem-solving performance in elementary school children. A total of 478 children from first and second grades (Mage = 7.44 years) participated in our study. They performed a Go/No-go task (inhibition), a Corsi blocks backward task (working memory), a flexible item selection task (cognitive flexibility), and three science problem-solving tasks, including two gear turning tasks and one stabilization task. Structural equation modeling showed that working memory and cognitive flexibility individually contributed to problem-solving performance, whereas inhibition did not. We conclude that maintaining task requirements and dynamic object relations (working memory) and switching between different problem-solving phases (cognitive flexibility) are essential components of successful science problem-solving in elementary school children. Inhibitory processes may be more relevant in tasks involving a higher degree of interference at the task or response level.
Delegated online search
(2024)
In a delegation problem, a principal P with commitment power tries to pick one out of 𝑛 options. Each option is drawn independently from a known distribution. Instead of inspecting the options herself, P delegates the information acquisition to a rational and self-interested agent A. After inspection, A proposes one of the options, and P can accept or reject. Delegation is a classic setting in economic information design with many prominent applications, but the computational problems are only poorly understood. In this paper, we study a natural online variant of delegation, in which the agent searches through the options in an online fashion. For each option, he has to irrevocably decide if he wants to propose the current option or discard it, before seeing information on the next option(s). How can we design algorithms for P that approximate the utility of her best option in hindsight? We show that in general P can obtain a Θ(1∕𝑛)-approximation and extend this result to ratios of Θ(𝑘∕𝑛) in case (1) A has a lookahead of 𝑘 rounds, or (2) A can propose up to 𝑘 different options. We provide fine-grained bounds independent of 𝑛 based on three parameters. If the ratio of maximum and minimum utility for A is bounded by a factor 𝛼, we obtain an Ω(loglog 𝛼∕ log 𝛼)- approximation algorithm, and we show that this is best possible. Additionally, if P cannot distinguish options with the same value for herself, we show that ratios polynomial in 1∕𝛼 cannot be avoided. If there are at most 𝛽 different utility values for A, we show a Θ(1∕𝛽)-approximation. If the utilities of P and A for each option are related by a factor 𝛾, we obtain an Ω(1∕ log 𝛾)- approximation, where 𝑂(log log 𝛾∕ log 𝛾) is best possible.
Highlights
• Extreme weather events (floods, droughts, extreme heat) impact freshwater ecosystems.
• Effects of extreme events are site-specific, varying by organism traits and site hydrography.
• Cumulative impact of events is more significant than single events' magnitude.
• Temporal dynamics and biological characteristics are crucial for evaluating impacts.
• Freshwater ecosystem resilience depends on complex factors, not just event severity.
Abstract
Understanding the impacts of extreme weather events on freshwater ecosystems is imperative during a time when a multitude of challenges compromises these environments' health. Exploring how such events affect macroinvertebrate communities in rivers sheds light on the resilience of freshwater ecosystems, which is essential for human well-being and biodiversity conservation. In this study, long-term time series of benthic macroinvertebrate communities from four sites along three freshwater streams within the Rhine-Main-Observatory Long-Term Ecological Research site in Germany were analyzed. Each of them was sampled annually over a span of ~20 years to assess the impacts of extreme weather events (floods, droughts, and extreme heat) on macroinvertebrate communities. The findings reveal that the effects of extreme events are site-specific, suggesting that the impacts of an extreme event can vary based on several potential factors, including the life history traits of the organisms within the community and, among others, the hydrography of the site. Moreover, the analysis highlights that the cumulative impact of these events over time is more significant than the impact of a single event's magnitude, while following distinct temporal dynamics. This underscores the importance of considering both the temporal dynamics and the biological characteristics of communities when evaluating the consequences of extreme weather events on biodiversity, illustrating that the resilience of freshwater ecosystems and their biodiversity under such conditions depends on a complex interplay of factors rather than the severity of individual events.
By linearly parameterizing the QCD Landau free energy near the critical point in the baryon chemical potential and temperature plane, we study the fluctuations of the QCD chiral order parameter field (the σ field) in the equilibrium case and dynamical phase transition, respectively. By setting the system size to the typical size of the QGP fireball (≈103 fm3), we show that in the equilibrium case, the discontinuity of the order parameter in the first order phase transition region is replaced by smooth crossover, and the corresponding fluctuations are broadened. Meanwhile, the quartic cumulant κ4 of the σ field is generally negative near the phase transition line. We further derive the dynamical evolution of the QCD Landau free energy in the Fokker-Plank framework, based on which we deduce the dynamical cumulants of the σ field. Assuming the temperature decreases as a known function of time, we numerically evaluate the dynamical cumulants and confirm that the cumulants present clear memory effects. Moreover, the memory effects on the first order phase transition side is stronger than that on the crossover side, and the dynamical cumulants at the hypothetical freeze-out line present rich non-monotonic structures.
Plants and insects often use the same compounds for chemical communication, but not much is known about the genetics of convergent evolution of chemical signals. The terpene (E)-β-ocimene is a common component of floral scent and is also used by the butterfly Heliconius melpomene as an anti-aphrodisiac pheromone. While the biosynthesis of terpenes has been described in plants and microorganisms, few terpene synthases (TPSs) have been identified in insects. Here, we study the recent divergence of 2 species, H. melpomene and Heliconius cydno, which differ in the presence of (E)-β-ocimene; combining linkage mapping, gene expression, and functional analyses, we identify 2 novel TPSs. Furthermore, we demonstrate that one, HmelOS, is able to synthesise (E)-β-ocimene in vitro. We find no evidence for TPS activity in HcydOS (HmelOS ortholog of H. cydno), suggesting that the loss of (E)-β-ocimene in this species is the result of coding, not regulatory, differences. The TPS enzymes we discovered are unrelated to previously described plant and insect TPSs, demonstrating that chemical convergence has independent evolutionary origins.
Behaviorally irrelevant feature matching increases neural and behavioral working memory readout
(2024)
There is an ongoing debate about whether working memory (WM) maintenance relies on persistent activity and/or short-term synaptic plasticity. This is a challenging question, because neuroimaging techniques in cognitive neuroscience measure activity only. Recently, neural perturbation techniques have been developed to tackle this issue, such as visual impulse perturbation or “pinging”, which reveals (un)attended WM content during maintenance. There are contrasting explanations of how pinging reveals WM content, which is central to the debate. Pinging could reveal mnemonic representations by perturbing content-specific networks or by increasing the neural signal-to-noise ratio of active neural states. Here we tested the extent to which the neural impulse response is patterned by the WM network, by presenting two different impulse stimuli. If the impulse interacts with WM networks, the WM-specific impulse response should be enhanced by physical overlap between the initial memory item and the subsequent external perturbation stimulus. This prediction was tested in a delayed orientation match-to-sample task by matching or mismatching task-irrelevant spatial frequencies between memory items and impulse stimuli, as well as probes. Matching probe spatial frequency with memory items resulted in faster behavioral response times and matching impulse spatial frequency with memory items increased the specificity of the neural impulse response as measured from EEG. Matching spatial frequencies did neither result in globally stronger neural responses nor in a larger decrease in trial-to-trial variability compared to mismatching spatial frequencies. The improved neural and behavioural readout of irrelevant feature matching provide evidence that impulse perturbation interacts directly with the memory representations.
The activity-silent framework of working memory (WM) posits that the neural activity during object perception and encoding leaves behind patterned, “activity-silent” neural traces that enable WM maintenance without the need for continuous, memory-specific neural activity. The presence of such traces in the memory network subsequently patterns its responses to external stimulation, which can be used to readout the contents of WM using an impulse perturbation or “pinging” approach. The extent to which the neural impulse response is patterned by the WM network should be modulated by the physical overlap between the initial memory item and the subsequent external perturbation stimulus, with higher overlap increasing WM readout. Here we tested this prediction in a delayed orientation match-to-sample task, by either matching or mismatching task-irrelevant spatial frequencies between memory items and impulse stimuli, and between memory items and probes. Matching frequencies resulted in faster behavioral response times, and increased the WM-specificity of the neural impulse response as measured from the EEG signal. We found no evidence that matching spatial frequencies resulted in globally stronger or different neural responses, but rather in distinct neural activation patterns. The beneficial effects of feature matching in our task support the tenets of the activity-silent framework of WM, and confirm that impulse perturbation interacts directly with the representations that are held in memory.
The activity-silent framework of working memory (WM) posits that the neural activity during object perception and encoding leaves behind patterned, “activity-silent” neural traces that enable WM maintenance without the need for continuous, memory-specific neural activity. The presence of such traces in the memory network subsequently patterns its responses to external stimulation, which can be used to readout the contents of WM using an impulse perturbation or “pinging” approach. The extent to which the neural impulse response is patterned by the WM network should be modulated by the physical overlap between the initial memory item and the subsequent external perturbation stimulus, with higher overlap increasing WM readout. Here we tested this prediction in a delayed orientation match-to-sample task, by either matching or mismatching task-irrelevant spatial frequencies between memory items and impulse stimuli, and between memory items and probes. Matching frequencies resulted in faster behavioral response times, and increased the WM-specificity of the neural impulse response as measured from the EEG signal. We found no evidence that matching spatial frequencies resulted in globally stronger or different neural responses, but rather in distinct neural activation patterns. The beneficial effects of feature matching in our task support the tenets of the activity-silent framework of WM, and confirm that impulse perturbation interacts directly with the representations that are held in memory.
The dynamic process of membrane shaping and remodeling plays a vital role in cellular functions, with proteins and cellular membranes interacting intricately to adapt to various cellular needs and environmental cues. Ubiquitination—a posttranslational modification—was shown to be essential in regulating membrane structure and shape. It influences virtually all pathways relying on cellular membranes, such as endocytosis and autophagy by directing protein degradation, sorting, and oligomerization. Ubiquitin is mostly known as a protein modifier; however, it was reported that ubiquitin and ubiquitin-like proteins can associate directly with lipids, affecting membrane curvature and dynamics. In this review, we summarize some of the current knowledge on ubiquitin-mediated membrane remodeling in the context of endocytosis, autophagy, and ER-phagy.
The singly Cabibbo-suppressed decay Λ+c→nπ+ is observed for the first time with a statistical significance of 7.3σ by using 3.9 fb−1 of e+e− collision data collected at center-of-mass energies between 4.612 and 4.699 GeV with the BESIII detector at BEPCII. The branching fraction of Λ+c→nπ+ is measured to be (6.6±1.2stat±0.4syst)×10−4. By taking the upper limit of branching fractions of Λ+c→pπ0 from the Belle experiment, the ratio of branching fractions between Λ+c→nπ+ and Λ+c→pπ0 is calculated to be larger than 7.2 at the 90% confidence level, which disagrees with the current predictions of available phenomenological models. In addition, the branching fractions of the Cabibbo-favored decays Λ+c→Λπ+ and Λ+c→Σ0π+ are measured to be (1.31±0.08stat±0.05syst)×10−2 and (1.22±0.08stat±0.07syst)×10−2, respectively, which are consistent with previous results.
The singly Cabibbo-suppressed decay Λ+c→nπ+ is observed for the first time with a statistical significance of 7.3σ by using 3.9 fb−1 of e+e− collision data collected at center-of-mass energies between 4.612 and 4.699 GeV with the BESIII detector at BEPCII. The branching fraction of Λ+c→nπ+ is measured to be (6.6±1.2stat±0.4syst)×10−4. By taking the upper limit of branching fractions of Λ+c→pπ0 from the Belle experiment, the ratio of branching fractions between Λ+c→nπ+ and Λ+c→pπ0 is calculated to be larger than 7.2 at the 90% confidence level, which disagrees with the current predictions of available phenomenological models. In addition, the branching fractions of the Cabibbo-favored decays Λ+c→Λπ+ and Λ+c→Σ0π+ are measured to be (1.31±0.08stat±0.05syst)×10−2 and (1.22±0.08stat±0.07syst)×10−2, respectively, which are consistent with previous results.
The singly Cabibbo-suppressed decay Λ+c→nπ+ is observed for the first time with a statistical significance of 7.3σ by using 3.9 fb−1 of e+e− collision data collected at center-of-mass energies between 4.612 and 4.699 GeV with the BESIII detector at BEPCII. The branching fraction of Λ+c→nπ+ is measured to be (6.6±1.2stat±0.4syst)×10−4. By taking the upper limit of branching fractions of Λ+c→pπ0 from the Belle experiment, the ratio of branching fractions between Λ+c→nπ+ and Λ+c→pπ0 is calculated to be larger than 7.2 at the 90% confidence level, which disagrees with the current predictions of available phenomenological models. In addition, the branching fractions of the Cabibbo-favored decays Λ+c→Λπ+ and Λ+c→Σ0π+ are measured to be (1.31±0.08stat±0.05syst)×10−2 and (1.22±0.08stat±0.07syst)×10−2, respectively, which are consistent with previous results.
Objective: The aim of the study was to find out whether it is possible to successfully convert a communication course for around 400 students to a blended-learning format (asynchronous theoretical course/synchronous digital practical course). The main focus thereby was on assessing subjective learning progress and the extent to which the importance of communication and doctor-patient communication can be conveyed online. The study is based on the results of an evaluation of the opinions of both the students and the lecturers that participated in the course.
Methods: The students, who were in their fourth preclinical semester in 2020, were asked to fill in a self-assessment sheet at the beginning of the course, and following its completion. The feedback provided by the lecturers was also assessed. In order to compare the results and identify possible discrepancies, the corresponding self-assessment and evaluation results for the past 10 years (stemming from traditional classroom courses) were also taken into account.
Results: Participants in the online courses reported distinct subjective learning progress, and greater progress than was reported for traditional courses in previous years. The suitability of the online format was viewed critically by both students and lecturers, while the course atmosphere was seen positively. The relevance of doctor-patient communication was assessed particularly highly in the online format.
Conclusion: Based on the results of the evaluation, the experience gained from the blended-learning format will be included into future iterations of the communication course at Goethe University Frankfurt. The results have shown that doctor-patient communication can be learned well online. This format can therefore be recommended for new learning concepts in the future.
The cross sections of the e+e−→ϕη′ process at center-of-mass energies from 3.508 to 4.951 GeV are measured with high precision using 26.1 fb−1 data collected with the BESIII detector operating at the BEPCII storage ring. The cross sections are of the order of a few picobarn, and decrease as the center-of-mass energy increases as s−n/2 with n=4.35±0.14. This result is in agreement with the Nambu-Jona-Lasinio model prediction of n=3.5±0.9. In addition, the charmless decay ψ(3770)→ϕη′ is searched for by fitting the measured cross sections, yet no significant signal is observed. The upper limit of B(ψ(3770)→ϕη′) at the 90\% confidence level is determined to be 2.3×10−5.
The cross sections of the e+e−→ϕη′ process at center-of-mass energies from 3.508 to 4.951 GeV are measured with high precision using 26.1 fb−1 data collected with the BESIII detector operating at the BEPCII storage ring. The cross sections are of the order of a few picobarn, and decrease as the center-of-mass energy increases as s−n/2 with n=4.35±0.14. This result is in agreement with the Nambu-Jona-Lasinio model prediction of n=3.5±0.9. In addition, the charmless decay ψ(3770)→ϕη′ is searched for by fitting the measured cross sections, yet no significant signal is observed. The upper limit of B(ψ(3770)→ϕη′) at the 90\% confidence level is determined to be 2.3×10−5.
Using a data sample corresponding to an integrated luminosity of 2.93 fb−1 collected at a center-of-mass energy of 3.773~GeV with the BESIII detector at the BEPCII collider, we search for a scalar partner of the X(3872), denoted as X(3700), via ψ(3770)→γηη′ and γπ+π−J/ψ processes. No significant signals are observed and the upper limits of the product branching fractions B(ψ(3770)→γX(3700))⋅B(X(3700)→ηη′) and B(ψ(3770)→γX(3700))⋅B(X(3700)→π+π−J/ψ) are determined at the 90\% confidence level, for the narrow X(3700) with a mass ranging from 3710 to 3740 MeV/c2, which are from 0.8 to 1.8 (×10−5) and 0.9 to 3.4 (×10−5), respectively.
Using a data sample corresponding to an integrated luminosity of 2.93 fb−1 collected at a center-of-mass energy of 3.773~GeV with the BESIII detector at the BEPCII collider, we search for a scalar partner of the X(3872), denoted as X(3700), via ψ(3770)→γηη′ and γπ+π−J/ψ processes. No significant signals are observed and the upper limits of the product branching fractions B(ψ(3770)→γX(3700))⋅B(X(3700)→ηη′) and B(ψ(3770)→γX(3700))⋅B(X(3700)→π+π−J/ψ) are determined at the 90\% confidence level, for the narrow X(3700) with a mass ranging from 3710 to 3740 MeV/c2, which are from 0.8 to 1.8 (×10−5) and 0.9 to 3.4 (×10−5), respectively.
Using a data sample corresponding to an integrated luminosity of 2.93 fb−1 collected at a center-of-mass energy of 3.773~GeV with the BESIII detector at the BEPCII collider, we search for a scalar partner of the X(3872), denoted as X(3700), via ψ(3770)→γηη′ and γπ+π−J/ψ processes. No significant signals are observed and the upper limits of the product branching fractions B(ψ(3770)→γX(3700))⋅B(X(3700)→ηη′) and B(ψ(3770)→γX(3700))⋅B(X(3700)→π+π−J/ψ) are determined at the 90\% confidence level, for the narrow X(3700) with a mass ranging from 3710 to 3740 MeV/c2, which are from 0.8 to 1.8 (×10−5) and 0.9 to 3.4 (×10−5), respectively.
Using 4.7fb−1 of e+e− collision data at center-of-mass energies from 4.661 to 4.951 GeV collected by the BESIII detector at the BEPCII collider, we observe the X(3872) production process e+e−→ωX(3872) for the first time. The significance is 7.5σ, including both the statistical and systematic uncertainties. The e+e−→ωX(3872) Born cross section and the corresponding upper limit at 90\% confidence level at each energy point are reported. The line shape of the cross section indicates that the ωX(3872) signals may be from the decays of some non-trivial structures.
Using 4.7 fb−1 of e+e− collision data at center-of-mass energies from 4.661 to 4.951 GeV collected by the BESIII detector at the BEPCII collider, we observe the X(3872) production process e+e−→ωX(3872) for the first time. The significance is 7.8σ, including both the statistical and systematic uncertainties. The e+e−→ωX(3872) Born cross section and the corresponding upper limit at 90\% confidence level at each energy point are reported. The line shape of the cross section indicates that the ωX(3872) signals may be from the decays of some non-trivial structures.
It usually only takes a single glance to categorize our environment into different scene categories (e.g. a kitchen or a highway). Object information has been suggested to play a crucial role in this process, and some proposals even claim that the recognition of a single object can be sufficient to categorize the scene around it. Here, we tested this claim in four behavioural experiments by having participants categorize real-world scene photographs that were reduced to a single, cut-out object. We show that single objects can indeed be sufficient for correct scene categorization and that scene category information can be extracted within 50 ms of object presentation. Furthermore, we identified object frequency and specificity for the target scene category as the most important object properties for human scene categorization. Interestingly, despite the statistical definition of specificity and frequency, human ratings of these properties were better predictors of scene categorization behaviour than more objective statistics derived from databases of labelled real-world images. Taken together, our findings support a central role of object information during human scene categorization, showing that single objects can be indicative of a scene category if they are assumed to frequently and exclusively occur in a certain environment.
Osteoarthritis of the hip is a common condition that affects older adults. Total hip replacement is the end-stage treatment to relief pain and improve joint function. Little is known about the mechanical load distribution during the activity of bipedal stance, which is an important daily activity for older adults who need to rest more frequently. This study investigated the distribution of the hip and knee joint moments during bipedal stance in patients with unilateral hip osteoarthritis and how the distribution changed 1 year after total hip replacement. Kinematic and kinetic data from bipedal stance were recorded. External hip and knee adduction moments were calculated and load distribution over both limbs was calculated using the symmetry angle. Preoperatively, the non-affected limb carried 10% more body weight than the affected limb when standing on two legs. Moreover, the mean external hip and knee adduction moments of the non-affected limb were increased compared to the affected limb. At follow-up no significant differences were observed between the patients’ limbs. Preoperative and postoperative changes in hip adduction moment were mainly explained by the combination of the vertical ground reaction force and the hip adduction angle. Stance width also explained changes in the hip and knee adduction moments of the affected leg. Furthermore, as with walking, bipedal standing also showed an asymmetric mechanical load distribution in patients with unilateral hip osteoarthritis. Overall, the findings suggest the need for preventive therapy concepts that focus not only on walking but also on optimizing stance towards a balanced load distribution of both legs.
Background.
While computed tomography (CT)-guided liver biopsies are commonly performed using unenhanced images, contrast-enhanced images are beneficial for challenging puncture pathways and lesion locations. This study aimed to evaluate the accuracy of CT-guided biopsies for intrahepatic lesions using unenhanced, intravenous (IV)-enhanced, or intra-arterial Lipiodol-marked CT for lesion marking.
Patients and methods.
Six-hundred-seven patients (men: 358 [59.0%], mean age 61 years; SD ±12.04) with suspect hepatic lesions and CT-guided liver biopsies were retrospectively evaluated. Successful biopsies were histopathological findings other than typical liver tissue or non-specific findings. Data was ascertained regarding the use of contrast medium for the biopsy-planning CT, unenhanced (group 1) vs. Lipiodol (group 2) vs. IV contrast (group 3). Technical success and influencing factors were insulated. Complications were noted. The results were analyzed using the Wilcoxon-Man-Whitney t-test, Chi-square test, and Spearman-Rho.
Results.
Overall lesion hitting rate was 73.1%, with significantly better rates using Lipiodol-marked lesions (79.3%) compared to group 1 (73.8%) and group 3 (65.2%) (p = 0.037). Smaller lesions (<20 mm diameter) benefited significantly from Lipiodol-marking with 71.2% successful biopsy rate compared to group 1 (65.5%) and group 3 (47.7%) (p = 0.021). Liver cirrhosis (p = 0.94) and entity of parenchymal lesions (p = 0.78) had no impact on the hitting rate between the groups. No major complications occurred during the interventions.
Conclusions.
Pre-biopsy Lipiodol marking of suspect hepatic lesions significantly increases the lesion-hitting rate and is especially beneficial for biopsy of smaller targets below 20 mm diameter. Further, Lipiodol marking is superior to IV contrast for non-visible lesions in unenhanced CT. Target lesion entity has no impact on the hitting rate.
Philosophische Logik" bezeichnet einen Fundus von Theorien und Methoden, ohne die weite und zentrale Teile der heutigen Philosophe - in beinahe wörtlichem Sinne - gar nicht denkbar sind. Im Wechselspiel mit ihren Anwendungen hat sich dabei der Begriff der Logik selbst weiterentwickelt. An den Schnittstellen zu Nachbardisziplinen der Philosophie, wie der Informatik und Linguistik, hat sich die Entwicklung besonders rasant vollzogen und ist wiederum fruchtbar für die philosophische Theorienbildung geworden. Fuhrmanns Frankfurter Vorlesungen versuchen in dieses moderne Verständnis philosophischer Logik einzuführen. Das Buch ist als Lehrbuch geeignet, leitet den Leser jedoch auch zur kritischen Beurteilung formaler Theorien in der Philosophie an. Zentrale Themen werden kapitelübergreifend entwickelt. Dennoch sind die Kapitel in sich abgeschlossen und können so als gründliche Einführungen in ausgewählte Theorien gelesen werden.
We search for the process e+e−→π+π−χcJ (J=0,1,2) and for a charged charmonium-like state in the π±χcJ subsystem. The search uses data sets collected with the BESIII detector at the BEPCII storage ring at center-of-mass energies between 4.18 GeV and 4.60 GeV. No significant π+π−χcJ signals are observed at any center-of-mass energy, and thus upper limits are provided which also serve as limits for a possible charmonium-like structure in the invariant π±χcJ mass.
Using data taken at 23 center-of-mass energies between 4.0 and 4.6 GeV with the BESIII detector at the BEPCII collider and with a total integrated luminosity of approximately 15 fb−1, the process e+e−→2(pp¯) is studied for the first time. The Born cross sections for e+e−→2(pp¯) are measured, and no significant structure is observed in the lineshape. The baryon pair (pp and p¯p¯) invariant mass spectra are consistent with phase space, therefore no hexaquark or di-baryon state is found.
How do German general practitioners manage Long-/Post-COVID? A qualitative study in primary care
(2023)
Background: Many patients with ongoing complaints after a SARS-CoV-2 infection are treated in primary care. Existing medical guidelines on how to diagnose and treat Long-/Post-COVID are far from being comprehensive. This study aims to describe how German general practitioners (GPs) deal with this situation, what problems they experience when managing such patients, and how they solve problems associated with the diagnosis and treatment of Long-/Post-COVID.
Methods and Findings: We conducted a qualitative study and interviewed 11 GPs. The most commonly described symptoms were ongoing fatigue, dyspnea, chest tightness and a decrease in physical capacity. The most common way to identify Long-/Post-COVID was by exclusion. Patients suffering from Long-/Post-COVID were generally treated by their GPs and rarely referred. A very common non-pharmacological intervention was to take a wait-and-see approach and grant sick leave. Other non-pharmacological interventions included lifestyle advices, physical exercise, acupuncture and exercises with intense aromas. Pharmacological treatments focused on symptoms, like respiratory symptoms or headaches. Our study’s main limitations are the small sample size and therefore limited generalizability of results.
Conclusions: Further research is required to develop and test pharmaceutical and non-pharmaceutical interventions for patients with Long-/Post-COVID. In addition, strategies to prevent the occurrence of Long-/Post-COVID after an acute infection with SARS-CoV-2 have to be developed. The routine collection of data on the diagnosis and management of Long-/Post-COVID may help in the formulation of best practices. It is up to policymakers to facilitate the necessary implementation of effective interventions in order to limit the huge societal consequences of large groups of patients suffering from Long-/Post-COVID.
Using data taken at 23 center-of-mass energies between 4.0 and 4.6 GeV with the BESIII detector at the BEPCII collider and with a total integrated luminosity of approximately 15 fb−1, the process e+e−→2(pp¯) is studied for the first time. The Born cross sections for e+e−→2(pp¯) are measured, and no significant structure is observed in the lineshape. The baryon pair (pp and p¯p¯) invariant mass spectra are consistent with phase space, therefore no hexaquark or di-baryon state is found.
Using data taken at 23 center-of-mass energies between 4.0 and 4.6 GeV with the BESIII detector at the BEPCII collider and with a total integrated luminosity of approximately 15 fb−1, the process e+e−→2(pp¯) is studied for the first time. The Born cross sections for e+e−→2(pp¯) are measured, and no significant structure is observed in the lineshape. The baryon pair (pp and p¯p¯) invariant mass spectra are consistent with phase space, therefore no hexaquark or di-baryon state is found.
We present cross sections for the reaction e+e−→K0SK0L at center-of-mass energies ranging from 3.51 GeV to 4.95 GeV using data samples collected in the BESIII experiment, corresponding to a total integrated luminosity of 26.5 fb−1. The ratio of neutral-to-charged kaon form factors at large momentum transfers (12 GeV2<Q2<25 GeV2) is determined to be 0.21±0.01, which indicates a small but significant effect of flavor-SU(3) breaking in the kaon wave function, and consequently excludes the possibility that flavor-SU(3) breaking is the primary reason for the strong experimental violation of the pQCD prediction |F(π±)|/|F(K±)|=f2π/f2K, where F(π±) and F(K±) are the form factors, and fπ and fK are the decay constants of charged pions and kaons, respectively. We also observe a significant signal for the charmless decay ψ(3770)→K0SK0L for the first time. Within a 1σ contour of the likelihood value, the the branching fraction for ψ(3770)→K0SK0L is determined to be B=(2.63+1.40−1.59)×10−5, and the relative phase between the continuum and ψ(3770) amplitudes is ϕ=(−0.39+0.05−0.10)π. The branching fraction is in good agreement with the S- and D-wave charmonia mixing scheme proposed in the interpretation of the "ρπ puzzle" between J/ψ and ψ(3686) decays.
With a data sample corresponding to an integrated luminosity of 11.5~fb−1 collected with the BESIII detector operating at the BEPCII storage ring, for the first time the light hadron decay χc1(3872)→π+π−η is searched for. While no significant signal is observed, the upper limits at the 90\% confidence level for σ[e+e−→γχc1(3872)]B[χc1(3872)→π+π−η] at center-of-mass energies from 4.13 to 4.34 GeV are determined. By normalizing to the χc1(3872)→π+π−J/ψ decay channel, a 90\% confidence level upper limit for the branching fraction ratio R=B[χc1(3872)→π+π−η]/B[χc1(3872)→π+π−J/ψ]<0.12 is given. These measurements provide important inputs for understanding the internal structure of the χc1(3872) resonance.
A massless particle beyond the Standard Model is searched for in the two-body decay Σ+→p+invisible using (1.0087±0.0044)×1010 J/ψ events collected at a center-of-mass energy of s√=3.097 GeV with the BESIII detector at the BEPCII collider. No significant signal is observed, and the upper limit on the branching fraction B(Σ+→p+invisible) is determined to be 3.2×10−5 at the 90% confidence level. This is the first search for a flavor-changing neutral current process with missing energy in hyperon decays which plays an important role in constraining new physics models.
A massless particle beyond the Standard Model is searched for in the two-body decay Σ+→p+invisible using (1.0087±0.0044)×1010 J/ψ events collected with the BESIII detector at the BEPCII collider. No significant signal is observed, and the upper limit on the branching fraction B(Σ+→p+invisible) is determined to be 3.2×10−5 at the 90% confidence level. This is the first search for a flavor-changing neutral current process with missing energy in hyperon decays which plays an important role in constraining new physics models.
A massless particle beyond the Standard Model is searched for in the two-body decay Σ+→p+invisible using (1.0087±0.0044)×1010 J/ψ events collected at a center-of-mass energy of s√=3.097 GeV with the BESIII detector at the BEPCII collider. No significant signal is observed, and the upper limit on the branching fraction B(Σ+→p+invisible) is determined to be 3.2×10−5 at the 90% confidence level. This is the first search for a flavor-changing neutral current process with missing energy in hyperon decays which plays an important role in constraining new physics models.
In selective autophagy, cargo recruitment is mediated by LC3-interacting regions (LIRs) / Atg8-interacting motifs (AIMs) in the cargo or cargo receptor proteins. The binding of these motifs to LC3/Atg8 proteins at the phagophore membrane is often modulated by post-translational modifications, especially phosphorylation. As a challenge for computational LIR predictions, sequences may contain the short canonical (W/F/Y)XX(L/I/V) motif without being functional. Conversely, LIRs may be formed by non-canonical but functional sequence motifs. AlphaFold2 has proven to be useful for LIR predictions, even if some LIRs are missed and proteins with thousands of residues reach the limits of computational feasibility. We present a fragment-based approach to address these limitations. We find that fragment length and phosphomimetic mutations modulate the interactions predicted by AlphaFold2. Systematic fragment screening for a range of target proteins yields structural models for interactions that AlphaFold2 and AlphaFold3 fail to predict for full-length targets. We provide guidance on fragment choice, sequence tuning, and LC3 isoform effects for optimal LIR screens. Finally, we also test the transferability of this general framework to SUMO-SIM interactions, another type of protein-protein interaction involving short linear motifs (SLiMs).
In selective autophagy, cargo recruitment is mediated by LC3-interacting regions (LIRs) / Atg8-interacting motifs (AIMs) in the cargo or cargo receptor proteins. The binding of these motifs to LC3/Atg8 proteins at the phagophore membrane is often modulated by post-translational modifications, especially phosphorylation. As a challenge for computational LIR predictions, sequences may contain the short canonical (W/F/Y)XX(L/I/V) motif without being functional. Conversely, LIRs may be formed by non-canonical but functional sequence motifs. AlphaFold2 has proven to be useful for LIR predictions, even if some LIRs are missed and proteins with thousands of residues reach the limits of computational feasibility. We present a fragment-based approach to address these limitations. We find that fragment length and phosphomimetic mutations modulate the interactions predicted by AlphaFold2. Systematic fragment screening for a range of target proteins yields structural models for interactions that AlphaFold2 and AlphaFold3 fail to predict for full-length targets. We provide guidance on fragment choice, sequence tuning, and LC3 isoform effects for optimal LIR screens. Finally, we also test the transferability of this general framework to SUMO-SIM interactions, another type of protein-protein interaction involving short linear motifs (SLiMs).
The low-threshold L-type calcium channel Cav1.3 accelerates the pacemaker rate in the heart, but its functional role for the extended dynamic range of neuronal firing is still unresolved. Here, we show that Cav1.3 calcium channels act as unexpectedly simple, full-range linear amplifiers of firing rates for lateral dopamine substantia nigra (DA SN) neurons in mice. This means that they boost in vitro or in vivo firing frequencies between 2 and 50 hertz by about 30%. Furthermore, we demonstrate that clinically relevant, low nanomolar concentrations of the L-type channel inhibitor isradipine selectively reduce the in vivo firing activity of these nigrostriatal DA SN neurons at therapeutic plasma concentrations. Thus, our study identifies the pacemaker function of neuronal Cav1.3 channels and provides direct evidence that repurposing dihydropyridines such as isradipine is feasible to selectively modulate the in vivo activity of highly vulnerable DA SN subpopulations in Parkinson's disease.
Abstract
Inhibition of midbrain dopamine neurons is thought to underlie the signaling of events that are less rewarding than expected and drive learning based on these negative prediction errors. It has recently been shown that Kv4.3 channels influence the integration of inhibitory inputs in specific subpopulations of dopamine neurons. The functional properties of Kv4.3 channels are themselves strongly determined by the binding of auxiliary β-subunits; among them KChIP4a stands-out for its unique combination of modulatory effects. These include decreasing surface membrane trafficking and slowing inactivation kinetics. Therefore, we hypothesized that KChIP4a expression in dopamine neurons could play a crucial role in behavior, in particular by affecting the computation of negative prediction errors. We developed a mouse line where the alternative exon that codes for the KChIP4a splice variant was selectively deleted in midbrain dopamine neurons. In a reward-based reinforcement learning task, we observed that dopamine neuron-specific KChIP4a deletion selectively accelerated the rate of extinction learning, without impacting the acquisition of conditioned responses. We further found that this effect was due to a faster decrease in the initiation rate of goal-directed behaviors, and not faster increases in action disengagement. Furthermore, computational fitting of the behavioral data with a Rescorla-Wagner model confirmed that the observed phenotype was attributable to a selective increase in the learning rate from negative prediction errors. Finally, KChIP4a deletion did not affect performance in other dopamine-sensitive behavioral tasks that did not involve learning from disappointing events, including an absence of effects on working memory, locomotion and novelty preference. Taken together, our results demonstrate that an exon- and midbrain dopamine neuron-specific deletion of an A-type K+ channel β-subunit leads to a selective gain of function in extinction learning.
One Sentence Summary
Exon- and midbrain dopamine neuron-specific deletion of the Kv4 channel β-subunit KChIP4a selectively accelerates extinction learning
Dopamine (DA) neurons in the substantia nigra (SN) control several essential functions, including the voluntary movement, learning and motivated behavior. Healthy DA SN neurons show diverse firing patterns in vivo, ranging from slow pacemaker-like activity (1-10 Hz) to transient high frequency bursts (<100 Hz), interspersed with pauses that can last hundreds of milliseconds. Recent in vivo patch experiments have started to reveal the subthreshold mechanisms underlying this physiological diversity, but the impact of challenges like cell loss on the in vivo activity of adult DA SN neurons, and how these may relate to behavioral disturbances, are still largely unknown. We investigated the in vivo electrophysiological properties of surviving SN DA neurons after partial unilateral 6-OHDA lesions, a single-hit, non-progressive model of neuronal cell loss. We show that mice subjected to this model have an initial motor impairment, measured by asymmetrical rotations in the open field test, which recovered over time. At 3 weeks post-lesion, when open field locomotion was strongly impaired, surviving DA SN neurons showed a compressed in vivo dynamic firing range, characterized by a 10-fold reduction of in vivo burst firing compared to controls. This in vivo phenotype was accompanied by pronounced in vitro pacemaker instability. In contrast, in the chronic post-lesion phase (>2 months), where turning symmetry in open field locomotion had recovered, surviving SN DA neurons displayed the full dynamic range of in vivo firing, including in vivo bursting, similar to controls. The normalized in vivo firing pattern was associated with a 2-fold acceleration of stable in vitro pacemaking, mediated by Kv4.3 potassium channel downregulation. Our findings demonstrate the existence of a homeostatic pacemaker plasticity mechanism in surviving DA SN neurons after pronounced cell loss.
Marine stratocumuli are the most dominant cloud type by area coverage in the Southern Ocean (SO). They can be divided into different self-organized cellular morphological regimes known as open and closed mesoscale-cellular convective (MCC) clouds. Open and closed cells are the two most frequent types of organizational regimes in the SO. Using the liDAR-raDAR (DARDAR) version 2 retrievals, we quantify 59 % of all MCC clouds in this region as mixed-phase clouds (MPCs) during a 4-year time period from 2007 to 2010. The net radiative effect of SO MCC clouds is governed by changes in cloud albedo. Both cloud morphology and phase have previously been shown to impact cloud albedo individually, but their interactions and their combined impact on cloud albedo remain unclear.
Here, we investigate the relationships between cloud phase, organizational patterns, and their differences regarding their cloud radiative properties in the SO. The mixed-phase fraction, which is defined as the number of MPCs divided by the sum of MPC and supercooled liquid cloud (SLC) pixels, of all MCC clouds at a given cloud-top temperature (CTT) varies considerably between austral summer and winter. We further find that seasonal changes in cloud phase at a given CTT across all latitudes are largely independent of cloud morphology and are thus seemingly constrained by other external factors. Overall, our results show a stronger dependence of cloud phase on cloud-top height (CTH) than CTT for clouds below 2.5 km in altitude.
Preconditioning through ice-phase processes in MPCs has been observed to accelerate individual closed-to-open cell transitions in extratropical stratocumuli. The hypothesis of preconditioning has been further substantiated in large-eddy simulations of open and closed MPCs. In this study, we do not find preconditioning to primarily impact climatological cloud morphology statistics in the SO. Meanwhile, in-cloud albedo analysis reveals stronger changes in open and closed cell albedo in SLCs than in MPCs. In particular, few optically thick (cloud optical thickness >10) open cell stratocumuli are characterized as ice-free SLCs. These differences in in-cloud albedo are found to alter the cloud radiative effect in the SO by 21 to 39 W m−2 depending on season and cloud phase.
Acute myeloid leukemia (AML) is a heterogeneous malignancy characterized by the accumulation of undifferentiated white blood cells (blasts) in the bone marrow. Valosin-containing protein (VCP) is an abundant molecular chaperone that extracts ubiquitylated substrates from protein complexes and cellular compartments prior to their degradation by the proteasome. We found that treatment of AML cell lines with the VCP inhibitor CB-5083 leads to an accumulation of ubiquitylated proteins, activation of unfolded protein response (UPR) and apoptosis. Using quantitative mass spectrometry-based proteomics we assessed the effects of VCP inhibition on the cellular ubiquitin-modified proteome. We could further show that CB-5083 decreases the survival of the AML cell lines THP-1 and MV4-11 in a concentration-dependent manner, and acts synergistically with the antimetabolite cytarabine and the BH3-mimetic venetoclax. Finally, we showed that prolonged treatment of AML cells with CB-5083 leads to development of resistance mediated by mutations in VCP. Taken together, inhibition of VCP leads to a lethal unfolded protein response in AML cells and might be a relevant therapeutic strategy for treatment of AML, particularly when combined with other drugs. The toxicity and development of resistance possibly limit the utility of VCP inhibitors and have to be further explored in animal models and clinical trials.
Background: Only one previously published study by Nocera et al. addressed the risk of upstaging to ≥pT3 in cT1 clear cell renal cell carcinoma (ccRCC) by using characteristics of the R.E.N.A.L and PADUA score (age, tumor size, rim location, exophytic rate, polar involvement) developing an accurate nomogram. However, this nomogram has never been externally validated yet.
Material and methods: The study cohort consisted of 288 patients with cT1a-b ccRCC, diagnosed between 2008-2021 at the University Hospital Frankfurt, Germany. Analyses addressed clinical, tumor and radiographic characteristics. The external validation of the nomogram relied on accuracy calculations derived from the area under the curve of the receiver operator characteristic analysis.
Results: Overall, 11.8% (n=34) patients harbored ≥pT3 ccRCC. Median radiographic tumor size (3.6 vs. 5.3cm), R.E.N.A.L. (8 vs. 9 points) and PADUA score (9 vs. 11 points), as well as proportions of renal sinus involvement (82.4% vs. 51.6%), renal hilus involvement (44.1 vs. 13.0%), and medial rim location significantly differed between the pT1-2 and ≥pT3 group (all p ≤ 0.01). In subgroup analyses of small renal mass ccRCC patients (<4cm, cT1a), only 3.8% (n=6) patients had ≥pT3 pathology. Upstaged patients were significantly older and more frequently had endophytic tumor than pT1-2 counterparts (p<0.05). The external validation of the Nocera nomogram showed a good accuracy of 76.6%. Using the suggested cut-off of 21%, 26.5% of patients exhibited ≥pT3 ccRCC. Conversely, within patients below cut-off, 5.9% patients exhibited ≥pT3 ccRCC.
Conclusion: We reported the first external validation of the nomogram addressing the risk of ≥pT3 in cT1 ccRCC patients, demonstrating a good accuracy, with a low false-negative rate. Therefore, the nomogram can accurately be used for patients’ counselling and treatment decision making.
Implementation and evaluation of a Tele-OSCE in oral and maxillofacial surgery – a pilot report
(2022)
Background: The ongoing changes in learning and education towards digitalisation have been rapidly accelerated by the COVID-19 pandemic. Especially in dental education where contact to the oral cavity is an integral part of training the chosen digital examination methods and training formats must undergo high requirements to full fill the goal of a real alternative to face-to-face exams. Therefore, this study compared student performance in a newly developed Tele-OSCE with a prior OSCE examinations in presence within an oral- and maxillofacial surgery curriculum.
Methods: Study participants were fourth-year (in a five year curriculum) dental students and board certified maxillofacial surgeons (examiners) that took part in a newly developed Tele-OSCE that comprised three five-minute stations (structured facial examination, management mandibular fracture and squamous cell carcinoma) using the zoom® software. Student performance was measured using validated OSCE-Checklists and compared to a previous OSCE examination from the winter term 2019 with the same OSCE stations that was conducted in presence. Significant differences were tested using the Mann-Whitney U test. Furthermore, the new Tele-OSCE was evaluated by students and examiners using previously developed questionnaires.
Results: Sixty-six dental students (study group: n=34, summer term 2021, control group: n=32 winter term 2019) and nine examiners participated in the study. Compared to previous non-pandemic OSCEs, there were no significant (p=0.53) differences in overall student performance. Evaluation of the Tele-OSCE showed that the demonstration and rating of practical skills was limited due to missing standard patients or phantoms, however, students did not fear to be misjudged. The demonstration and rating of anamnestic and consultation competencies was seen as unproblematic by students and examiners.
Discussion: This pilot-study showed the feasibility of a Tele-OSCE as a formative examination in dental education. However, both students and examiners felt that the demonstration and assessment of practical skills was limited due the new examination format. Nevertheless, Tele-OSCEs might offer an alternative to enable students to complete their dental training.
Seismic arrays provide tools for the localization of events without clear phases or events outside the network, where the station coverage prohibits classical localization techniques. Beam forming allows the determination of the direction (back azimuth) and horizontal (apparent) velocity of an incoming wavefront. Here we combine multiple arrays to retrieve event epicentres from the area of intersecting beams without the need to specify a velocity model. The analysis is performed in the time domain, which allows selecting a relatively narrow time window around the phase of interest while preserving frequency bandwidth. This technique is applied to earthquakes and hybrid events in the region of Fogo and Brava, two islands of the southern chain of the Cape Verde archipelago. The results show that the earthquakes mainly originate near Brava, whereas the hybrid events are located on Fogo. By multiple-event beam stacking we are able to further constrain the epicentral locations of the hybrid events in the northwestern part of the collapse scar of Fogo. In previous studies, these events were attributed to shallow hydrothermal processes. However, we obtain relatively high apparent velocities at the arrays, pointing to either deeper sources or complex ray paths. For a better understanding of possible errors of the multi-array analysis, we also compare slowness values obtained from the array analysis with those derived from earthquake locations from classical (local network) localizations. In general, the results agree well. Nevertheless, some systematic deviations of the array-derived back-azimuth and slowness values occur that can be quantified for certain event locations.
Seismic arrays provide tools for the localization of events without clear phases or events outside the network, where the station coverage prohibits classical localization techniques. Beam forming allows the determination of the direction (back azimuth) and horizontal (apparent) velocity of an incoming wavefront. Here we combine multiple arrays to retrieve event epicentres from the area of intersecting beams without the need to specify a velocity model. The analysis is performed in the time domain, which allows selecting a relatively narrow time window around the phase of interest while preserving frequency bandwidth. This technique is applied to earthquakes and hybrid events in the region of Fogo and Brava, two islands of the southern chain of the Cape Verde archipelago. The results show that the earthquakes mainly originate near Brava, whereas the hybrid events are located on Fogo. By multiple-event beam stacking we are able to further constrain the epicentral locations of the hybrid events in the northwestern part of the collapse scar of Fogo. In previous studies, these events were attributed to shallow hydrothermal processes. However, we obtain relatively high apparent velocities at the arrays, pointing to either deeper sources or complex ray paths. For a better understanding of possible errors of the multi-array analysis, we also compare slowness values obtained from the array analysis with those derived from earthquake locations from classical (local network) localizations. In general, the results agree well. Nevertheless, some systematic deviations of the array-derived back-azimuth and slowness values occur that can be quantified for certain event locations.
Treatment of relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT) remains a great challenge. Aiming to evaluate the combination of venetoclax and hypomethylating agents (HMAClax) for the treatment of relapse of myeloid malignancies after alloHSCT, we retrospectively collected data from 32 patients treated at 11 German centers. Venetoclax was applied with azacitidine (n = 13) or decitabine (n = 19); 11 patients received DLI in addition. HMAClax was the first salvage therapy in 8 patients. The median number of cycles per patient was 2 (1–19). All but 1 patient had grade 3/4 neutropenia. Hospital admission for grade 3/4 infections was necessary in 23 patients (72%); 5 of these were fatal. In 30 evaluable patients, overall response rate (ORR) was 47% (14/30, 3 CR MRDneg, 5 CR, 2 CRi, 1 MLFS, 3 PR). ORR was 86% in first salvage patients versus 35% in later salvage patients (p = 0.03). In 6 patients with molecular relapse (MR), ORR was 67% versus 42% in patients with hematological relapse (HR) (n = 24, p = n.s.). After a median follow-up of 8.4 months, 25 patients (78%) had died and 7 were alive. Estimated median overall survival was 3.7 months. Median survival of patients with HMAClax for first versus later salvage therapy was 5.7 and 3.4 months (p = n.s.) and for patients with MR (not reached) compared to HR (3.4 months, p = 0.024). This retrospective case series shows that venetoclax is utilized in various different combinations, schedules, and doses. Toxicity is substantial and patients who receive venetoclax/HMA combinations for MR or as first salvage therapy derive the greatest benefit.
The present study examined the impact of the COVID-19 pandemic on the emotional quality of dreams, the incorporation of pandemic-related themes, and the occurrence of lucid dreaming. Dream reports and lucidity ratings of psychiatric outpatients (n = 30) and healthy controls (n = 81) during two lockdowns in Germany were compared to those of healthy controls (n = 33) before the pandemic. Results confirmed previous reports that pandemic-specific themes were incorporated into dreams. Overall, however, incorporation into dreams was rare. Contrary to expectations, psychiatric outpatients did not differ from controls in the frequency of dream incorporation of pandemic-related content. Moreover, incorporation was independent of psychiatric symptoms and loneliness. Loneliness was, however, associated with threat-related content, suggesting that it represents a risk for bad dreams but not for crisis-specific dream incorporation. Regarding lucid dreaming, both groups had similar scores for its underlying core dimensions, i.e., insight, control, and dissociation, during the two lockdowns. Scores for control and dissociation but not insight were lower compared to the pre-pandemic sample. Our working hypothesis is that REM sleep during lockdowns intensified as a means of increased emotional consolidation, rendering the associated mental state less hybrid and thereby less lucid.
Researchers have suggested that the recognition memory effects resulting from two separate attentional manipulations—attentional boost and perceptual degradation—may share a common cause; namely a transient up-regulation of attention at the time of encoding that leads to enhanced memory performance at the time of retrieval. Prior research has demonstrated that inducing two similar transient shifts of attention simultaneously produces redundant performance in memory. In the present study, we sought to evaluate the combined influence of the attentional boost and perceptual degradation on recognition memory. If these two effects share a common cause, then we ought to observe a redundancy in memory performance, such that these two factors interact. Yet, across four experiments we fail to observe such a redundancy in recognition memory. We evaluate these results using the limited resource model of attention and speculate on how combining transient shifts of attention may produce redundant memory performance in the one case, but non-redundant performance in the other case.
We show a shift in the prevalence of respiratory viral pathogens in community-acquired pneumonia patients during the COVID-19 pandemic. Our data support the efficiency of non-pharmaceutical interventions on virus circulation except for rhinoviruses. The consequences of an altered circulation on subsequent winter seasons remain unclear and support the importance of systematic virological surveillance.
Background: Since mammography belongs to the most important preventive techniques in modern medicine, this study maps the related worldwide research output, which encompasses quantitative and qualitative aspects of the scientific activity and socio-economic features.
Methods: The New Quality and Quantity Indices in Science (NewQIS) computing platform identified all mammography-specific articles in the Web of Science within two time periods, from 1900 to 2014 (P1) and from 2015 to 2020 (P2), a combination of density-equalizing mapping projections (DEMP) and socio-economic benchmarking was applied for analysis.
Results: A total of 13,629 articles were retrieved. 8,744 articles were identified in P1 and 4,885 in P2. More than 100 articles were published annually since the 1980s. Regarding productivity and collaborative efforts, the United States was the leading nation in both evaluation periods. In our socioeconomic analysis, it was also ranked at the first place in P1 [72.68 mammography-related publications per GDP/capita (RGDP)]. The US was followed by the UK and Germany in P1 and by UK and India in P2. When population sizes were related to mammography research activities, Scandinavian countries and the Netherlands showed the highest research activity in P1 (e.g., Sweden: 31.89 publications per 1 million inhabitants). Gender analysis illustrated a relative dominance of female researchers in most countries with the exception of Japan.
Conclusions: The global mammography research activity over the last century is paralleled by strong international collaborative efforts and follows largely economic figures and prevalence rates but displays distinct differences in comparison to the research landscape of other biomedical entities.
Prognostic assessment of patients with liver cirrhosis allocated for implantation of a transjugular intrahepatic portosystemic shunt (TIPS) is a challenging task in clinical practice. The aim of our study was to assess the prognostic value of the CLIF‐C AD (Acute Decompensation) score in patients with TIPS implantation. Transplant‐free survival (TFS) and 3‐month mortality were reviewed in 880 patients who received de novo TIPS implantation for the treatment of cirrhotic portal hypertension. The prognostic value of the CLIF‐C AD score was compared with the Model for End‐Stage Liver Disease (MELD) score, Child‐Pugh score, and albumin‐bilirubin (ALBI) score using Harrell’s C concordance index. The median TFS after TIPS implantation was 40.0 (34.6‐45.4) months. The CLIF‐C AD score (c = 0.635 [0.609‐0.661]) was superior in the prediction of TFS in comparison to MELD score (c = 0.597 [0.570‐0.623], P = 0.006), Child‐Pugh score (c = 0.579 [0.552‐0.606], P < 0.001), and ALBI score (c = 0.573 [0.545‐0.600], P < 0.001). However, the CLIF‐C AD score did not perform significantly better than the MELD‐Na score (c = 0.626 [0.599‐0.653], P = 0.442). There were no profound differences in the scores’ ranking with respect to indication for TIPS implantation, stent type, or underlying liver disease. Subgroup analyses revealed that a CLIF‐C AD score >45 was a predictor of 3‐month mortality in the supposed low‐risk group of patients with a MELD score ≤12 (14.7% vs. 5.1%, P < 0.001). Conclusion: The CLIF‐C AD score is suitable for prognostic assessment of patients with cirrhotic portal hypertension receiving TIPS implantation. In the prediction of TFS, the CLIF‐C AD score is superior to MELD score, Child‐Pugh score, and ALBI score but not the MELD‐Na score.
ISOE-Newsletter Nr. 4/2024
(2024)
„Das ist eine Mammutaufgabe“ – ISOE-Experte Thomas Friedrich über den Stand der Klimaanpassung in Kommunen +++ „Der Biodiversitätsverlust nimmt auf zögerliche politische Prozesse keine Rücksicht“ – ISOE-Forscherin Marion Mehring im Interview +++ Neuartiger landwirtschaftlicher Anbau mit aufbereitetem Wasser: Erstes Reallabor in Betrieb +++ Lösungen für die nachhaltige Wasserversorgung in boomenden Urlaubsregionen +++ Wie kann eine Trendwende zum Schutz der Artenvielfalt erreicht werden? Neues Analysetool gibt Antworten +++ Aktuelle Beiträge im ISOE Blog +++ Aus dem ISOE +++ Das ISOE in den Medien +++ Termine +++ Publikationen
Der Beitrag stellt am Beispiel der dritten Phase der Lehrer:innenbildung den Professionalisierungsansatz vor, der in dem Forschungs- und Entwicklungsprojekt „Reflexion, Leistung und Inklusion“ (ReLInk) konzipiert und in Fortbildungsworkshops für Lehrkräfte der Sekundarstufe I erprobt wurde. Nach einer Projektdarstellung (Abschnitt 1) werden ausgewählte Ergebnisse der im Rahmen von ReLInk durchgeführten qualitativen Studie vorgestellt (Abschnitt 2). Diese Ergebnisse bildeten den Ausgangspunkt für die Entwicklung kasuistischer Materialien für die Aus- und Fortbildung von (angehenden) Lehrkräften. Für die Gestaltung der Fortbildungsworkshops stellte die Arbeit mit der Methode der sequenzanalytischen praxisreflexiven Kasuistik den Kern des Professionalisierungsansatzes von ReLInk dar. Die Materialien stehen online in einem Open-Access-Themenheft zur Verfügung (Abschnitt 3). Hierzu werden Erfahrungen aus den Workshops und Ergebnisse einer qualitativen Evaluation dieses Ansatzes präsentiert (Abschnitt 4). Am Ende werden anschließende Fragen sowohl für die Professionalisierung sowie für die Forschung aufgeworfen (Abschnitt 5).
Ausgehend von dem Spannungsverhältnis von Leistung und Inklusion als Anlass zur Reflexion wird in diesem Beitrag das Verständnis von Reflexion als soziale Praxis vorgestellt. Auf Basis der im Projekt „Reflexion, Leistung und Inklusion“ (ReLInk) durchgeführten Fortbildungsworkshops wird dazu mit Blick auf die Frage der Gestaltung entsprechender institutioneller Reflexionsräume die Methode der sequenzanalytischen praxisreflexiven Kasuistik fokussiert. Im Anschluss an die zusammenfassende Darstellung der Erfahrungen und Evaluationsergebnisse werden als Ausblick konzeptionelle Überlegungen zu einer längerfristigen schulinternen Fortbildung zum reflexiven Umgang mit Leistung in inklusiven Settings skizziert.
Cancer is the second leading cause of mortality worldwide. Despite recent advances in cancer treatment including immunotherapy with immune checkpoint inhibitors, new unconventional biomarkers and targets for the detection, prognosis, and treatment of cancer are still in high demand. Tumor cells are characterized by mutations that allow their unlimited growth, program their local microenvironment to support tumor growth, and spread towards distant sites. While a major focus has been on altered tumor genomes and proteomes, crucial signaling molecules such as lipids have been underappreciated. One of these molecules is the membrane phospholipid phosphatidylserine (PS) that is usually found at cytosolic surfaces of cellular membranes but can be rapidly and massively shuttled to the extracellular leaflet of the plasma membrane during apoptosis to serve as a limiting factor for immune responses. These immunosuppressive interactions are exploited by tumor cells to evade the immune system. In this review, we describe mechanisms of immune regulation in tumors, discuss if PS may constitute an inhibitory immune checkpoint, and describe current and future strategies for targeting PS to reactivate the tumor-associated immune system.
The signaling lipid phosphatidylinositol-4,5-bisphosphate (PIP2) regulates many ion channels. It inhibits eukaryotic cyclic nucleotide-gated (CNG) channels while activating their relatives, the hyperpolarization-activated and cyclic nucleotide-modulated (HCN) channels. The prokaryotic SthK channel from Spirochaeta thermophila shares features with CNG and HCN channels and is an established model for this channel family. Here, we show SthK activity is inhibited by PIP2. A cryo-EM structure of SthK in nanodiscs reveals a PIP2-fitting density coordinated by arginine and lysine residues from the S4 helix and the C-linker, located between voltage-sensing and pore domains of adjacent subunits. Mutation of two arginine residues weakens PIP2 inhibition with the double mutant displaying insensitivity to PIP2. We propose that PIP2 inhibits SthK by gluing S4 and S6 together, stabilizing a resting channel conformation. The PIP2 binding site is partially conserved in CNG channels suggesting the possibility of a similar inhibition mechanism in the eukaryotic homologs.
Competition of inhomogeneous chiral phases and two-flavor color superconductivity in the NJL model
(2021)
We study the phase structure of the two-flavor Nambu–Jona-Lasinio (NJL) model in the chiral limit, extending a previous study of the competition of an inhomogeneous chiral phase and a two-flavor color-superconducting (2SC) phase [M. Sadzikowski, Phys. Lett. B 553, 45 (2003); M. Sadzikowski, Phys. Lett. B 642, 238 (2006)]. There, an analytic expression for the dispersion relations for quasiparticle excitations in the presence of both a particular inhomogeneous chiral condensate, the so-called chiral density wave (CDW), and a homogeneous 2SC condensate was found. In this work we show how to determine the dispersion relations for arbitrary modulations of the chiral condensate in the presence of a homogeneous 2SC condensate, if the dispersion relations in the absence of color superconductivity are known. In our calculations, we employ two different Ansätze for the inhomogeneous chiral condensate, the CDW as well as the real-kink crystal (RKC). Depending on the value of the diquark coupling we find a region of the phase diagram where the inhomogeneous chiral and the 2SC condensates coexist, confirming results of M. Sadzikowski [Phys. Lett. B 553, 45 (2003); 642, 238 (2006)]. Decreasing the diquark coupling favors the inhomogeneous phase over the coexistence phase. On the other hand, increasing the diquark coupling leads to a larger 2SC phase, while the inhomogeneous chiral and the coexistence phases become smaller. In agreement with previous studies the RKC Ansatz is energetically preferred over the CDW Ansatz. Both Ansätze lead to a qualitatively similar phase diagram, however, the coexistence phase is smaller for the RKC Ansatz.
In this Letter we report the first results on π±, K±, p and pp¯¯¯ production at mid-rapidity (|y|<0.5) in central Pb-Pb collisions at sNN−−−√ = 2.76 TeV, measured by the ALICE experiment at the LHC. The pT distributions and yields are compared to previous results at sNN−−−√ = 200 GeV and expectations from hydrodynamic and thermal models. The spectral shapes indicate a strong increase of the radial flow velocity with sNN−−−√, which in hydrodynamic models is expected as a consequence of the increasing particle density. While the K/π ratio is in line with predictions from the thermal model, the p/π ratio is found to be lower by a factor of about 1.5. This deviation from thermal model expectations is still to be understood.
The ALICE Collaboration has measured the inclusive production of muons from heavy flavour decays at forward rapidity, 2.5 < y < 4, in pp and Pb-Pb collisions at sNN−−−−√ = 2.76 TeV. The pT-differential inclusive cross section of muons from heavy flavour decays in pp collisions is compared to perturbative QCD calculations. The nuclear modification factor is studied as a function of pt and collision centrality. A weak suppression is measured in peripheral collisions. In the most central collisions, a suppression of a factor of about 3-4 is observed in 6 < pT < 10 GeV/c. The suppression shows no significant pT dependence.
We report on the first measurement of inclusive J/ψ elliptic flow, v2, in heavy-ion collisions at the LHC. The measurement is performed with the ALICE detector in Pb-Pb collisions at sNN−−−√=2.76 TeV in the rapidity range 2.5<y<4.0. The dependence of the J/ψ v2 on the collision centrality and on the J/ψ transverse momentum is studied in the range 0<pT<10 GeV/c. For semi-central Pb-Pb collisions at sNN−−−√=2.76 TeV, an indication of non-zero v2 is observed with a maximum value of v2=0.116±0.046(stat.)±0.029(syst.) for J/ψ in the transverse momentum range 2<pT<4 GeV/c. The elliptic flow measurement complements the previously reported ALICE results on the inclusive J/ψ nuclear modification factor and favors the scenario of a significant fraction of J/ψ production from charm quarks in a deconfined partonic phase.
Measurements of cross sections of inelastic and diffractive processes in proton--proton collisions at LHC energies were carried out with the ALICE detector. The fractions of diffractive processes in inelastic collisions were determined from a study of gaps in charged particle pseudorapidity distributions: for single diffraction (diffractive mass MX<200 GeV/c2) σSD/σINEL=0.21±0.03,0.20+0.07−0.08, and 0.20+0.04−0.07, respectively at centre-of-mass energies s√=0.9,2.76, and 7~TeV; for double diffraction (for a pseudorapidity gap Δη>3) σDD/σINEL=0.11±0.03,0.12±0.05, and 0.12+0.05−0.04, respectively at s√=0.9,2.76, and 7~TeV. To measure the inelastic cross section, beam properties were determined with van der Meer scans, and, using a simulation of diffraction adjusted to data, the following values were obtained: σINEL=62.8+2.4−4.0(model)±1.2(lumi) mb at s√= 2.76~TeV and 73.2+2.0−4.6(model)±2.6(lumi) mb at s√ = 7~TeV. The single- and double-diffractive cross sections were calculated combining relative rates of diffraction with inelastic cross sections. The results are compared to previous measurements at proton--antiproton and proton--proton colliders at lower energies, to measurements by other experiments at the LHC, and to theoretical models.
The production of the ψ(2S) charmonium state was measured with ALICE in Pb-Pb collisions at sNN−−−√=5.02 TeV, in the dimuon decay channel. A significant signal was observed for the first time at LHC energies down to zero transverse momentum, at forward rapidity (2.5<y<4). The measurement of the ratio of the inclusive production cross sections of the ψ(2S) and J/ψ resonances is reported as a function of the centrality of the collisions and of transverse momentum, in the region pT<12 GeV/c. The results are compared with the corresponding measurements in pp collisions, by forming the double ratio [σψ(2S)/σJ/ψ]Pb−Pb/[σψ(2S)/σJ/ψ]pp. It is found that in Pb-Pb collisions the ψ(2S) is suppressed by a factor of ∼2 with respect to the J/ψ. The ψ(2S) nuclear modification factor RAA was also obtained as a function of both centrality and pT. The results show that the ψ(2S) resonance yield is strongly suppressed in Pb-Pb collisions, by a factor up to ∼3 with respect to pp. Comparisons of cross section ratios with previous SPS findings by the NA50 experiment and of RAA with higher-pT results at LHC energy are also reported. These results and the corresponding comparisons with calculations of transport and statistical models address questions on the presence and properties of charmonium states in the quark-gluon plasma formed in nuclear collisions at the LHC.
The production of the ψ(2S) charmonium state was measured with ALICE in Pb-Pb collisions at sNN−−−√=5.02 TeV, in the dimuon decay channel. A significant signal was observed for the first time at LHC energies down to zero transverse momentum, at forward rapidity (2.5<y<4). The measurement of the ratio of the inclusive production cross sections of the ψ(2S) and J/ψ resonances is reported as a function of the centrality of the collisions and of transverse momentum, in the region pT<12 GeV/c. The results are compared with the corresponding measurements in pp collisions, by forming the double ratio [σψ(2S)/σJ/ψ]Pb−Pb/[σψ(2S)/σJ/ψ]pp. It is found that in Pb-Pb collisions the ψ(2S) is suppressed by a factor of ∼2 with respect to the J/ψ. The ψ(2S) nuclear modification factor RAA was also obtained as a function of both centrality and pT. The results show that the ψ(2S) resonance yield is strongly suppressed in Pb-Pb collisions, by a factor up to ∼3 with respect to pp. Comparisons of cross section ratios with previous SPS findings by the NA50 experiment and of RAA with higher-pT results at LHC energy are also reported. These results and the corresponding comparisons with calculations of transport and statistical models address questions on the presence and properties of charmonium states in the quark-gluon plasma formed in nuclear collisions at the LHC.
The production of the ψ(2S) charmonium state was measured with ALICE in Pb-Pb collisions at sNN−−−√=5.02 TeV, in the dimuon decay channel. A significant signal was observed for the first time at LHC energies down to zero transverse momentum, at forward rapidity (2.5<y<4). The measurement of the ratio of the inclusive production cross sections of the ψ(2S) and J/ψ resonances is reported as a function of the centrality of the collisions and of transverse momentum, in the region pT<12 GeV/c. The results are compared with the corresponding measurements in pp collisions, by forming the double ratio [σψ(2S)/σJ/ψ]Pb−Pb/[σψ(2S)/σJ/ψ]pp. The ψ(2S) nuclear modification factor RAA was also obtained as a function of both centrality and pT. The results show that the ψ(2S) resonance yield is strongly suppressed in Pb-Pb collisions, by a factor up to ∼3 with respect to pp. Furthermore, the ψ(2S) suppression in Pb-Pb collisions is stronger than the one observed for the J/ψ by a factor ∼2. Comparisons of cross section ratios with previous SPS findings by the NA50 experiment, and of RAA with higher-pT results at LHC energy are also reported. These results and the corresponding comparisons with calculations of transport and statistical models address questions on the existence and properties of charmonium states in the quark-gluon plasma formed in nuclear collisions at the LHC.
The production of the ψ(2S) charmonium state was measured with ALICE in Pb-Pb collisions at sNN−−−√=5.02 TeV, in the dimuon decay channel. A significant signal was observed for the first time at LHC energies down to zero transverse momentum, at forward rapidity (2.5<y<4). The measurement of the ratio of the inclusive production cross sections of the ψ(2S) and J/ψ resonances is reported as a function of the centrality of the collisions and of transverse momentum, in the region pT<12 GeV/c. The results are compared with the corresponding measurements in pp collisions, by forming the double ratio [σψ(2S)/σJ/ψ]Pb−Pb/[σψ(2S)/σJ/ψ]pp. The ψ(2S) nuclear modification factor RAA was also obtained as a function of both centrality and pT. The results show that the ψ(2S) resonance yield is strongly suppressed in Pb-Pb collisions, by a factor up to ∼3 with respect to pp. Furthermore, the ψ(2S) suppression in Pb-Pb collisions is stronger than the one observed for the J/ψ by a factor ∼2. Comparisons of cross section ratios with previous SPS findings by the NA50 experiment, and of RAA with higher-pT results at LHC energy are also reported. These results and the corresponding comparisons with calculations of transport and statistical models address questions on the existence and properties of charmonium states in the quark-gluon plasma formed in nuclear collisions at the LHC.
ALICE (A Large Ion Collider Experiment) is studying the physics of strongly interacting matter, and in particular the properties of the Quark–Gluon Plasma (QGP), using proton–proton, proton–nucleus and nucleus–nucleus collisions at the CERN LHC (Large Hadron Collider). The ALICE Collaboration is preparing a major upgrade of the experimental apparatus, planned for installation in the second long LHC shutdown in the years 2018–2019. These plans are presented in the ALICE Upgrade Letter of Intent, submitted to the LHCC (LHC experiments Committee) in September 2012. In order to fully exploit the physics reach of the LHC in this field, high-precision measurements of the heavy-flavour production, quarkonia, direct real and virtual photons, and jets are necessary. This will be achieved by an increase of the LHC Pb–Pb instant luminosity up to 6×1027 cm−2s−1 and running the ALICE detector with the continuous readout at the 50 kHz event rate. The physics performance accessible with the upgraded detector, together with the main detector modifications, are presented.
The first measurement of the cross section for incoherent photonuclear production of 𝐽/𝜓 vector mesons as a function of the Mandelstam |𝑡| variable is presented. The measurement was carried out with the ALICE detector at midrapidity, |𝑦|<0.8, using ultraperipheral collisions of Pb nuclei at a center-of-mass energy per nucleon pair of √𝑠NN=5.02 TeV. This rapidity interval corresponds to a Bjorken-𝑥 range (0.3–1.4)×10−3. Cross sections are given in five |𝑡| intervals in the range 0.04<|𝑡|<1 GeV2 and compared to the predictions by different models. Models that ignore quantum fluctuations of the gluon density in the colliding hadron predict a |𝑡| dependence of the cross section much steeper than in data. The inclusion of such fluctuations in the same models provides a better description of the data.
The first measurement of the cross section for incoherent photonuclear production of J/ψ vector mesons as a function of the Mandelstam |t| variable is presented. The measurement was carried out with the ALICE detector at midrapidity, |y|<0.8, using ultra-peripheral collisions of Pb nuclei at a centre-of-mass energy per nucleon pair of sNN−−−√=5.02 TeV. This rapidity interval corresponds to a Bjorken-x range (0.3−1.4)×10−3. Cross sections are given in five |t| intervals in the range 0.04<|t|<1 GeV2 and compared to the predictions by different models. Models that ignore quantum fluctuations of the gluon density in the colliding hadron predict a |t|-dependence of the cross section much steeper than in data. The inclusion of such fluctuations in the same models provides a better description of the data.
The ALICE experiment was proposed in 1993, to study strongly interacting matter at extreme energy densities via a comprehensive investigation of nuclear collisions at the LHC. Its physics programme initially focused on the determination of the properties of the Quark-Gluon Plasma (QGP), a deconfined state of quarks and gluons and was extended along the years, covering a diverse ensemble of observables related to Quantum Chromodynamics (QCD), the theory of strong interactions. The experiment has studied Pb-Pb, Xe-Xe, p-Pb and pp collisions in the multi-TeV energy range, during the Run 1 and Run 2 data taking periods at the LHC (2009-2018). The aim of this review article is to gather and summarise a selection of ALICE physics results and to discuss their implications on the current understanding of the macroscopic and microscopic properties of strongly interacting matter at the highest temperature reached in the laboratory. It will be shown that it is possible to have a quantitative description of the properties of the QGP produced in Pb--Pb collisions. We also show that various features, commonly ascribed to QGP formation, are detected for a wide range of interacting system sizes. Precision measurements of QCD-related observables not directly connected to the study of the QGP will also be discussed. Prospects for future measurements with the ALICE detector and its foreseen upgrades will also be briefly described.
Highlights
• Histone modifications alter chromatin structure and gene accessibility, allowing timely stress response, and enhancing tomato's ability to cope with environmental challenges.
• miRNAs and lncRNAs fine-tune gene expression, playing essential roles in stress tolerance, particularly in heat and drought stress responses.
• Leveraging epigenetic modifications can develop tomato varieties that maintain high productivity and quality under adverse environmental conditions.
• Detailed mapping of the tomato epigenome under various stress conditions can identify key regulatory regions and guide targeted breeding programs
Abstract
Climate change poses a major challenge to agriculture, affecting crop production through shifting weather patterns and an increase in extreme conditions such as heat waves, droughts, and floods, all of which are further compounded by biotic stress factors. Tomatoes, a vital dietary staple and significant agricultural product worldwide, are particularly susceptible to these changes. The need for developing climate-resilient tomato varieties is more urgent than ever to ensure food security. Epigenetic modifications, such as DNA methylation and histone modifications, play essential roles in gene expression regulation. These modifications can affect plant traits and responses to environmental stresses, enabling tomatoes to maintain productivity despite variable climates or disease pressures. Tomato, as a model plant, offers valuable insights into the epigenetic mechanisms underlying fruit development and responses to stress. This review provides an overview of key discoveries regarding to tomato response and resilience mechanisms related to epigenetics, highlighting their potential in breeding strategies to enhance tomato resilience against both abiotic and biotic challenges, thereby promoting sustainable agricultural practices in the context of global climate change.
Purpose: Polycystic ovary syndrome (PCOS) management has hardly been standardized until recent years. Despite the existence of a detailed, evidence-based guideline published by the European Society of Human Reproduction and Embryology (ESHRE), it remains unclear to what extent healthcare providers adhere to this guideline. Our aim is to evaluate the gynaecological medical care provided in women with PCOS, particularly in terms of mental health, from the patients' perspective.
Methods: For this cross-sectional online cohort study in women with PCOS, we designed a standardized, non-validated questionnaire covering aesthetic aspects, metabolism, menstrual cycle, reproduction, mental health, and prevention of chronic non-communicable diseases.
Results: Among 1879 participants, various mental health aspects were reported: body image (n = 1879), eating patterns/habits (n = 1878), and emotional well-being (n = 1874). Although nearly all women (99.7%) reported complaints on at least one session of mental health, consultation rates were low (body image 9.7%, eating patterns/habits 16.6%, emotional well-being 4.4%). Mean satisfaction with counselling on the different domains varied from moderate to fairly satisfying, with scores of 56.0 points (SD 31.7), 53.5 points (SD 32.0), and 63.7 points (SD 30.2), respectively. More complaints were associated with lower satisfaction. The overall satisfaction with the management provided by the healthcare practitioner (HCP) was low, averaging 36.5 points (SD 29.7). Consequently, most women wished for more counselling (58.9%).
Conclusion: Women affected by PCOS are not properly managed according to ESHRE guideline in regard to mental health issues. Overall consultation rates and corresponding satisfaction with management were poor, highlighting the need for significant improvements in healthcare provision.
Background: Bacteria of the genus Photorhabdus and Xenorhabdus are motile, Gram-negative bacteria that live in symbiosis with entomopathogenic nematodes. Due to their complex life cycle, they produce a large number of specialized metabolites (natural products) encoded in biosynthetic gene clusters (BGC). Genetic tools for Photorhabdus and Xenorhabdus have been rare and applicable to only a few strains. In the past, several tools have been developed for the activation of BGCs and the deletion of individual genes. However, these often have limited efficiency or are time consuming. Among the limitations, it is essential to have versatile expression systems and genome editing tools that could facilitate the practical work.
Results: In the present study, we developed several expression vectors and a CRISPR-Cpf1 genome editing vector for genetic manipulations in Photorhabdus and Xenorhabdus using SEVA plasmids. The SEVA collection is based on modular vectors that allow exchangeability of different elements (e.g. origin of replication and antibiotic selection markers with the ability to insert desired sequences for different end applications). Initially, we tested different SEVA vectors containing the broad host range origins and three different resistance genes for kanamycin, gentamycin and chloramphenicol, respectively. We demonstrated that these vectors are replicative not only in well-known representatives, e.g. Photorhabdus laumondii TTO1, but also in other rarely described strains like Xenorhabdus sp. TS4. For our CRISPR/Cpf1-based system, we used the pSEVA231 backbone to delete not only small genes but also large parts of BGCs. Furthermore, we were able to activate and refactor BGCs to obtain high production titers of high value compounds such as safracin B, a semisynthetic precursor for the anti-cancer drug ET-743.
Conclusions: The results of this study provide new inducible expression vectors and a CRISPR/CPf1 encoding vector all based on the SEVA (Standard European Vector Architecture) collection, which can improve genetic manipulation and genome editing processes in Photorhabdus and Xenorhabdus.
Lipid droplets (LDs) are essential for cellular pathophysiology. In two recent reports, Kim et al. and Boutagy et al. show that accumulation of LDs in endothelial cells (ECs) elevates blood pressure and accelerates progression of atherosclerosis. These findings identify a novel mechanism of EC lipid metabolism which drives cardiometabolic diseases.
To understand the function of cells such as neurons within an organism, it can be instrumental to inhibit cellular function, or to remove the cell (type) from the organism, and thus to observe the consequences on organismic and/or circuit function and animal behavior. A range of approaches and tools were developed and used over the past few decades that act either constitutively or acutely and reversibly, in systemic or local fashion. These approaches make use of either drugs or genetically encoded tools. Also, there are acutely acting inhibitory tools that require an exogenous trigger like light. Here, we give an overview of such methods developed and used in the nematode Caenorhabditis elegans.
Abstract
One of the most frequent applications of optogenetic tools is for depolarization and stimulation of excitable cells such as neurons and muscles. Equally important, but less frequently used, are inhibitory tools that suppress activity through cellular hyperpolarization. These tools often rely on chloride conductance. Yet, in vivo, re- and hyperpolarization is typically mediated by potassium. In recent years, light-gated ion channels with a high preference for potassium were identified (Kalium channelrhodopsins, KCRs), and their inhibitory potential described in different organisms. Here, we characterized HcKCR1 and WiChR, in cholinergic neurons and muscles of Caenorhabditis elegans. Hyperpolarization of these cell types both induces muscle relaxation and, consequently, an elongation of the animals. Thus, we analyzed body length before, during, and after illumination, to assess KCR effectiveness, and to benchmark stimulation parameters like light intensity and duration. For HcKCR1 in cholinergic neurons, continuous illumination at high light intensities (1-4.5 mW/mm2) evoked only a transient elongation, while stimulation at 0.1 mW/mm2 could maintain inhibition for the duration of the stimulus in some transgenic strains. For animals expressing WiChR in body wall muscle cells or cholinergic neurons, we again observed brief hyperpolarization during continuous illumination, however, still during the stimulus, this changed to body contraction, corresponding to depolarization. This effect was long lasting, and required dozens of seconds for reversion, but could be reduced by pulsed illumination and fully avoided by less efficient channel activation using green or orange light. Hence, KCRs can be applied to hyperpolarize C. elegans cells, but require optimized illumination parameters.
Article summary
To inhibit excitable cells, light-gated, potassium-selective channels (KCRs) can be used. This study explores whether stimulation of KCRs HcKCR1 and WiChR in cholinergic neurons and muscle cells of Caenorhabditis elegans can induce inhibition during illumination. While inhibition could be achieved, depending on light conditions, the authors unexpectedly also observed excitation. These effects may occur due to a combination of high conductivity of KCRs, and partial conductance of other cations. These findings highlight the need for specific experimental conditions in future studies utilizing these tools. The authors also present conditions that can partially or fully avoid the unwanted depolarizing effects.
Akut- und Mittelzeitergebnisse von Koronar-Stents unterschiedlicher Materialien im Kaninchenmodell
(2005)
In dieser Versuchsreihe wurden drei neuartige Stent-Modelle (a-SiC:H-Stent, PHB-Stent und PTFE-Membran-Stent) mit zwei bereits in der klinischen Praxis eingesetzten Referenz-Stents (TA-Stent und be-StentTM) im Tierversuch (Arteriae femorales von New Zealand White Rabbits) getestet.
Die Studie war so konzipiert, die Stents nach drei unterschiedlichen Zeitspannen (1-10 Wochen, 11-20 Wochen und 21-30 Wochen) zu explantieren und die Parameter „verbleibendes Lumen“, „Elastica-intema-Durchmesser“, „Mediadicke“, „ Anteil elastischer Fasern“ und „Anteil kollagenen Bindegewebes“ zu bestimmen und zu vergleichen, um so indirekt Aussagen über die biomechanischen Eigenschaften, wie Auslösung einer überschiessenden Gewebereaktion oder Thrombogenität treffen zu können.
Der Vergleich der einzelnen Parameter gibt Aufschluss über die durch den Stent ausgelösten Reaktionen und damit über die Bioverträglichkeit, über die mechanischen Wirkungen, die maßgeblich vom Stent-Design abhängen und über die destruktiven Veränderungen (Durchbrechen einzelner Gefäßschichten).
Die Untersuchungen wurden in drei Hauptgruppen unterteilt:
• a-SiC:H-Stent vs. TA-Stent
• PHB-Stent vs. TA-Stent
• PTFE-Membran-Stent vs. be-Stent™
Hierbei zeigte der mit amorphen Siliziumkarbid beschichtete Stent eine designbedingt starke mechanische Gefäßwandschädigung. Dennoch muss für die Siliziumkarbid-Schicht ein protektiver Langzeiteffekt diskutiert werden.
Der bioresorbierbare Polyhydroxybutyriat-Stent (PHB) erfüllte aufgrund einer massiven vaskulären Entzündungsreaktion und der zu geringen Abbaurate bereits in der gesunden Arterie des Kaninchenmodells nicht die theoretischen Erwartungen, sodass weitere Versuche nur mit einem chemisch und technisch überarbeitetem Modell empfohlen werden können.
Die besten Ergebnisse aller Versuchsreihen zeigten sich durch eine geringe Restenoseneigung sowie eine geringe Gefäßwandreaktion für den mit einer Polytetrafluoroethylenmembran ummantelten 316L Edelstahl-Stent (PTFE).
Das Tiermodell (Kaninchen) scheint eine allgemein anerkannt qualitative Vorhersage über die Reaktion am Menschen zu treffen. Eine exakte quantitative Aussage ist jedoch nicht möglich. Eine Verlängerung des Beobachtungszeitraumes von 26 Wochen 275 auf 52 Wochen dürfte zumindest im Einzelfall die Aussagefähigkeit zur Implantat-Verträglichkeit im Tiermodell erhöhen.
Rearrangements des MLL Gens sind für 5-10% aller akuten Leukämien, biphenotypischen Leukämien und myelodysplastischen Syndrome im Kindes- und Erwachsenenalter verantwortlich. 5-10% dieser MLL Aberrationen sind wiederum therapiebedingt.
Die 43 heute schon bekannten Partnergene und die mindestens 36 noch nicht identifizierten Partnergene stellen dabei ein großes Problem für die MLL-Diagnostik dar, denn nach der zytogenetischen Analyse werden nur die am häufigsten auftretenden Partnergene MLLT2, MLLT3, MLLT1, MLLT4, ELL, und MLLT10 über RT-PCR untersucht. Dagegen werden die nicht so häufig auftretenden oder unbekannten Partnergene von einer weiteren Untersuchung ausgeschlossen.
Wenn auch alle MLL Translokationen mit einer Hochrisiko-Leukämie in Verbindung gebracht werden, bestimmt jedoch das Partnergen den Verlauf der Leukämie mit günstiger oder schlechter Prognose. Deshalb ist eine schnelle Identifizierung des Partnergens wichtig, um somit einer optimalen Behandlung beginnen zu können.
Aus diesem Grund ist eine universelle Diagnostik-Methode entwickelt worden, die es ermöglicht, alle MLL Rearrangements innerhalb der MLL Bruchpunktsregion zu ermitteln, auch wenn das Partnergen noch nicht bekannt ist. Diese Methode beruht auf der inversen Long Range PCR (LDI-PCR), einer Methode zur Amplifizierung von unbekannten DNA Sequenzen (Partnergen), die von bekannten DNA Sequenzen (MLL Gen) flankiert werden.
Mit dieser universellen Diagnostik-Methode konnten 340 Patienten aus 15 unterschiedlichen europäischen Diagnostikzentren erfolgreich untersucht werden. Die 340 Patienten setzen sich aus 238 Kindern und 102 Erwachsenen zusammen. Bei 157 Patienten (66 Kinder und 91 Erwachsene) konnte über eine Voruntersuchung ein MLL Rearrangement festgestellt werde. 183 Patienten (172 Kinder und 11 Erwachsene) sind vorher nicht auf eine MLL Aberration hin untersucht worden. Insgesamt konnten mit dieser Methode 144 Patienten mit mindestens einem MLL Rearrangement identifiziert werden. Bei diesen Rearrangements handelte es sich in den meisten Fällen um reziproke balancierte Translokationen, aber es konnten mit dieser Methode auch Deletionen, Inversionen, Insertionen und eine Tandem-Duplikation (MLL-PTD) identifiziert werden. Von den 172 vorher nicht untersuchten pädiatrischen Patienten konnten 11 (ca. 6%) mit einer MLL Aberration identifiziert werden. Dies entspricht in etwa der in der Literatur beschriebenen Häufigkeit von 10%. 12 (8%) der schon voruntersuchten Patienten konnten mit dieser Methode nicht verifiziert werden. Diese Fälle sollten weiter untersucht werden, um die Methode dieser Problematik entsprechend zu optimieren.
Während dieser Arbeit konnten auch die 6 neuen Partnergene ACACA, ARHGEF17, SMAP1, SELB und TIRAP (DCPS) identifiziert werden. Damit steigt die Zahl der charakterisierten Partnergene von 43 auf 49.
Diese Ergebnisse zeigen, dass sich diese Methode sehr gut für die Identifizierung von bekannten und unbekannten Partnergenen des MLL Gens eignet. In Verbindung mit der Split-Signal FISH Technik kann diese Methode sehr gut für eine Routinediagnostik und einen hohen Durchsatz an Proben herangezogen werden. Ein langfristiges Ziel wird die Analyse des MLL Rekombinoms sein, denn mindestens 36 Partnergene (40%) warten noch auf ihre Identifizierung.
Darüber hinaus können die patientenspezifischen chromosomalen Fusionssequenzen für das Monitoren von leukämischen Zellen über quantitative PCR Methoden herangezogen werden. Diese genomischen MRD Marker können dann in den einzelnen Zentren genutzt werden und dazu beitragen, dass in Zukunft die Therapieprotokolle und der Therapieerfolg verbessert werden. Erste Studien sind mit Hilfe der von uns generierten molekularen Marker bereits an zwei Zentren durchgeführt worden.
Dank intensiver Forschung konnte Stickstoffmonoxid (NO) innerhalb der letzten Jahrzehnte als ein gasförmiges Signalmolekül (second messenger) identifiziert werden, das innerhalb der Zelle verschiedene Signalkaskaden beeinflusst. Dabei spielt sowohl der Syntheseort als auch die synthetisierte NO-Menge eine entscheidende Rolle für die Spezifität des über NO vermittelten Signals. Dies spiegelt sich unter Anderem in den zahlreichen regulatorischen Mechanismen, denen die NO-Synthasen unterliegen, wider. In jüngster Vergangenheit konnte gezeigt werden, dass nicht nur der Aktivitätsstatus der NO-Synthasen, sondern ebenfalls deren subzelluläre Lokalisation durch solche Mechanismen entscheidend beeinflusst werden. Von besonderer Bedeutung scheinen dabei mit den NO-Synthasen interagierende Proteine zu sein. So resultiert beispielsweise eine Überexpression von NOSIP – einem eNOS interagierenden Protein – in CHO-NOS-Zellen in einer Umverteilung von eNOS von der Plasmamembran hin zu intrazellulären Kompartimenten. Diese Umverteilung führt zu einem signifikanten Aktivitätsverlust der eNOS. Die physiologische Relevanz dieser Interaktion wird sowohl durch den Interaktionsnachweis der endogenen Proteine in Endothelzellen als auch durch eine weitreichende Co-Expression in Gastro-Intestinaltrakt, Leber und Bauchspeicheldrüse der Ratte gestützt.
Eine nähere Charakterisierung dieser Interaktion war bisher jedoch noch nicht erfolgt. Auch blieben die biochemischen Eigenschaften von endogenem NOSIP bisher unerforscht. Daher war es Ziel dieser Arbeit, endogenes NOSIP näher zu charakterisieren und dadurch die Voraussetzungen für eine physiologische Interaktion zwischen NOSIP und eNOS aufzuklären. Dabei konnte festgestellt werden, dass es sich bei NOSIP um ein überwiegend nukleär lokalisiertes Protein handelt. Diese nukleäre Lokalisation wird über ein zweiteiliges Kernlokalisationssignal (NLS = nuclear localisation signal) vermittelt. Sukzessive Mutation dieses Signals resultiert in einer zytoplasmatischen Akkumulation von NOSIP. Ferner ist das NLS nach Fusion an heterologe Proteine in der Lage, deren Lokalisation in Richtung Zellkern zu verschieben. In Heterokaryon-Assays konnte gezeigt werden, dass NOSIP zusätzlich aus dem Kern exportiert wird und daher ein zwischen Kern und Zytoplasma wanderndes Protein ist. Dieses „trafficking“ wird über ein dynamisches Gleichgewicht aus Kernimport und Kernexport reguliert. Der Kernexport von NOSIP wird durch einen ungewöhnlichen - nicht durch Leptomycin B inhibierbaren - Mechanismus bewerkstelligt. Entsprechend findet sich innerhalb der NOSIP-Sequenz kein typisches, leucinreiches Exportsignal, durch welches gewöhnlich Kernexport über Bindung an Crm1 (chromosome region maintenance 1) vermittelt wird. Das dynamische Gleichgewicht zwischen Kernimport und Kernexport, verschiebt sich in Abhängigkeit vom Zellzyklus in der G2-Phase in Richtung Export, was in einer zytoplasmatischen Akkumulation von NOSIP resultiert. Beeinflusst wird das dynamische Gleichgewicht dabei möglicherweise von einer Interaktion zwischen NOSIP und der Zellzyklus-regulatorischen Kinase CDK1 (cyclin dependent kinase 1).
In Bezug auf eNOS ist diese zytoplasmatische Lokalisation von NOSIP von entscheidender Bedeutung, wie in vergleichenden Transfektionsexperimenten mit zytoplasmatischen NOSIP-Mutanten in CHO-NOS-Zellen gezeigt werden konnte. Danach vermittelt ausschließlich Transfektion dieser Mutanten eine Translokation von eNOS an das Aktin-Zytoskelett, während natives, primär nukleär lokalisiertes NOSIP keinen Einfluss auf die eNOS-Lokalisation hat. Analog dazu resultiert die zytoplasmatische Akkumulation von endogenem NOSIP in der G2-Phase des Zellzyklus ebenfalls in einer Translokation von eNOS an das Aktin-Zytoskelett, welche eine signifikante Aktivitätsminderung der NO-Synthase zur Folge hat. Diese zellzyklusspezifischen, eNOS-regulativen Effekte erfolgen in Abhängigkeit von endogenem zytoplasmatischem NOSIP, wie mittels RNA-Interferenzexperimente belegt werden konnte. Danach können sowohl die Umverteilung von eNOS als auch die daraus resultierende Aktivitätsminderung durch eine Expressionsunterdrückung von NOSIP vollständig inhibiert werden.
Die innerhalb dieser Arbeit erhobenen Daten stellen den ersten Bericht über eine Zellzyklusabhängige Regulation einer NOS-Isoform dar. Diese negative Regulation wird durch eine Umverteilung von eNOS an ein inaktives Kompartiment erreicht, welche wiederum über eine zellzyklusabhängige Lokalisationsänderung von NOSIP bewerkstelligt wird. In der Literatur finden sich zahlreiche Berichte über die Auswirkungen von exogen verabreichtem NO auf Zellzyklus-gesteuerte Ereignisse, wie Apoptose oder Proliferation. In diesem Zusammenhang zeigen die hier erhobenen Daten, dass die endogene NO-Menge tatsächlich zellzyklusspezifisch reguliert wird. Diese Regulation könnte möglicherweise ein Teil eines endogenen, NO-abhängigen Mechanismus darstellen, der die Apoptose und/oder die Proliferation beeinflusst.
This paper empirically examines differences in how 50-year-olds imagine their future. It draws on answers to an open-ended survey question in a large British cohort study—the National Child Development Study. Over 6,700 written responses about respondents’ imagined future are examined using text mining methods. Results from a relative frequency analysis and a topic model reveal differences according to gender, occupational class, and educational qualification. The cohort members’ written texts reflect different lifestyles. Men are more likely to mention sport, like golf and football, whereas women are more prone to use words related to family and friends. Respondents with a degree are more likely to write about cultural activities, such as museum or theater visits. Overall, the findings reveal gendered and socially stratified patterns in individual future perceptions, contextualized in relation to leisure, health, and family.
Background: Efficacy of treatment after failure of check point inhibitors (ICI) therapy remains ill-defined in metastatic renal cell carcinoma (mRCC).
Objective: To evaluate the safety and effectiveness of cabozantinib after failure of ICI-based therapies.
Design, setting and participants: Patients with mRCC who concluded cabozantinib treatment directly after an ICI-based therapy were eligible. Data was collected retrospectively from participating sites in Germany.
Interventions: Cabozantinib was administered as a standard of care.
Outcome measurements and statistical analysis
Adverse events (AE) were reported according to CTCAE v5.0. Objective response rate according to RECIST 1.1 and Progression Free Survival (PFS) were collected from medical records. Descriptive statistics and Kaplan-Meyer-plots were utilized.
Results and limitations: About 56 eligible patients (71.4% male) with median age of 66 years and clear cell histology in 66.1% (n = 37) were analyzed. 87.5% (n = 49) had ≥ 2 previous lines. IMDC risk was intermediate or poor in 17 patients (30.4%) and missing in 66.1%. 20 patients (35.7%) started with 60 mg. 55.4% (n = 31) required dose reductions, 26.8% (n = 15) treatment delays and 1.8% (n = 1) treatment discontinuation. Partial response was reported in 10.7% (n = 6), stable and progressive disease were reported in 19.6% (n = 11) and in 12.5% (n = 7). 32 patients were not evaluable (57.1%). Median treatment duration was 6.1 months. Treatment related AE were reported in 76.8% (n = 43) and 19.6% (n = 11) had grade 3-5. Fatigue (26.8%), diarrhea (26.8%) and hand-foot-syndrome (25.0%) were the 3 most frequent AEs of any grade and causality. SAE were reported in 21.4% (n = 12), 2 were fatal. Major limitation was the retrospective data capture in our study.
Conclusions: Cabozantinib followed directly after ICI-based therapy was safe and feasible. No new safety signals were reported. A lower starting dose was frequently utilized in this real-world cohort, which was associated with a favorable tolerability profile. Our data supports the use of cabozantinib after ICI treatment.
The CP-even fractions (F+) of the decays D0→π+π−π0 and D0→K+K−π0 are measured with a quantum-correlated ψ(3770)→DD¯ data sample collected by the BESIII experiment corresponding to an integrated luminosity of 7.93 fb−1. The results are Fπ+π−π0+=0.9406±0.0036±0.0021 and FK+K−π0+=0.631±0.014±0.011, where the first uncertainties are statistical and the second systematic. These measurements are consistent with the previous determinations, and the uncertainties for Fπ+π−π0+ and FK+K−π0+ are reduced by factors of 3.9 and 2.6, respectively. The reported results provide important inputs for the precise measurement of the angle γ of the Cabibbo-Kobayashi-Maskawa matrix and indirect CP violation in charm mixing.
Charge-dependent two- and three-particle correlations measured in Xe-Xe collisions at sNN−−−√=5.44 TeV are presented. Results are obtained for charged particles in the pseudorapidity range |η|<0.8 and transverse momentum interval 0.2≤pT<5.0 GeV/c for different collision centralities. The three-particle correlator γαβ≡⟨cos(φα+φβ−2Ψ2)⟩, calculated for different combinations of charge sign α and β, is expected to be sensitive to the presence of the Chiral Magnetic Effect (CME). Its magnitude is similar to the one observed in Pb-Pb collisions in contrast to a smaller CME signal in Xe-Xe collisions than in Pb-Pb collisions predicted by Monte Carlo (MC) calculations including a magnetic field induced by the spectator protons. These observations point to a large non-CME contribution to the correlator. Furthermore, the charge dependence of γαβ can be described by a blast wave model calculation that incorporates background effects and by the Anomalous Viscous Fluid Dynamics model with values of the CME signal consistent with zero. The Xe-Xe and Pb-Pb results are combined with the expected CME signal dependence on the system size from the MC calculations including a magnetic field to obtain the fraction of CME contribution in γαβ, fCME. The CME fraction is compatible with zero for the 30% most central events in both systems and then becomes positive; averaging over the 0-70% centrality interval yields an upper limit of 2% (3%) and 25% (32%) at 95% (99.7%) confidence level for the CME signal contribution to γαβ in Xe-Xe and Pb-Pb collisions, respectively.
In high-energy heavy-ion collisions, the correlations between the emitted particles can be used as a probe to gain insight into the charge creation mechanisms. In this article, we report the first results of such studies using the electric charge balance function in the relative pseudorapidity \Delta\eta and azimuthal angle \Delta\phi in Pb-Pb collisions at sqrt{s_{NN}} = 2.76 TeV with the ALICE detector at the Large Hadron Collider. The width of the balance function decreases with growing centrality (i.e. for more central collisions) in both projections. This centrality dependence is not reproduced by HIJING, while AMPT, a model which incorporates strings and parton rescattering, exhibits qualitative agreement with the measured correlations in \Delta\phi but fails to describe the correlations in \Delta\eta. A thermal blast wave model incorporating local charge conservation and tuned to describe the p_T spectra and v_2 measurements reported by ALICE, is used to fit the centrality dependence of the width of the balance function and to extract the average separation of balancing charges at freeze-out. The comparison of our results with measurements at lower energies reveals an ordering with sqrt{s_{NN}}: the balance functions become narrower with increasing energy for all centralities. This is consistent with the effect of larger radial flow at the LHC energies but also with the late stage creation scenario of balancing charges. However, the relative decrease of the balance function widths in \Delta\eta and \Delta\phi with centrality from the highest SPS to the LHC energy exhibits only small differences. This observation cannot be interpreted solely within the framework where the majority of the charge is produced at a later stage in the evolution of the heavy-ion collision.
In high--energy heavy--ion collisions, the correlations between the emitted particles can be used as a probe to gain insight into the charge creation mechanisms. In this Letter, we report the first results of such studies using the electric charge balance function in the relative pseudorapidity (Δη) and azimuthal angle (Δφ) in Pb--Pb collisions at sNN−−−−√=2.76 TeV with the ALICE detector at the Large Hadron Collider. The width of the balance function decreases with growing centrality (i.e. for more central collisions) in both projections. This centrality dependence is not reproduced by HIJING, while AMPT, a model which incorporates strings and parton rescattering, exhibits qualitative agreement with the measured correlations in Δφ but fails to describe the correlations in Δη. A thermal blast--wave model incorporating local charge conservation and tuned to describe the pmT spectra and v2 measurements reported by ALICE, is used to fit the centrality dependence of the width of the balance function and to extract the average separation of balancing charges at freeze--out. The comparison of our results with measurements at lower energies reveals an ordering with sNN−−−−√:the balance functions become narrower with increasing energy for all centralities. This is consistent with the effect of larger radial flow at the LHC energies but also with the late stage creation scenario of balancing charges. However, the relative decrease of the balance function widths in Δη and \dphi with centrality from the highest SPS to the LHC energy exhibits only small differences. This observation cannot be interpreted solely within the framework where the majority of the charge is produced at a later stage in the evolution of the heavy--ion collision.
In high-energy heavy-ion collisions, the correlations between the emitted particles can be used as a probe to gain insight into the charge creation mechanisms. In this Letter, we report the first results of such studies using the electric charge balance function in the relative pseudorapidity (Δη) and azimuthal angle (Δφ) in Pb--Pb collisions at sNN−−−√=2.76 TeV with the ALICE detector at the Large Hadron Collider. The width of the balance function decreases with growing centrality (i.e. for more central collisions) in both projections. This centrality dependence is not reproduced by HIJING, while AMPT, a model which incorporates strings and parton rescattering, exhibits qualitative agreement with the measured correlations in Δφ but fails to describe the correlations in Δη. A thermal blast-wave model incorporating local charge conservation and tuned to describe the pT spectra and v2 measurements reported by ALICE, is used to fit the centrality dependence of the width of the balance function and to extract the average separation of balancing charges at freeze-out. The comparison of our results with measurements at lower energies reveals an ordering with sNN−−−√: the balance functions become narrower with increasing energy for all centralities. This is consistent with the effect of larger radial flow at the LHC energies but also with the late stage creation scenario of balancing charges. However, the relative decrease of the balance function widths in Δη and Δφ with centrality from the highest SPS to the LHC energy exhibits only small differences. This observation cannot be interpreted solely within the framework where the majority of the charge is produced at a later stage in the evolution of the heavy--ion collision.
In high--energy heavy--ion collisions, the correlations between the emitted particles can be used as a probe to gain insight into the charge creation mechanisms. In this Letter, we report the first results of such studies using the electric charge balance function in the relative pseudorapidity (Δη) and azimuthal angle (Δφ) in Pb--Pb collisions at sNN−−−−√=2.76 TeV with the ALICE detector at the Large Hadron Collider. The width of the balance function decreases with growing centrality (i.e. for more central collisions) in both projections. This centrality dependence is not reproduced by HIJING, while AMPT, a model which incorporates strings and parton rescattering, exhibits qualitative agreement with the measured correlations in Δφ but fails to describe the correlations in Δη. A thermal blast--wave model incorporating local charge conservation and tuned to describe the pmT spectra and v2 measurements reported by ALICE, is used to fit the centrality dependence of the width of the balance function and to extract the average separation of balancing charges at freeze--out. The comparison of our results with measurements at lower energies reveals an ordering with sNN−−−−√:the balance functions become narrower with increasing energy for all centralities. This is consistent with the effect of larger radial flow at the LHC energies but also with the late stage creation scenario of balancing charges. However, the relative decrease of the balance function widths in Δη and \dphi with centrality from the highest SPS to the LHC energy exhibits only small differences. This observation cannot be interpreted solely within the framework where the majority of the charge is produced at a later stage in the evolution of the heavy--ion collision.
Measurements of the sphericity of primary charged particles in minimum bias proton--proton collisions at s√=0.9, 2.76 and 7 TeV with the ALICE detector at the LHC are presented. The observable is linearized to be collinear safe and is measured in the plane perpendicular to the beam direction using primary charged tracks with pT≥0.5 GeV/c in |η|≤0.8. The mean sphericity as a function of the charged particle multiplicity at mid-rapidity (Nch) is reported for events with different pT scales ("soft" and "hard") defined by the transverse momentum of the leading particle. In addition, the mean charged particle transverse momentum versus multiplicity is presented for the different event classes, and the sphericity distributions in bins of multiplicity are presented. The data are compared with calculations of standard Monte Carlo event generators. The transverse sphericity is found to grow with multiplicity at all collision energies, with a steeper rise at low Nch, whereas the event generators show the opposite tendency. The combined study of the sphericity and the mean pT with multiplicity indicates that most of the tested event generators produce events with higher multiplicity by generating more back-to-back jets resulting in decreased sphericity (and isotropy). The PYTHIA6 generator with tune PERUGIA-2011 exhibits a noticeable improvement in describing the data, compared to the other tested generators.
n this paper measurements are presented of π+, π−, K+, K−, p and p¯¯¯ production at mid-rapidity < 0.5, in Pb-Pb collisions at sNN−−−√=2.76 TeV as a function of centrality. The measurement covers the transverse momentum (pT) range from 100, 200, 300 MeV/c up to 3, 3, 4.6 GeV/c, for π, K, and p respectively. The measured pT distributions and yields are compared to expectations based on hydrodynamic, thermal and recombination models. The spectral shapes of central collisions show a stronger radial flow than measured at lower energies, which can be described in hydrodynamic models. In peripheral collisions, the pT distributions are not well reproduced by hydrodynamic models. Ratios of integrated particle yields are found to be nearly independent of centrality. The yield of protons normalized to pions is a factor ~1.5 lower than the expectation from thermal models.
We present first measurements of the evolution of the differential transverse momentum correlation function, {\it C}, with collision centrality in Au+Au interactions at sNN−−−−√=200 GeV. {\it C} exhibits a strong dependence on collision centrality that is qualitatively similar to that of number correlations previously reported. We use the observed longitudinal broadening of the near-side peak of {\it C} with increasing centrality to estimate the ratio of the shear viscosity to entropy density, η/s, of the matter formed in central Au+Au interactions. We obtain an upper limit estimate of η/s that suggests that the produced medium has a small viscosity per unit entropy.
The present study examines for the first time the emission patterns and olfactory signatures of 9 complete human corpses of different stages of decomposition. Air sampling was performed inside the body bags with solid sorbents and analysed by coupled gas chromatography-mass spectrometry after thermal desorption (TD-GC-MS). Furthermore, odour-related substances were detected by gas chromatography-olfactometry (GC-O). Sulfurous compounds (mainly dimethyl di- and trisulfide) were identified as most important to the odour perception. Around 350 individual organic substances were detected by TD-GC-MS, notably sulfurous and nitrogenous substances as well as branched alkanes, aldehydes, ketones, alcohols, carboxylic acids, carboxylic acid esters and ethers. A range of terpenes was detected for the first time in a characteristic emission pattern over all decomposition stages. Concentrations of the substances varied greatly, and no correlation between the emission patterns, the stage of decomposition and the cause of death could be found. While previous studies often analysed pig cadavers or only parts of human tissue, the present study shows the importance of analysing complete human corpses over a range of decomposition stages. Moreover, it is shown that using body bags as a kind of “emission test chamber” is a very promising approach, also because it is a realistic application considering the usual transport and store of a body before autopsy.
Background: Transfusion of red blood cell concentrate can be life-saving, but requires accurate dose calculations in children. Aims: We tested the hypothesis that cognitive aids would improve identification of the correct recommended volumes and products, according to the German National Transfusion guidelines, in pediatric transfusion scenarios. Methods: Four online questionnaire-based scenarios, two with hemodynamically stable and two with hemodynamically unstable children, were sent to German and international pediatric anesthetists for completion. In the two stable scenarios, participants were given pre-filled tables that contained all required information. For the two emergency scenarios, existing algorithms were used and required calculation by the user. The results were classified into three categories of deviations from the recommended values (DRV): DRV120 (<80% or >120%), as the acceptable variation; DRV 300 (<33% or >300%), the deviation of concern for potential harm; and DRV 1000 (<10% or >1000%), the excessive deviation with a high probability of harm. Results: A total of 1.458 pediatric anesthetists accessed this simulation questionnaire, and 402 completed questionnaires were available for analysis. A pre-filled tabular aid, avoiding calculations, led to a reduction in deviation rates in the category of DRV120 by 60% for each and of DRV300 by 17% and 20%, respectively. The use of algorithms as aids for unstable emergencies led to a reduction in the deviation rate only for DRV120 (20% and 15% respectively). In contrast, the deviation rates for DRV300 and DRV1000 rose by 37% and 16%, respectively. Participants used higher transfusion thresholds for the emergency case of a 2-year-old compromised child than for the stable case with a patient of the same age (on average, 8.6 g/dL, 95% CI 8.5–8.8 versus 7.1 g/dL, 95% CI 7.0–7.2, p < 0.001) if not supported by our aids. Participants also used a higher transfusion threshold for unstable children aged 3 months than for stable children of the same age (on average, 8.9 g/dL, 95% CI 8.7–9.0 versus 7.9 g/dL, 95% CI 7.7–8.0, p < 0.001). Conclusions: The use of cognitive aids with precalculated transfusion volumes for determining transfusion doses in children may lead to improved adherence to published recommendations, and could potentially reduce dosing deviations outside those recommended by the German national transfusion guidelines.
Distinct immune patterns of hepatocellular carcinoma (HCC) may have prognostic implications in the response to transarterial chemoembolization (TACE). Thus, we aimed to exploratively analyze tumor tissue of HCC patients who do or do not respond to TACE, and to identify novel prognostic biomarkers predictive of response to TACE. We retrospectively included 15 HCC patients who had three consecutive TACE between January 2019 and November 2019. Eight patients had a response while seven patients had no response to TACE. All patients had measurable disease according to mRECIST. Corresponding tumor tissue samples were processed for differential expression profiling using NanoString nCounter® PanCancer immune profiling panel. Immune-related pathways were broadly upregulated in TACE responders. The top differentially regulated genes were the upregulated CXCL1 (log2fc 4.98, Benjamini–Hochberg (BH)-p < 0.001), CXCL6 (log2fc 4.43, BH-p = 0.016) and the downregulated MME (log2fc −4.33, BH-p 0.001). CD8/T-regs was highly increased in responders, whereas the relative number of T-regs to tumor-infiltrating lymphocytes (TIL) was highly decreased. We preliminary identified CXCL1 and CXCL6 as candidate genes that might have the potential to serve as therapeutically relevant biomarkers in HCC patients. This might pave the way to improve patient selection for TACE in HCC patients beyond expert consensus.
For acute and chronic soft tissue infections, radical surgical debridement is required and is considered the gold standard, along with its immediate systemic antibiotic therapy. Treatment with local antibiotics and/or antibiotic-containing materials is commonly used as an additional tool in clinical practice. Spraying with fibrin and antibiotics is a newer technique that has been studied for some antibiotics. However, for gentamicin, data are not yet available on absorption, optimal application, antibiotic fate at the site and transfer of antibiotic into the blood. In an animal study involving 29 Sprague Dawley rats, 116 back wounds were sprayed with gentamicin using either gentamicin alone or one of two possible spray combinations of gentamicin and fibrin. Simultaneous application of gentamicin and fibrin via a spray system to soft tissue wounds resulted in significant antibiotic concentration over a long period of time. The technique is easy and cost-effective. The systemic crossover was significantly minimized in our study, which may have led to fewer side effects in patients. These results could lead to an improvement in local antibiotic therapy.