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Ferroptosis is a regulated form of cell death which is considered an oxidative iron-dependent process. The lipid hydroperoxidase glutathione peroxidase 4 prevents the iron (Fe2+)-dependent formation of toxic lipid reactive oxygen species. While emerging evidence indicates that inhibition of glutathione peroxidase 4 as a hallmark of ferroptosis in many cancer cell lines, the involvement of this biochemical pathway in neuronal death remains largely unclear. Here, we investigate, first whether the ferroptosis key players are involved in the neuronal cell death induced by erastin. The second objective was to examine whether there is a cross talk between ferroptosis and autophagy. The third main was to address neuron response to erastin, with a special focus on ferritin and nuclear receptor coactivator 4-mediated ferritinophagy. To test this in neurons, erastin (0.5–8 µM) was applied to hippocampal HT22 neurons for 16 hours. In addition, cells were cultured with the autophagy inhibitor, 3-methyladenin (10 mM) and/or ferroptosis inhibitors, ferrostatin 1 (10–20 µM) or deferoxamine (10–200 µM) before exposure to erastin. In this study, we demonstrated by immunofluorescence and western blot analysis, that erastin downregulates dramatically the expression of glutathione peroxidase 4, the sodium-independent cystine-glutamate antiporter and nuclear receptor coactivator 4. The protein levels of ferritin and mitochondrial ferritin in HT22 hippocampal neurons did not remarkably change following erastin treatment. In addition, we demonstrated that not only the ferroptosis inhibitor, ferrostatin1/deferoxamine abrogated the ferroptotic cell death induced by erastin in hippocampal HT22 neurons, but also the potent autophagy inhibitor, 3-methyladenin. We conclude that (1) erastin-induced ferroptosis in hippocampal HT22 neurons, despite reduced nuclear receptor coactivator 4 levels, (2) that either nuclear receptor coactivator 4-mediated ferritinophagy does not occur or is of secondary importance in this model, (3) that ferroptosis seems to share some features of the autophagic cell death process.
In the basal, proliferative layer of healthy skin, the mTOR complex 1 (mTORC1) is activated, thus regulating proliferation while preventing differentiation. When cells leave the proliferative, basal compartment, mTORC1 signaling is turned off, which allows differentiation. Under inflammatory conditions, this switch is hijacked by cytokines and prevents proper differentiation. It is currently unknown how mTORC1 is regulated to mediate these effects on keratinocyte differentiation. In other tissues, mTORC1 activity is controlled through various pathways via the tuberous sclerosis complex (TSC). Thus, we investigated whether the TS complex is regulated by proinflammatory cytokines and contributes to the pathogenesis of psoriasis. TNF-α as well as IL-1β induced the phosphorylation of TSC2, especially on S939 via the PI3-K/AKT and MAPK pathway. Surprisingly, increased TSC2 phosphorylation could not be detected in psoriasis patients. Instead, TSC2 was strongly downregulated in lesional psoriatic skin compared to non-lesional skin of the same patients or healthy skin. In vitro inflammatory cytokines induced dissociation of TSC2 from the lysosome, followed by destabilization of the TS complex and degradation. Thus, we assume that in psoriasis, inflammatory cytokines induce strong TSC2 phosphorylation, which in turn leads to its degradation. Consequently, chronic mTORC1 activity impairs ordered keratinocyte differentiation and contributes to the phenotypical changes seen in the psoriatic epidermis.
The culture of primary intestinal epithelia cells is not possible in a normal culture system. In 2009 a three-dimensional culture system of intestinal stem cells was established that shows many of the physiological features of the small intestine, such as crypt-villus structure, stem cell niche and all types of differentiated intestinal epithelial cells. These enteroids can be used to analyze biology of intestinal stem cells, gut homeostasis and the development of diseases. They also give the possibility to reduce animal numbers, as enteroids can be cryo-conserved and cultivated for many passages. To investigate the influence of genes such as NADPH oxidases on the gut homeostasis, transgenic approached are the method of choice. The generation of enteroids from knockout mice allows real-time observations of knockout effects. Often conditional knockout or overexpression strategies using inducible Cre recombinase are applied to avoid effects of adaption to the knockout. However, the Cre recombinase has many known caveats from unspecific binding and its endonuclease activity. In this study, we show that although NADPH oxidases are important for in vivo differentiation and proliferation of the intestine, their expression is drastically reduced in the organoid system. Activation of Cre recombinase by 4-hydroxy tamoxifen in freshly isolated enteroids, independently of floxed genes, leads to decreased diameter of organoids. This effect is concentration-dependent and is caused by reduced cell proliferation and induction of apoptosis and DNA damage. In contrast, constitutive expression of Cre has no impact on the enteroids. Therefore, reduction of tamoxifen concentration and treatment duration should be carefully titrated, and appropriate controls are necessary.
Using a sample of about 1010 𝐽/𝜓 events collected at a center-of-mass energy √𝑠=3.097 GeV with the BESIII detector, the electromagnetic Dalitz decays 𝐽/𝜓→𝑒+𝑒−𝜋+𝜋−𝜂′, with 𝜂′→𝛾𝜋+𝜋− and 𝜂′→𝜋+𝜋−𝜂, have been studied. The decay 𝐽/𝜓→𝑒+𝑒−𝑋(1835) is observed with a significance of 15𝜎, and also an 𝑒+𝑒− invariant-mass dependent transition form factor of 𝐽/𝜓→𝑒+𝑒−𝑋(1835) is presented for the first time. The intermediate states 𝑋(2120) and 𝑋(2370) are also observed in the 𝜋+𝜋−𝜂′ invariant-mass spectrum with significances of 5.3𝜎 and 7.3𝜎. The corresponding product branching fractions for 𝐽/𝜓→𝑒+𝑒−𝑋, 𝑋→𝜋+𝜋−𝜂′ [𝑋=𝑋(1835), 𝑋(2120), and 𝑋(2370)] are reported.
Die ethnografische Feldstudie untersucht die Lebenswege von jungen muslimischen Männern, die in einer armutsbetroffenen und stigmatisierten Hochhaussiedlung in der urbanen Peripherie aufwachsen. Sie vergleicht die Lebenswege derjenigen, die ein Hochschulstudium aufnehmen (college boys) mit der Gruppe derjenigen, die sich in der informellen Ökonomie der 'Straße' mit dem Drogenhandel als wichtigstem Zweig betätigen (corner boys). Die Lebensverläufe der jungen Männer, deren Familien meist im Zuge der Anwerbemigration ab den 1960er Jahren aus Marokko oder aus der Türkei eingewandert sind, werden anhand der Lebensverlaufstheorie (life course theory) von Glen Elder und Janet Giele erklärt. Die ethnografischen Beschreibungen werden methodisch um biografische Interviews mit college boys und corner boys und um Expertinneninterviews mit Fachleuten aus Organisationen wie Kitas, Schulen oder einer Moschee ergänzt. Die ethnografischen Beobachtungen werden auch ins Verhältnis zu Befunden aus der interdisziplinären sozialwissenschaftlichen Literatur gesetzt, die wiederum mit den in der Studie erhobenen und sehr persönlichen Lebensgeschichten von corner boys und college boys kombiniert werden. Der Forscher hatte während der Feldarbeit eine Doppelrolle, da er nicht nur als Ethnograf tätig war, sondern auch für die Stadt als Streetworker bzw. Sozialarbeiter in der Hochhaussiedlung beschäftigt war. Insofern gibt die Feldstudie auch einen Einblick in die staatlichen Unterstützungssysteme der Sozialen Arbeit.
Im Ergebnis entsteht die Geschichte eines sozialräumlich segregierten Milieus seit der Migration der Großeltern nach Deutschland. Sowohl für college boys als auch für corner boys dient die harte Lohnarbeit ihrer Eltern und Großeltern als negative Kontrastfolie. College boys streben nach beruflichem Erfolg und Anerkennung durch Bildungsabschlüsse. Corner boys hingegen leisten Widerstand gegen die Arbeitsethik und andere dominante Normen und wenden sich von der Lohnarbeit im Allgemeinen ab. In den Lebensverläufen von college boys wirken bestimmte Schutzfaktoren, die ihnen einen Bildungsaufstieg trotz armutsgeprägter Lebensverhältnisse ermöglichen. Zu diesen Schutzfaktoren zählen ein stabiler Familienkontext mit engen Bindungen, die Organisation eines strukturierten Alltags in Kindheit und Jugend mit Aktivitäten wie Nachhilfe und Sportvereinen und der praktizierte Islam mit seiner engen Verbindung von Glaube, Bildung und Abstinenz.
Durch die Arbeit entsteht ein Perspektivwechsel auf Hochhaussiedlungen der untersuchten Art. Statt der üblichen symbolischen Abwertung erscheinen sie durch die beschriebenen intergenerationalen Bildungsaufstiege als Orte mit besonders hoher sozialer Mobilität. Auf der anderen Seite wird mit den corner boys aber auch eine Gruppe beschrieben, in der sich Prekarität aufgrund von Ausgrenzungserfahrungen und einer anschließenden Resignation verfestigt hat. Die college boys bekommen Raum zur Entfaltung, während die corner boys metaphorisch gesprochen im Raum der Hochhaussiedlung gefangen bleiben. Die Faktoren, die diesen Unterschied erklären, werden in der Arbeit beleuchtet.
Four different structural models, which all fit the same X-ray powder pattern, were obtained in the structure determination of 4,11-difluoroquinacridone (C20H10N2O2F2) from unindexed X-ray powder data by a global fit. The models differ in their lattice parameters, space groups, Z, Z′, molecular packing and hydrogen bond patterns. The molecules form a criss-cross pattern in models A and B, a layer structure built from chains in model C and a criss-cross arrangement of dimers in model D. Nevertheless, all models give a good Rietveld fit to the experimental powder pattern with acceptable R-values. All molecular geometries are reliable, except for model D, which is slightly distorted. All structures are crystallochemically plausible, concerning density, hydrogen bonds, intermolecular distances etc. All models passed the checkCIF test without major problems; only in model A a missed symmetry was detected. All structures could have probably been published, although 3 of the 4 structures were wrong. The investigation, which of the four structures is actually the correct one, was challenging. Six methods were used: (1) Rietveld refinements, (2) fit of the crystal structures to the pair distribution function (PDF) including the refinement of lattice parameters and atomic coordinates, (3) evaluation of the colour, (4) lattice-energy minimizations with force fields, (5) lattice-energy minimizations by two dispersion-corrected density functional theory methods, and (6) multinuclear CPMAS solid-state NMR spectroscopy (1H, 13C, 19F) including the comparison of calculated and experimental chemical shifts. All in all, model B (perhaps with some disorder) can probably be considered to be the correct one. This work shows that a structure determination from limited-quality powder data may result in totally different structural models, which all may be correct or wrong, even if they are chemically sensible and give a good Rietveld refinement. Additionally, the work is an excellent example that the refinement of an organic crystal structure can be successfully performed by a fit to the PDF, and the combination of computed and experimental solid-state NMR chemical shifts can provide further information for the selection of the most reliable structure among several possibilities.
Mexico’s role in the US-Central American migration regime is threefold: not only is it a country of origin, and a transit country, but also increasingly becoming a receiving country for migrants who flee from violence, insecurity and poverty. The Mexican state responds with detention enforcement. Clinical research usually puts emphasise on the negative impact of detention enforcement on the detainees‘ mental health. Yet, it often disregards the spatial configurations of detention centres and their socio-political context. This study aims to fill this gap by analysing how such factors create harmful environments that affect both the detainees‘ mental health and their social life in Mexico’s migration detention centres. The study’s mixed method approach builds on semi-structured interviews with a sample of N = 56 migrants of diverse nationalities and varying socioeconomic status of whom 22 were still detained while 34 had been released. The interviews include the Torturing Environment Scale (TES), a novel instrument for the analysis of detention environments, as well as clinical psychological measures of emotional distress. Additional n = 10 in-depth interviews with human rights advocates to explore the interconnections between the detention environments, their impact on mental health, and Mexican migration politics. Facultative counter-mappings of the detention centres complement the interviews. Without exception, all interviews of detainees underline that the manipulation of detention conditions creates torturing environments that cause harm to basic physiological and psychological needs. A comparison between detained vs. released interviewees revealed lasting feelings of fear and shame. The study emphasises that immigration detention immobilises migrants in a necropolitical limbo, which destroys hope as much as human integrity. It indicates that detention is part of deterrence politics, which perpetuates harm and inequality through detention and deportation. Highlighting structural human rights violations, the findings stress the need to review current migration policies.
Diurnal and nocturnal behaviour of cheetahs (Acinonyx jubatus) and lions (Panthera leo) in zoos
(2022)
Mammals are constantly exposed to exogenous and endogenous influences that affect their behaviour and daily activity. Light and temperature, as well as anthropogenic factors such as husbandry routines, visitors, and feeding schedules are potential influences on animals in zoological gardens. In order to investigate the effects of some of these factors on animal behaviour, observational studies based on the analyses of activity budgets can be used. In this study, the daily and nightly activity budgets of six lions (Panthera leo) and five cheetahs (Acinonyx jubatus) from four EAZA institutions were investigated. Focused on the influencing factor light and feeding, we analysed these activity budgets descriptively. Behaviour was recorded and analysed during the winter months over an observation period of 14 days and 14 nights using infrared-sensitive cameras. Our results show that lions and cheetahs exhibit activity peaks at crepuscular and feeding times, regardless of husbandry. Thus, lions in captivity shift nocturnal behaviour familiar from the wild to crepuscular and diurnal times. In cheetahs, in contrast, captive and wild individuals show similar 24 h behavioural rhythms. The resting behaviour of both species is more pronounced at night, with cheetahs having a shorter overall sleep duration than lions. This study describes the results of the examined animals and is not predictive. Nevertheless, the results of this study make an important contribution to gaining knowledge about possible factors influencing the behaviour of lions and cheetahs in zoos and offer implications that could be useful for improving husbandry and management.
Magnetoencephalography (MEG) and Electroencephalography (EEG) provide direct electrophysiological measures at an excellent temporal resolution, but the spatial resolution of source-reconstructed current activity is limited to several millimetres. Here we show, using simulations of MEG signals and Bayesian model comparison, that non-invasive myelin estimates from high-resolution quantitative magnetic resonance imaging (MRI) can enhance MEG/EEG source reconstruction. Our approach assumes that MEG/EEG signals primarily arise from the synchronised activity of pyramidal cells, and since most of the myelin in the cortical sheet originates from these cells, myelin density can predict the strength of cortical sources measured by MEG/EEG. Leveraging recent advances in quantitative MRI, we exploit this structure-function relationship and scale the leadfields of the forward model according to the local myelin density estimates from in vivo quantitative MRI to inform MEG/EEG source reconstruction. Using Bayesian model comparison and dipole localisation errors (DLEs), we demonstrate that adapting local forward fields to reflect increased local myelination at the site of a simulated source explains the simulated data better than models without such leadfield scaling. Our model comparison framework proves sensitive to myelin changes in simulations with exact coregistration and moderate-to-high sensor-level signal-to-noise ratios (≥10 dB) for the multiple sparse priors (MSP) and empirical Bayesian beamformer (EBB) approaches. Furthermore, we sought to infer the microstructure giving rise to specific functional activation patterns by comparing the myelin-informed model which was used to generate the activation with a set of test forward models incorporating different myelination patterns. We found that the direction of myelin changes, however not their magnitude, can be inferred by Bayesian model comparison. Finally, we apply myelin-informed forward models to MEG data from a visuo-motor experiment. We demonstrate improved source reconstruction accuracy using myelin estimates from a quantitative longitudinal relaxation (R1) map and discuss the limitations of our approach.
Highlights
We use quantitative MRI to implement myelin-informed forward models for M/EEG
Local myelin density was modelled by adapting the local leadfields
Myelin-informed forward models can improve source reconstruction accuracy
We can infer the directionality of myelination patterns, but not their strength
We apply our approach to MEG data from a visuo-motor experiment
Purpose
To assess the diagnostic value of different imaging modalities in distinguishing systemic vasculitis from other internal and immunological diseases.
Methods
This retrospective study included 134 patients with suspected vasculitis who underwent ultrasound, magnetic resonance imaging (MRI), or 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) between 01/2010 and 01/2019, finally consisting of 70 individuals with vasculitis. The main study parameter was the confirmation of the diagnosis using one of the three different imaging modalities, with the adjudicated clinical and histopathological diagnosis as the gold standard. A secondary parameter was the morphological appearance of the vessel affected by vasculitis.
Results
Patients with systemic vasculitis had myriad clinical manifestations with joint pain as the most common symptom. We found significant correlations between different imaging findings suggestive of vasculitis and the final adjudicated clinical diagnosis. In this context, on MRI, vessel wall thickening, edema, and diameter differed significantly between vasculitis and non-vasculitis groups (p < 0.05). Ultrasound revealed different findings that may serve as red flags in identifying patients with vasculitis, such as vascular occlusion or halo sign (p = 0.02 vs. non-vasculitis group). Interestingly, comparing maximal standardized uptake values from PET/CT examinations with vessel wall thickening or vessel diameter did not result in significant differences (p > 0.05).
Conclusions
We observed significant correlations between different imaging findings suggestive of vasculitis on ultrasound or MRI and the final adjudicated diagnosis. While ultrasound and MRI were considered suitable imaging methods for detecting and discriminating typical vascular changes, 18F-FDG PET/CT requires careful timing and patient selection given its moderate diagnostic accuracy.
The success of the increasing use of technology in education is highly dependent on learner acceptance. Although the Technology Acceptance Model (TAM) is dominant in research for surveying acceptance of technology, it does not allow the prediction of a successful first time use of technology. The successful first time use can be determined with the survey of technology affinity, as it corresponds to the expression of certain personality traits of users and is thus detached from the specific technology. Since there are no measurement instruments for the educational sector so far and existing instruments for measuring technology affinity do not meet the specific requirements for use in the educational context (e.g., limited time for questioning), we present the single item Inclusion of Technology Affinity in Self-Scale (ITAS). In study 1 we provide evidence of convergent and discriminant validity within the general population so that a generalization of its applicability is possible. In study 2 we subsequently tested ITAS in the actual target group, the educational sector. The high correlations of the ITAS with the ATI and the control instrument TA-EG (ranging from rs = 0.679 to rs = 0.440) show that ITAS is suitable for use in research. Furthermore, the newly developed instrument convinces with its low complexity, the graphical component, which requires little text understanding and the high time saving. This research thus can contribute to the investigation of technology affinity in the educational sector helping educators to conduct technical activities with their learning group, to predict possible difficulties and adjust their planning accordingly.
Bilder stellen auf vielfältige Weise Bezüge zu Räumen und raumbezogenen Praktiken her. Als humangeographische Forschungsmethode fragt die Bildanalyse nach der Wirklichkeit und der Wirkungsweise von Bildern im Verhältnis von Gesellschaft und Raum. Der Beitrag führt fachlich und methodisch in die humangeographische Bildanalyse ein und diskutiert ihren Beitrag zur geographischen Bildungsforschung im Hinblick auf die Vermittlung von Bild(lese)kompetenz und den mündigen Umgang mit medialer Bildlichkeit. Als Unterrichtsbeispiel wird eine Analyse visuellen Materials für eine differenzierte Auseinandersetzung mit dem Problem Müll vorgestellt.
During winter 2015/2016, the Arctic stratosphere was characterized by extraordinarily low temperatures in connection with a very strong polar vortex and with the occurrence of extensive polar stratospheric clouds. From mid-December 2015 until mid-March 2016, the German research aircraft HALO (High Altitude and Long-Range Research Aircraft) was deployed to probe the lowermost stratosphere in the Arctic region within the POLSTRACC (Polar Stratosphere in a Changing Climate) mission. More than 20 flights have been conducted out of Kiruna, Sweden, and Oberpfaffenhofen, Germany, covering the whole winter period. Besides total reactive nitrogen (NOy), observations of nitrous oxide, nitric acid, ozone, and water were used for this study. Total reactive nitrogen and its partitioning between the gas and particle phases are key parameters for understanding processes controlling the ozone budget in the polar winter stratosphere. The vertical redistribution of total reactive nitrogen was evaluated by using tracer–tracer correlations (NOy–N2O and NOy–O3). The trace gases are well correlated as long as the NOy distribution is controlled by its gas-phase production from N2O. Deviations of the observed NOy from this correlation indicate the influence of heterogeneous processes. In early winter no such deviations have been observed. In January, however, air masses with extensive nitrification were encountered at altitudes between 12 and 15 km. The excess NOy amounted to about 6 ppb. During several flights, along with gas-phase nitrification, indications for extensive occurrence of nitric acid containing particles at flight altitude were found. These observations support the assumption of sedimentation and subsequent evaporation of nitric acid-containing particles, leading to redistribution of total reactive nitrogen at lower altitudes. Remnants of nitrified air masses have been observed until mid-March. Between the end of February and mid-March, denitrified air masses have also been observed in connection with high potential temperatures. This indicates the downward transport of air masses that have been denitrified during the earlier winter phase. Using tracer–tracer correlations, missing total reactive nitrogen was estimated to amount to 6 ppb. Further, indications of transport and mixing of these processed air masses outside the vortex have been found, contributing to the chemical budget of the winter lowermost stratosphere. Observations within POLSTRACC, at the bottom of the vortex, reflect heterogeneous processes from the overlying Arctic winter stratosphere. The comparison of the observations with CLaMS model simulations confirm and complete the picture arising from the present measurements. The simulations confirm that the ensemble of all observations is representative of the vortex-wide vertical NOy redistribution.
Uniform sampling from the set G(d) of graphs with a given degree-sequence d=(d1,…,dn)∈Nn is a classical problem in the study of random graphs. We consider an analogue for temporal graphs in which the edges are labeled with integer timestamps. The input to this generation problem is a tuple D=(d,T)∈Nn×N>0 and the task is to output a uniform random sample from the set G(D) of temporal graphs with degree-sequence d and timestamps in the interval [1,T]. By allowing repeated edges with distinct timestamps, G(D) can be non-empty even if G(d) is, and as a consequence, existing algorithms are difficult to apply.
We describe an algorithm for this generation problem which runs in expected time O(M) if Δ2+ϵ=O(M) for some constant ϵ>0 and T−Δ=Ω(T) where M=∑idi and Δ=maxidi. Our algorithm applies the switching method of McKay and Wormald [1] to temporal graphs: we first generate a random temporal multigraph and then remove self-loops and duplicated edges with switching operations which rewire the edges in a degree-preserving manner.
Purpose:
The purpose of the study was to provide a consensus definition of the infrarenal sealing zone and develop an algorithm to determine when and if adjunctive procedure(s) or reintervention should be considered in managing patients undergoing endovascular aortic repair (EVAR) for infrarenal abdominal aortic aneurysm (AAA).
Methods:
A European Advisory Board (AB), made up of 11 vascular surgeons with expertise in EVAR for AAA, was assembled to share their opinion regarding the definition of preoperative and postoperative infrarenal sealing zone. Information on their current clinical practice and level of agreement on proposed reintervention paths was used to develop an algorithm. The process included 2 virtual meetings and 2 rounds of online surveys completed by the AB (Delphi method). Consensus was defined as reached when ≥ 8 of 11 (73%) respondents agreed or were neutral.
Results:
The AB reached complete consensus on definitions and measurement of the pre-EVAR target anticipated sealing zone (TASZ) and the post-EVAR real achieved sealing zone (RASZ), namely, the shortest length between the proximal and distal reference points as defined by the AB, in case of patients with challenging anatomies. Also, agreement was achieved on a list of 4 anatomic parameters and 3 prosthesis-/procedure-related parameters, considered to have the most significant impact on preoperative and postoperative sealing zones. Furthermore, the agreement was reached that in the presence of visible neck-related complications, both adjunctive procedure(s) and reintervention should be contemplated (100% consensus). In addition, adjunctive procedure(s) or reintervention can be considered in the following cases (% consensus): insufficient sealing zone on completion imaging (91%) or on the first postoperative computed tomography (CT) scan (91%), suboptimal sealing zone on completion imaging (73%) or postoperative CT scan (82%), and negative evolution of the actual sealing zone over time (91%), even in the absence of visible complications.
Conclusions:
AB members agreed on definitions of the pre- and post-EVAR infrarenal sealing zone, as well as factors of influence. Furthermore, a clinical decision algorithm was proposed to determine the timing and necessity of adjunctive procedure(s) and reinterventions.
Uniform sampling from the set G(d) of graphs with a given degree-sequence d=(d1,…,dn)∈Nn is a classical problem in the study of random graphs. We consider an analogue for temporal graphs in which the edges are labeled with integer timestamps. The input to this generation problem is a tuple D=(d,T)∈Nn×N>0 and the task is to output a uniform random sample from the set G(D) of temporal graphs with degree-sequence d and timestamps in the interval [1,T]. By allowing repeated edges with distinct timestamps, G(D) can be non-empty even if G(d) is, and as a consequence, existing algorithms are difficult to apply.
We describe an algorithm for this generation problem which runs in expected time O(M) if Δ2+ϵ=O(M) for some constant ϵ>0 and T−Δ=Ω(T) where M=∑idi and Δ=maxidi. Our algorithm applies the switching method of McKay and Wormald [1] to temporal graphs: we first generate a random temporal multigraph and then remove self-loops and duplicated edges with switching operations which rewire the edges in a degree-preserving manner.
Background
Musclin is an activity‐stimulated and cardioprotective myokine that attenuates pathological cardiac remodeling. Musclin deficiency, in turn, results in reduced physical endurance. The aim of this study was to assess the prognostic value of circulating musclin as a novel, putative biomarker to identify patients undergoing transcatheter aortic valve implantation (TAVI) who are at a higher risk of death.
Methods and Results
In this study, we measured systemic musclin levels in 368 patients undergoing TAVI who were at low to intermediate clinical risk (median EuroSCORE [European System for Cardiac Operative Risk Evaluation] II: 3.5; quartile 1–quartile, 2.2%–5.3%), whereby 209 (56.8%) patients were at low and 159 (43.2%) were at intermediate risk. Median preprocedural musclin levels were 2.7 ng/mL (quartile 1–quartile 3, 1.5–4.6 ng/mL). Musclin levels were dichotomized in low (<2.862 ng/mL, n=199 [54.1%]) or high (≥ 2.862 ng/mL, n=169 [45.9%]) groups using cutoff values determined by classification and regression tree analysis. The primary end point was 1‐year overall survival. Patients with low circulating musclin levels exhibited a significantly higher prevalence of frailty, low albumin values, hypertension, and history of stroke as well as higher N‐terminal pro‐B‐type natriuretic peptide. Low musclin levels significantly predicted risk of death in univariable (hazard ratio, 1.81; 95% CI, 1.00–3.53 [P=0.049]) and multivariable (adjusted hazard ratio, 2.45; 95% CI, 1.06–5.69 [P=0.037]) Cox regression analyses. Additionally, low musclin levels in combination with conventional EuroSCORE II suggested improved risk stratification in patients undergoing TAVI who were at low to intermediate clinical risk into subgroups with reduced 1‐year survival rates by log‐rank test (P for trend=0.003).
Conclusions
Circulating musclin is an independent predictor of 1‐year overall survival in patients undergoing TAVI. Combined with EuroSCORE II, circulating musclin might help to improve prediction of mortality in patients undergoing TAVI who are at low to intermediate clinical risk.
In this dissertation, we look at environmental effects in extreme and intermediate mass ratio inspirals into massive black holes. In these systems, stellar mass compact objects orbit massive black holes and lose orbital energy due to gravitational wave emission and other dissipative forces. We explore environmental interactions with dark matter spikes, stellar distributions, accretion disks, and combine and compare them. We discuss the existence and properties of dark matter spikes in the presence of these environmental effects. The signatures of the environmental effects, such as the phase space flow, dephasing, deshifting of the periapse, and alignment with accretion disks, are examined. These signatures are quantified in isolated spike systems, in dry, and in wet inspirals. We generally find dark matter effects to be subdominant to the other environmental effects, but their impact on the waveform is still observable and identifiable. Lastly, the rates of inspirals and the impact of spikes are estimated. All of these results are obtained with the help of a code imripy that is published alongside. If dark matter spikes exist, they should be observable with space-based gravitational wave observatories.
Emissions of the potent greenhouse gas perfluorocyclobutane (c-C4F8, PFC-318, octafluorocyclobutane) into the global atmosphere inferred from atmospheric measurements have been increasing sharply since the early 2000s. We find that these inferred emissions are highly correlated with the production of hydrochlorofluorocarbon-22 (HCFC-22, CHClF2) for feedstock (FS) uses, because almost all HCFC-22 FS is pyrolyzed to produce (poly)tetrafluoroethylene ((P)TFE) and hexafluoropropylene (HFP), a process in which c-C4F8 is a known by-product, causing a significant fraction of global c-C4F8 emissions. We find a global emission factor of ∼0.003 kg c-C4F8 per kilogram of HCFC-22 FS pyrolyzed. Mitigation of these c-C4F8 emissions, e.g., through process optimization, abatement, or different manufacturing processes, such as refined methods of electrochemical fluorination and waste recycling, could reduce the climate impact of this industry. While it has been shown that c-C4F8 emissions from developing countries dominate global emissions, more atmospheric measurements and/or detailed process statistics are needed to quantify c-C4F8 emissions at country to facility levels.
During the co-translational assembly of protein complexes, a fully synthesized subunit engages with the nascent chain of a newly synthesized interaction partner. Such events are thought to contribute to productive assembly, but their exact physiological relevance remains underexplored. Here, we examine structural motifs contained in nucleoporins for their potential to facilitate co-translational assembly. We experimentally test candidate structural motifs and identify several previously unknown co-translational interactions. We demonstrate by selective ribosome profiling that domain invasion motifs of beta-propellers, coiled-coils, and short linear motifs may act as co-translational assembly domains. Such motifs are often contained in proteins that are members of multiple complexes (moonlighters) and engage with closely related paralogs. Surprisingly, moonlighters and paralogs assemble co-translationally in only some but not all of the relevant biogenesis pathways. Our results highlight the regulatory complexity of assembly pathways.
Protection against pathogens is a major function of the gut microbiota. Although bacterial natural products have emerged as crucial components of host-microbiota interactions, their exact role in microbiota-mediated protection is largely unexplored. We addressed this knowledge gap with the nematode Caenorhabditis elegans and its microbiota isolate Pseudomonas fluorescens MYb115 that is known to protect against Bacillus thuringiensis (Bt) infection. We find that MYb115-mediated protection depends on sphingolipids that are derived from an iterative type I polyketide synthase (PKS), thereby describing a noncanonical pathway of bacterial sphingolipid production. We provide evidence that MYb115-derived sphingolipids affect C. elegans tolerance to Bt infection by altering host sphingolipid metabolism. This work establishes sphingolipids as structural outputs of bacterial PKS and highlights the role of microbiota-derived sphingolipids in host protection against pathogens.
Infection with the SARS (Severe Acute Respiratory Syndrome)-associated coronavirus results in respiratory failure probably by immunological mechanisms in 10% of patients. Laboratory markers that predict subsequent respiratory failure would therefore be useful in patient management.
We describe the clinical course, hematologic parameters, lymphocyte subpopulations and markers of inflammation in two patients with SARS, i.e., one man with diabetes mellitus and one pregnant woman, infected by the same viral isolate.
The patient with underlying diabetes mellitus developed respiratory failure after admission in the second week of the illness while the second patient developed only a mild disease without respiratory failure. Subsequent respiratory dysfunction was associated with lown umbers of Natural Killer (NK) cells at presentation and elevated CRP levels during the illness.
NK cells and CRP levels at the end of the first week of the disease might be related to subsequent respiratory dysfunction and may link underlying conditions to disease severity.
The transcription factor hypoxia-inducible factor 1 (HIF1) is an important driver of cancer and is therefore an attractive drug target. Acriflavine (ACF) has been suggested to inhibit HIF1, but its mechanism of action is unknown. Here we investigated the interaction of ACF with DNA and long non-coding RNAs (lncRNAs) and its function in human endothelial cells. ACF promoted apoptosis and reduced proliferation, network formation, and angiogenic capacity. It also induced changes in gene expression, as determined by RNA sequencing (RNA-seq), which could not be attributed to specific inhibition of HIF1. A similar response was observed in murine lung endothelial cells. Although ACF increased and decreased a similar number of protein-coding genes, lncRNAs were preferentially upregulated under normoxic and hypoxic conditions. An assay for transposase accessibility with subsequent DNA sequencing (ATAC-seq) demonstrated that ACF induced strong changes in chromatin accessibility at lncRNA promoters. Immunofluorescence showed displacement of DNA:RNA hybrids. Such effects might be due to ACF-mediated topoisomerase inhibition, which was indeed the case, as reflected by DNA unwinding assays. Comparison with other acridine derivatives and topoisomerase inhibitors suggested that the specific function of ACF is an effect of acridinium-class compounds. This study demonstrates that ACF inhibits topoisomerases rather than HIF specifically and that it elicits a unique expression response of lncRNAs.
Objectives
To identify the main problem areas in the applicability of the current TNM staging system (8th ed.) for the radiological staging and reporting of rectal cancer and provide practice recommendations on how to handle them.
Methods
A global case-based online survey was conducted including 41 image-based rectal cancer cases focusing on various items included in the TNM system. Cases reaching < 80% agreement among survey respondents were identified as problem areas and discussed among an international expert panel, including 5 radiologists, 6 colorectal surgeons, 4 radiation oncologists, and 3 pathologists.
Results
Three hundred twenty-one respondents (from 32 countries) completed the survey. Sixteen problem areas were identified, related to cT staging in low-rectal cancers, definitions for cT4b and cM1a disease, definitions for mesorectal fascia (MRF) involvement, evaluation of lymph nodes versus tumor deposits, and staging of lateral lymph nodes. The expert panel recommended strategies on how to handle these, including advice on cT-stage categorization in case of involvement of different layers of the anal canal, specifications on which structures to include in the definition of cT4b disease, how to define MRF involvement by the primary tumor and other tumor-bearing structures, how to differentiate and report lymph nodes and tumor deposits on MRI, and how to anatomically localize and stage lateral lymph nodes.
Conclusions
The recommendations derived from this global survey and expert panel discussion may serve as a practice guide and support tool for radiologists (and other clinicians) involved in the staging of rectal cancer and may contribute to improved consistency in radiological staging and reporting.
Phosphatidylinositol 3-kinase type 2α (PI3KC2α) is an essential member of the structurally unresolved class II PI3K family with crucial functions in lipid signaling, endocytosis, angiogenesis, viral replication, platelet formation and a role in mitosis. The molecular basis of these activities of PI3KC2α is poorly understood. Here, we report high-resolution crystal structures as well as a 4.4-Å cryogenic-electron microscopic (cryo-EM) structure of PI3KC2α in active and inactive conformations. We unravel a coincident mechanism of lipid-induced activation of PI3KC2α at membranes that involves large-scale repositioning of its Ras-binding and lipid-binding distal Phox-homology and C-C2 domains, and can serve as a model for the entire class II PI3K family. Moreover, we describe a PI3KC2α-specific helical bundle domain that underlies its scaffolding function at the mitotic spindle. Our results advance our understanding of PI3K biology and pave the way for the development of specific inhibitors of class II PI3K function with wide applications in biomedicine.
While in large clinical laboratories the implementation of total laboratory automation is continuously proceeding, this concept is mostly not suitable for small- and middle-sized laboratories or for testing laboratories of blood donation services due to costs and required space. For these facilities, however, a rational level of automation can be achieved by the installation of stand-alone work cells for pre-analytical and selected analytical processes. In this review, the features of some automated pre-analytical sample processing systems and automated systems for the serological testing for infectious diseases are described exemplarily and compared with each other. The major advantages of automated systems, compared to a solely manual workflow, are described. Essential factors which have to be considered for making the choice for an appropriate automated system are pointed out.
Purpose: Discordance between pre-operative biopsy and final pathology for Upper Tract Urothelial Carcinoma (UTUC) is high and optimal management remains controversial. The aim of this study is to evaluate the accuracy of pre-operative biopsy, to identify prognostic factors and to evaluate the effect of adjuvant chemotherapy on survival and oncologic outcome in UTUC.
Methods: We analyzed records of patients receiving surgical treatment for UTUC. Pathology of pre-operative biopsy was compared to surgical specimen. We used Kaplan-Meier method to estimate survival probabilities and Cox's proportional hazards models to estimate the association between covariates and event times. Primary endpoint was overall survival (OS). A matched-pair analysis was performed to evaluate the effect of adjuvant chemotherapy.
Results: 151 patients underwent surgical treatment (28% open, 36% laparoscopic, 17% robotic radical nephroureterectomy; 14% segmental ureteral resections and 5% palliative nephrectomy) for UTUC and were included in the analysis. Upstaging from <pT1 in endoscopic biopsy to ≥pT1 in final pathology occurred in 61% of patients and upgrading from low-grade to high-grade occurred in 30% of patients. Five-year OS was 59.5%. In the univariate Cox-regression model pathological stage, grade, lymphovascular invasion and positive surgical margins were associated with OS. Matched pair analysis for stage (<pT3; ≥pT3; pN+) and age revealed a significant survival benefit for adjuvant chemotherapy (HR 0.40, 0.14–0.77, p < 0.018) in this cohort.
Conclusion: UTUC is often underestimated in pre-operative biopsy, and it is associated with significant mortality. Pathological stage and grade, lymphovascular invasion and lymph node metastases are predictors of oncologic outcome and survival.
Congenital diaphragmatic hernia (CDH) is a relatively common and life-threatening birth defect, characterized by an abnormal opening in the primordial diaphragm that interferes with normal lung development. As a result, CDH is accompanied by immature and hypoplastic lungs, being the leading cause of morbidity and mortality in patients with this condition. In recent decades, various animal models have contributed novel insights into the pathogenic mechanisms underlying CDH and associated pulmonary hypoplasia. In particular, the generation of genetically modified mouse models, which show both diaphragm and lung abnormalities, has resulted in the discovery of multiple genes and signaling pathways involved in the pathogenesis of CDH. This article aims to offer an up-to-date overview on CDH-implicated transcription factors, molecules regulating cell migration and signal transduction as well as components contributing to the formation of extracellular matrix, whilst also discussing the significance of these genetic models for studying altered lung development with regard to the human situation.
Background: Photochemical internalization (PCI) is a novel technology for light-induced enhancement of the local therapeutic effect of cancer drugs, utilizing a specially designed photosensitizing molecule (fimaporfin). The photosensitizing molecules are trapped in endosomes along with macromolecules or drugs. Photoactivation of fimaporfin disrupts the endosomal membranes so that drug molecules are released from endosomes inside cells and can reach their therapeutic target in the cell cytosol or nucleus. Compared with photodynamic therapy, the main cytotoxic effect with PCI is disruption of the endosomal membrane resulting in delivery of chemotherapy drug, and not to the photochemical reactions per se. In this study we investigated the effect of PCI with gemcitabine in patients with inoperable perihilar cholangiocarcinoma (CCA).
Methods: The in vitro cytotoxic effect of PCI with gemcitabine was studied on two CCA-derived cell lines. In a fimaporfin dose-escalation phase I clinical study, we administered PCI with gemcitabine in patients with perihilar CCA (n = 16) to establish a safe and tolerable fimaporfin dose and to get early signals of efficacy. The patients enrolled in the study had tumors in which the whole length of the tumor could be illuminated from the inside of the bile duct, using an optical fiber inserted via an endoscope (Fig. 1). Fimaporfin was administered intravenously at day 0; gemcitabine (i.v.) and intraluminal biliary endoscopic laser light application on day 4; followed by standard gemcitabine/cisplatin chemotherapy.
Results: Preclinical experiments showed that PCI enhanced the effect of gemcitabine. In patients with CCA, PCI with gemcitabine was well tolerated with no dose-limiting toxicities, and no unexpected safety signals. Disease control was achieved in 10 of 11 evaluable patients, with a clearly superior effect in the two highest dose groups. The objective response rate (ORR) was 42%, including two complete responses, while ORR at the highest dose was 60%. Progression-free survival at 6 months was 75%, and median overall survival (mOS) was 15.4 months, with 22.8 months at the highest fimaporfin dose.
Conclusion: Photochemical internalization with gemcitabine was found to be safe and resulted in encouraging response and survival rates in patients with unresectable perihilar CCA.
We study a relativistic fluid with longitudinal boost invariance in a quantum-statistical framework as an example of a solvable nonequilibrium problem. For the free quantum field, we calculate the exact form of the expectation values of the stress-energy tensor and the entropy current. For the stress-energy tensor, we find that a finite value can be obtained only by subtracting the vacuum of the density operator at some fixed proper time τ0. As a consequence, the stress-energy tensor acquires nontrivial quantum corrections to the classical free-streaming form.
Microplastics are small plastic fragments that are widely distributed in marine and terrestrial environments. While the soil ecosystem represents a large reservoir for plastic, research so far has focused mainly on the impact on aquatic ecosystems and there is a lack of information on the potentially adverse effects of microplastics on soil biota. Earthworms are key organisms of the soil ecosystem and are due to their crucial role in soil quality and fertility a suitable and popular model organism in soil ecotoxicology.
Therefore, the aim of this study was to gain insight into the effects of environmentally relevant concentrations of microplastics on the earthworm Eisenia andrei on multiple levels of biological organization after different exposure periods. Earthworms were exposed to two types of microplastics: (1) polystyrene-HBCD and (2) car tire abrasion in natural soil for 2, 7, 14 and 28 d. Acute and chronic toxicity and all subcellular investigations were conducted for all exposure times, avoidance behavior assessed after 48 h and reproduction after 28 d. Subcellular endpoints included enzymatic biomarker responses, namely, carboxylesterase, glutathione peroxidase, acetylcholinesterase, glutathione reductase, glutathione S-transferase and catalase activities, as well as fluorescence-based measurements of oxidative stress-related markers and multixenobiotic resistance activity. Multiple biomarkers showed significant changes in activity, but a recovery of most enzymatic activities could be observed after 28 d. Overall, only minor effects could be observed on a subcellular level, showing that in this exposure scenario with environmentally relevant concentrations based on German pollution levels the threat to soil biota is minimal. However, in areas with higher concentrations of microplastics in the environment, these results can be interpreted as an early warning signal for more adverse effects. In conclusion, these findings provide new insights regarding the ecotoxicological effects of environmentally relevant concentrations of microplastics on soil organisms.
Holocarpic oomycetes infecting freshwater diatoms are obligate endobiotic parasites reported from a wide range of habitats. So far, the taxonomy of and phylogeny of most species remains unresolved, since most have not been reported throughout the past decades and sequence data are available for only the four species, Aphanomycopsis bacillariacearum, Diatomophthora gillii, Ectrogella bacillariacearum, and the recently-discovered species Miracula moenusica. In the current study, a new freshwater diatom parasite resembling Ectrogella bacillariacearum in the sense of Scherffel was discovered from pennate diatoms (Ulnaria acus, Ulnaria ulna) collected from the small stream Einbúalækur on Víkurskarð, North Iceland and investigated for its life cycle and phylogenetic placement. In contrast to the original description, Scherffel reports an achlya-like spore discharge for Ectrogella bacillariacearum. The phylogenetic reconstruction and morphological characterisation in this study revealed that Scherffel’s E. bacillariacearum is largely unrelated to the epitype of the species and is a member of the early-diverging genus Miracula. Consequently, the new species is described as M. einbuarlaekurica in the present study. This adds a second freshwater member to the genus, demonstrating the high ecological adaptability of the genus, which thrives in both freshwater and marine ecosystems.
We report cumulants of the proton multiplicity distribution from dedicated fixed-target Au+Au collisions at sNN−−−√ = 3.0 GeV, measured by the STAR experiment in the kinematic acceptance of rapidity (y) and transverse momentum (pT) within −0.5<y<0 and 0.4<pT<2.0 GeV/c. In the most central 0--5\% collisions, a proton cumulant ratio is measured to be C4/C2=−0.85±0.09 (stat.)±0.82 (syst.), which is less than unity, the Poisson baseline. The hadronic transport UrQMD model reproduces our C4/C2 in the measured acceptance. Compared to higher energy results and the transport model calculations, the suppression in C4/C2 is consistent with fluctuations driven by baryon number conservation and indicates an energy regime dominated by hadronic interactions. These data imply that the QCD critical region, if created in heavy-ion collisions, could only exist at energies higher than 3\,GeV.
Microstates sind kurzzeitig andauernde, wiederkehrende elektrische Potentialfelder über dem Kortex. Ein Großteil der Signalvarianz des
Elektroenzephalogramms (EEG) wird durch vier repräsentative räumliche Potentialverteilungen (Topographien) abgedeckt, welche bereits im Wachzustand und im Schlaf identifiziert wurden und kanonisch als Karten A-D bezeichnet werden. Microstates wurden in den vergangenen Jahren vor allem im Ruhe-Wach-EEG untersucht, über andere Vigilanzzustände hingegen wissen wir bisher wenig. Klassischerweise analysieren wir verschiedene Vigilanzzustände im Elektroenzephalogramm anhand von Frequenzen und Graphoelementen, die Microstate-Analyse hingegen betrachtet in erster Linie die räumliche Verteilung des kortikalen Potentials zu einem jeweiligen Zeitpunkt.
Die vorliegende Studie hatte zum Ziel, die zeitliche Abfolge von Microstates im Wachzustand und im Schlaf zu charakterisieren. Mittels informationstheoretischer Ansätze können die dynamischen Eigenschaften der Microstate-Sequenz direkt mit den frequenzbasierten Eigenschaften des zugrundeliegenden EEG verglichen werden. Es wurden die Ruhe-Wach- und Schlafdaten von 32 gesunden Probanden analysiert. Hierbei fand sich eine Zunahme der mittleren Microstate-Dauer und der Relaxationszeit der Übergangsmatrix, was langsamere Dynamiken im Schlaf anzeigt. Erstaunlicherweise konnte im Tiefschlaf mehr als die Hälfte der Sequenzen nicht von einem simplen Markov-Modell unterschieden werden, was für eine Abnahme der Komplexität der Microstate-Sequenzen spricht. Die Entropierate der untersuchten Sequenzen nahm mit zunehmender Schlaftiefe ab, was weniger
Zufall bzw. eine größere Vorhersagbarkeit innerhalb der Sequenzen bedeutet.
Darüberhinaus konnte gezeigt werden, dass Microstates immer dann periodisch auftreten, wenn das zugrundeliegende EEG eine dominante Grundfrequenz aufweist, sodass oszillatorische Hirnaktivität auch auf der Microstate-Ebene verfolgbar ist. Hierdurch ist es möglich, physiologische Vigilanzzustände quantitativ voneinander zu unterscheiden.
Interpretiert man Microstates als Korrelate neuronaler Netzwerke, scheinen im Schlaf dieselben oder ähnliche Netzwerke aktiviert zu werden wie im Wachzustand, allerdings mit zunehmender Schlaftiefe langsamer und auf eine weniger komplexe Art und Weise.
We report cumulants of the proton multiplicity distribution from dedicated fixed-target Au+Au collisions at 3.0 GeV, measured by the STAR experiment in the kinematic acceptance of rapidity (y) and transverse momentum (pT) within −0.5<y<0 and 0.4<pT<2.0 GeV/c. In the most central 0--5\% collisions, a proton cumulant ratio is measured to be C4/C2=−0.85±0.09 (stat.)±0.82 (syst.), which is less than unity, the Poisson baseline. The hadronic transport UrQMD model reproduces our C4/C2 in the measured acceptance. Compared to higher energy results and the transport model calculations, the suppression in C4/C2 is consistent with fluctuations driven by baryon number conservation and indicates an energy regime dominated by hadronic interactions. These data imply that the QCD critical region, if created in heavy-ion collisions, could only exist at energies higher than 3\,GeV.
Despite islands contributing only 6.7% of land surface area, they harbor ~20% of the Earth's biodiversity, but unfortunately also ~50% of the threatened species and 75% of the known extinctions since the European expansion around the globe. Due to their geological and geographic history and characteristics, islands act simultaneously as cradles of evolutionary diversity and museums of formerly widespread lineages—elements that permit islands to achieve an outstanding endemicity. Nevertheless, the majority of these endemic species are inherently vulnerable due to genetic and demographic factors linked with the way islands are colonized. Here, we stress the great variation of islands in their physical geography (area, isolation, altitude, latitude) and history (age, human colonization, human density). We provide examples of some of the most species rich and iconic insular radiations. Next, we analyze the natural vulnerability of the insular biota, linked to genetic and demographic factors as a result of founder events as well as the typically small population sizes of many island species. We note that, whereas evolution toward island syndromes (including size shifts, derived insular woodiness, altered dispersal ability, loss of defense traits, reduction in clutch size) might have improved the ability of species to thrive under natural conditions on islands, it has simultaneously made island biota disproportionately vulnerable to anthropogenic pressures such as habitat loss, overexploitation, invasive species, and climate change. This has led to the documented extinction of at least 800 insular species in the past 500 years, in addition to the many that had already gone extinct following the arrival of first human colonists on islands in prehistoric times. Finally, we summarize current scientific knowledge on the ongoing biodiversity loss on islands worldwide and express our serious concern that the current trajectory will continue to decimate the unique and irreplaceable natural heritage of the world's islands. We conclude that drastic actions are urgently needed to bend the curve of the alarming rates of island biodiversity loss.
We report cumulants of the proton multiplicity distribution from dedicated fixed-target Au+Au collisions at 3.0 GeV, measured by the STAR experiment in the kinematic acceptance of rapidity (y) and transverse momentum (pT) within −0.5<y<0 and 0.4<pT<2.0 GeV/c. In the most central 0--5\% collisions, a proton cumulant ratio is measured to be C4/C2=−0.85±0.09 (stat.)±0.82 (syst.), which is less than unity, the Poisson baseline. The hadronic transport UrQMD model reproduces our C4/C2 in the measured acceptance. Compared to higher energy results and the transport model calculations, the suppression in C4/C2 is consistent with fluctuations driven by baryon number conservation and indicates an energy regime dominated by hadronic interactions. These data imply that the QCD critical region, if created in heavy-ion collisions, could only exist at energies higher than 3\,GeV.
The purpose of this study was to investigate which social groups are perceived as a threat target and which are perceived as a threat source during the COVID-19 outbreak. In a German sample (N = 1454) we examined perceptions of social groups ranging from those that are psychologically close and smaller (family, friends, neighbors) to those that are more distal and larger (people living in Germany, humankind). We hypothesized that psychologically closer groups would be perceived as less affected by COVID-19 as well as less threatening than more psychologically distal groups. Based on social identity theorizing, we also hypothesized that stronger identification with humankind would change these patterns. Furthermore, we explored how these threat perceptions relate to adherence to COVID-19 health guidelines. In line with our hypotheses, latent random-slope modelling revealed that psychologically distal and larger groups were perceived as more affected by COVID-19 and as more threatening than psychologically closer and smaller groups. Including identification with humankind as a predictor into the threat target model resulted in a steeper increase in threat target perception patterns, whereas identification with humankind did not predict differences in threat source perceptions. Additionally, an increase in threat source perceptions across social groups was associated with more adherence to health guidelines, whereas an increase in threat target perceptions was not. We fully replicated these findings in a subgroup from the original sample (N = 989) four weeks later. We argue that societal recovery from this and other crises will be supported by an inclusive approach informed by a sense of our common identity as human beings.
Spatial genome organization is tightly controlled by several regulatory mechanisms and is essential for gene expression control. Nuclear receptors are ligand-activated transcription factors that modulate physiological and pathophysiological processes and are primary pharmacological targets. DNA binding of the important loop-forming insulator protein CCCTC-binding factor (CTCF) was modulated by 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3). We performed CTCF HiChIP assays to produce the first genome-wide dataset of CTCF long-range interactions in 1,25(OH)2D3-treated cells, and to determine whether dynamic changes of spatial chromatin interactions are essential for fine-tuning of nuclear receptor signaling. We detected changes in 3D chromatin organization upon vitamin D receptor (VDR) activation at 3.1% of all observed CTCF interactions. VDR binding was enriched at both differential loop anchors and within differential loops. Differential loops were observed in several putative functional roles including TAD border formation, promoter-enhancer looping, and establishment of VDR-responsive insulated neighborhoods. Vitamin D target genes were enriched in differential loops and at their anchors. Secondary vitamin D effects related to dynamic chromatin domain changes were linked to location of downstream transcription factors in differential loops. CRISPR interference and loop anchor deletion experiments confirmed the functional relevance of nuclear receptor ligand-induced adjustments of the chromatin 3D structure for gene expression regulation.
Wissenschaftsbasierte und verständliche Gesundheitsinformationen sind ein Kernelement der Evidenzbasierten Medizin und von Public Health. Ziel ist es, informierte Entscheidungen zu ermöglichen, die auf realistischen Einschätzungen von Gesundheitsrisiken sowie von Nutzen und Schaden möglicher Interventionen beruhen. In Deutschland wurden während der COVID-19-Pandemie die Standards für eine evidenzbasierte Risikokommunikation wenig beachtet. Häufig war die öffentliche Berichterstattung einseitig, unvollständig und missverständlich. Bedrohungsszenarien haben emotionalen Stress und unnötige Angst ausgelöst. Eine systematische und umfassende Aufarbeitung der Pandemiemaßnahmen ist auch in Deutschland dringlich geboten. Dabei müsste eine kritisch-konstruktive Analyse der medialen Risikokommunikation von Expert*innen, Politiker*innen und Medien ein zentrales Element der Aufarbeitung sein. Die Ergebnisse sollen helfen, aus der vergangenen Pandemie zu lernen, um für künftige Krisen besser vorbereitet zu sein.
The long-term effect of protection by two doses of SARS-CoV-2 vaccination in patients receiving chronic intermittent hemodialysis (CIHD) is an urging question. We investigated the humoral and cellular immune response of 42 CIHD patients who had received two doses of SARS-CoV-2 vaccine, and again after a booster vaccine with mRNA-1273 six months later. We measured antibody levels and SARS-CoV-2-specific surrogate neutralizing antibodies (SNA). Functional T cell immune response to vaccination was assessed by quantifying interferon-γ (IFN-γ) and IL-2 secreting T cells specific for SARS-CoV-2 using an ELISpot assay. Our data reveal a moderate immune response after the second dose of vaccination, with significantly decreasing SARS-CoV-2-specific antibody levels and less than half of the study group showed neutralizing antibodies six months afterwards. Booster vaccines increased the humoral response dramatically and led to a response rate of 89.2% for antibody levels and a response rate of 94.6% for SNA. Measurement in a no response/low response (NR/LR) subgroup of our cohort, which differed from the whole group in age and rate of immunosuppressive drugs, indicated failure of a corresponding T cell response after the booster vaccine. We strongly argue in favor of a regular testing of surrogate neutralizing antibodies and consecutive booster vaccinations for CIHD patients to provide a stronger and persistent immunity.
Abstract
The co-occurrence of insulin resistance (IR)-related metabolic conditions with neuropsychiatric disorders is a complex public health challenge. Evidence of the genetic links between these phenotypes is emerging, but little is currently known about the genomic regions and biological functions that are involved. To address this, we performed Local Analysis of [co]Variant Association (LAVA) using large-scale (N=9,725-933,970) genome-wide association studies (GWASs) results for three IR-related conditions (type 2 diabetes mellitus, obesity, and metabolic syndrome) and nine neuropsychiatric disorders. Subsequently, positional and expression quantitative trait locus (eQTL)-based gene mapping and downstream functional genomic analyses were performed on the significant loci. Patterns of negative and positive local genetic correlations (|rg|=0.21-1, pFDR<0.05) were identified at 109 unique genomic regions across all phenotype pairs. Local correlations emerged even in the absence of global genetic correlations between IR-related conditions and Alzheimer’s disease, bipolar disorder, and Tourette’s syndrome. Genes mapped to the correlated regions showed enrichment in biological pathways integral to immune-inflammatory function, vesicle trafficking, insulin signalling, oxygen transport, and lipid metabolism. Colocalisation analyses further prioritised 10 genetically correlated regions for likely harbouring shared causal variants, displaying high deleterious or regulatory potential. These variants were found within or in close proximity to genes, such as SLC39A8 and HLA-DRB1, that can be targeted by supplements and already known drugs, including omega-3/6 fatty acids, immunomodulatory, antihypertensive, and cholesterol-lowering drugs. Overall, our findings underscore the complex genetic landscape of IR-neuropsychiatric multimorbidity, advocating for an integrated disease model and offering novel insights for research and treatment strategies in this domain.
Highlights
Local genetic correlations found even in the absence of global correlations.
Both positive and negative local correlations found for IR-neuropsychiatric pairs.
Enrichment for immune, and insulin signalling pathways, among others.
Pinpointed shared likely causal variants within 10 genomic regions.
Identified therapeutic targets, e.g., SLC39A8 and HLA-DRB1, for drug repurposing.
Die Nukleinsäure-Amplifikations Testung (NAT) von Blutprodukten wurde Mitte der 90er Jahre von europäischen Plasma verarbeitenden Firmen und großen deutschen Blutspendediensten entwickelt. Primäres Ziel war eine verbesserte Sicherheit von Blutprodukten, indem das so genannte diagnostische Fenster nach einer Virusinfektion bis zum ersten Nachweis von Antikörpern so weit wie möglich geschlossen werden sollte. Bei einer qualitätsgerechten PCR kommen bereits der Probenentnahme, dem Probentransport sowie der Probenlagerung große Bedeutung zu, da vermieden werden muß, daß es durch ungeeignete Antikoagulanzien oder Entnahmetechniken zu einem Sensitivitätsverlust kommt oder daß Kontaminationen falsch positive Ergebnisse hervorrufen. Wird ein Pooling von Proben durchgeführt, ergibt sich ein Verdünnungsfaktor, weshalb darauf zu achten ist, dass gegebenenfalls nachfolgende Anreicherungsschritte für Viren, wie z.B. eine Zentrifugation, implementiert werden. Der Gesamtprozeß von Pooling und Virusanreicherung ist ebenso wie die Probenvorbereitung durch geeignete Maßnahmen zu validieren und durch Qualitätssicherungsmaßnahmen zu flankieren. Die in der Extraktion der viralen Nukleinsäuren verwendeten Reagenzien sollten im Laboralltag möglichst einfach zu handhaben sein, keine Gefährdung des Laborpersonals darstellen und die Virus-Nukleinsäure gleichzeitig mit höchster Effizienz freisetzen und in sehr hoher Reinheit für die anschließende Amplifikation bereitstellen. Qualitätssicherungmaßnahmen sollen hier sowohl die geforderte Effizienz des Prozesses sichern als auch verhindern, daß es in dieser kritischen Phase zu Kontaminationen kommt. Zur Amplifikation stehen verschiedene Methoden zur Verfügung, wobei die PCR, insbesondere bei inhouse-Systemen, die weiteste Verbreitung gefunden hat. Der Prozeß der Amplifikation sollte möglichst im geschlossenen System erfolgen, wie dies z.B. in Real-time PCR-Systemen die Regel ist, ohne daß das Reaktionsgefäß während oder nach dem Amplifikationsprozeß geöffnet werden muß. Dies gewährleistet eine hohe Sicherheit vor Kontaminationen durch freigesetzte Amplifikate. Im Blutspendewesen ist es von höchster Bedeutung, daß negative Ergebnisse tatsächlich negative Blutspenden anzeigen. Interne Kontrollen, die eine korrekte Funktionsweise jeder individuellen PCR signalisieren, sollten deshalb in jeder Reaktion mitgeführt werden. Neben internen Kontrollen sind externe Negativ- und Positiv-Kontrollen mitzuführen, um falsch positive Reaktionen nachzuweisen bzw. auch die vor der PCR liegenden Prozesse wie Virusanreicherung und Extraktion zu überwachen. Alle Prozesse sind nach den von den Behörden festgelegten Kriterien durchgängig zu validieren, und es ist routinemäßig an externen Qualitätskontrollmaßnahmen (Ringversuchen) teilzunehmen.
Background: For rheumatoid arthritis (RA), the treat-to-target concept suggests attaining remission or at least low disease activity (LDA) after 12 weeks.
Objectives: This German, prospective, multicenter, non-interventional study aimed to determine the proportion of patients with RA who achieved their treat-to-target aim after 12 and 24 weeks of etanercept (ETN) treatment in a real-life setting, as opposed to patients achieving their therapeutic target at a later timepoint (week 36 or 52).
Methods: A total of 824 adults with a confirmed diagnosis of RA without prior ETN treatment were included. Remission and LDA were defined as DAS28 < 2.6 and DAS28 ≤ 3.2, respectively.
Results: The proportion of patients achieving remission was 24% at week 12 and 31% at week 24. The proportion of patients achieving LDA was 39% at week 12 and 45% at week 24. The proportion of patients achieving remission or LDA further increased beyond week 24 up to week 52. Improvement in pain and reduction in concomitant glucocorticoid treatment were observed. Improvements in patient-reported outcomes were also seen in patients who did not reach remission or LDA. No new safety signals were detected.
Conclusions: A considerable proportion of patients with RA attained the target of remission or LDA after 12 weeks of ETN treatment. Even beyond that timepoint, the proportion of patients achieving treatment targets continued to increase up to week 52.
Trial Registration
ClinicalTrials.gov Identifier: NCT02486302.
Plain Language Summary
Physicians measure response to treatment of rheumatoid arthritis using a disease activity score (DAS28). People with a DAS28 of less than 2.6 have very few to no symptoms (also called remission). People with a DAS28 of 3.2 or less, called low disease activity, may experience mild symptoms. When people do not respond to treatment after 12 weeks, it is usually recommended to prescribe a different treatment. Researchers do not know how many people who do not respond after 12 weeks would respond if treatment were continued. A total of 824 German people with rheumatoid arthritis who received a drug called etanercept for up to 52 weeks took part in this study. Researchers wanted to know how many people had remission or low disease activity after 12 weeks and 24 weeks of treatment.
After 12 weeks, 24 in 100 people had remission; this increased to 31 in 100 people after 24 weeks. Thirty-nine in 100 people had low disease activity after 12 weeks; this increased to 45 in 100 people after 24 weeks. The number of people with remission or low disease activity increased with longer treatment (up to 52 weeks). People needed less additional treatment with a type of drug called glucocorticoids. The people in this study experienced side effects that were similar to those reported by people who took etanercept in previous studies.
The researchers concluded that a considerable proportion of people responded to treatment with etanercept after 12 weeks. This proportion increased when treatment was continued for longer than 12 weeks.
Porous tantalum trabecular metal biomaterial has a similar structure to trabecular bone, and was recently added to titanium dental implants as a surface enhancement. The purpose of this prospective pilot study was to describe 5-year survival results and crestal bone level changes around immediately-provisionalized Trabecular Metal Dental Implants. Eligible patients were adults in need of ≥1 implants in the posterior jaw. A non-occluding single acrylic provisional crown was in place for up to 14 days before final restoration. Clinical evaluations with radiographs were conducted at each follow-up visit (1 month, 3 months, 6 months, and 1 to 5 years). The primary endpoint was implant survival, characterized using the Kaplan-Meier method. The secondary endpoint was changes in crestal bone level, evaluated using a paired t-test to compare mean crestal bone levels between the baseline, 6-month, and annual follow-up values. In total, 30 patients (37 implants) were treated. Mean patient age was 45.5 years, and 63% were female. There was one implant failure; cumulative survival at 5 years was 97.2%. After the initial bone loss of 0.40 mm in the first 6 months, there were no statistically significant changes in crestal bone level over time up to 5 years of follow-up.
Objective: Liver stiffness measurement (LSM) is a tool used to screen for significant fibrosis and portal hypertension. The aim of this retrospective multicentre study was to develop an easy tool using LSM for clinical outcomes in advanced chronic liver disease (ACLD) patients.
Design: This international multicentre cohort study included a derivation ACLD patient cohort with valid two-dimensional shear wave elastography (2D-SWE) results. Clinical and laboratory parameters at baseline and during follow-up were recorded. LSM by transient elastography (TE) was also recorded if available. The primary outcome was overall mortality. The secondary outcome was the development of first/further decompensation.
Results: After screening 2148 patients (16 centres), 1827 patients (55 years, 62.4% men) were included in the 2D-SWE cohort, with median liver SWE (L-SWE) 11.8 kPa and a model for end stage liver disease (MELD) score of 8. Combination of MELD score and L-SWE predict independently of mortality (AUC 0.8). L-SWE cut-off at ≥20 kPa combined with MELD ≥10 could stratify the risk of mortality and first/further decompensation in ACLD patients. The 2-year mortality and decompensation rates were 36.9% and 61.8%, respectively, in the 305 (18.3%) high-risk patients (with L-SWE ≥20 kPa and MELD ≥10), while in the 944 (56.6%) low-risk patients, these were 1.1% and 3.5%, respectively. Importantly, this M10LS20 algorithm was validated by TE-based LSM and in an additional cohort of 119 patients with valid point shear SWE-LSM.
Conclusion: The M10LS20 algorithm allows risk stratification of patients with ACLD. Patients with L-SWE ≥20 kPa and MELD ≥10 should be followed closely and receive intensified care, while patients with low risk may be managed at longer intervals.
Rationale: Studies have suggested mental health improvements following the use of the psychotropic plant concoction ayahuasca in non-clinical and clinical samples.
Objectives: The present observational study assessed depressive symptomatology in 20 clinically depressed patients (symptom score > 13 on the Beck’s Depression Inventory) before attendance of an ayahuasca ceremony and 1 month and 1 year after. Secondary measures included ratings of altered states of consciousness and ego dissolution during the ayahuasca ceremony as well as global measures of mindfulness, satisfaction with life, depression, anxiety, and stress.
Results: Twenty participants completed baseline and 1-day follow-up, 19 completed measures at 1-month follow-up, and 17 completed measures at 1-year follow-up. BDI scores reduced from baseline (M = 22.7) to all post-ceremony measures (Ms 11.45, 12.89, and 8.88, for 1-day, 1-month, and 1-year follow-up, respectively). After 1 day, 12/20 participants were in remission (BDI < 13). Remission rates after 1 month and 1 year were 13/19 and 12/17, respectively. Three participants remained mildly depressed (BDI 14–19) at the 1-month and 1-year follow-up. Two participants did not respond and remained at a moderate/severe level of depression at 1-year follow-up. Reductions on the secondary mental health measures and increases in mindfulness and satisfaction with life were found up to 1 year post-ceremony. Improvements in clinical depression and mental health correlated with levels of experienced ego dissolution and oceanic boundlessness during the ceremony up to 1 month after the ceremony. Engagement in additional mental health treatments or use of another psychedelic during study participation may have contributed to improved mental health ratings at 1-year follow-up.
Conclusion: Ayahuasca produces long-term mental health improvements in clinically depressed patients, which highlights its therapeutic potential.
Rapidity-odd directed flow measurements at midrapidity are presented for Λ, Λ¯, K±, K0s and ϕ at sNN−−−−√= 7.7, 11.5, 14.5, 19.6, 27, 39, 62.4 and 200 GeV in Au+Au collisions recorded by the STAR detector at the Relativistic Heavy Ion Collider. These measurements greatly expand the scope of data available to constrain models with differing prescriptions for the equation of state of quantum chromodynamics. Results show good sensitivity for testing a picture where flow is assumed to be imposed before hadron formation and the observed particles are assumed to form via coalescence of constituent quarks. The pattern of departure from a coalescence-inspired sum-rule can be a valuable new tool for probing the collision dynamics.
Surface temperature is a fundamental parameter of Earth’s climate. Its evolution through time is commonly reconstructed using the oxygen isotope and the clumped isotope compositions of carbonate archives. However, reaction kinetics involved in the precipitation of carbonates can introduce inaccuracies in the derived temperatures. Here, we show that dual clumped isotope analyses, i.e., simultaneous ∆47 and ∆48 measurements on the single carbonate phase, can identify the origin and quantify the extent of these kinetic biases. Our results verify theoretical predictions and evidence that the isotopic disequilibrium commonly observed in speleothems and scleractinian coral skeletons is inherited from the dissolved inorganic carbon pool of their parent solutions. Further, we show that dual clumped isotope thermometry can achieve reliable palaeotemperature reconstructions, devoid of kinetic bias. Analysis of a belemnite rostrum implies that it precipitated near isotopic equilibrium and confirms the warmer-than-present temperatures during the Early Cretaceous at southern high latitudes.
We report the triton (t) production in Au+Au collisions at sNN−−−√ = 7.7 -- 200 GeV measured at mid-rapidity (|y|< 0.5) by the STAR experiment from the first phase of the beam energy scan at the Relativistic Heavy Ion Collider (RHIC). The nuclear compound yield ratio (Nt×Np/N2d), which is predicted to be sensitive to the local density fluctuation of neutrons, monotonically decreases with increasing charged-particle multiplicity (dNch/dη) and exhibits a scaling behavior. The multiplicity dependence of the yield ratios are compared with calculations from coalescence and thermal models. Relative to the coalescence baseline, enhancements of the yield ratios are observed in the 0%-10% most central collisions at 19.6 and 27 GeV with a significance of 2.3σ and 3.4σ, respectively, with a combined significance of 4.1σ. The measured significance of these enhancements decreases with smaller pT acceptance. The enhancements are not observed in peripheral collisions and model calculations without critical fluctuation. Important implications on the QCD phase structure and the production mechanism of light nuclei in heavy-ion collisions are discussed.
The STAR collaboration presents jet substructure measurements related to both the momentum fraction and the opening angle within jets in \pp and \AuAu collisions at \sqrtsn =200 GeV. The substructure observables include SoftDrop groomed momentum fraction (\zg), groomed jet radius (\rg), and subjet momentum fraction (\zsj) and opening angle (\tsj). The latter observable is introduced for the first time. Fully corrected subjet measurements are presented for \pp collisions and are compared to leading order Monte Carlo models. The subjet \tsj~distributions reflect the jets leading opening angle and are utilized as a proxy for the resolution scale of the medium in \AuAu collisions. We compare data from \AuAu collisions to those from \pp which are embedded in minimum-bias \AuAu events in order to include the effects of detector smearing and the heavy-ion collision underlying event. The subjet observables are shown to be more robust to the background than \zg~and \rg.
We observe no significant modifications of the subjet observables within the two highest-energy, back-to-back jets, resulting in a distribution of opening angles and the splittings that are vacuum-like. We also report measurements of the differential di-jet momentum imbalance (AJ) for jets of varying \tsj. We find no qualitative differences in energy loss signatures for varying angular scales in the range 0.1< \tsj <0.3, leading to the possible interpretation that energy loss in this population of high momentum di-jet pairs, is due to soft medium-induced gluon radiation from a single color-charge as it traverses the medium.
Oxytocin, welches primär als Hormon bekannt ist, beeinflusst als Neuromodulator viele kognitive Prozesse, die an sozialem Verhalten, wie Sprache, beteiligt sind. Einerseits verändert es akustische Merkmale von gesprochener Sprache, andererseits erleichtert es auf perzeptueller Ebene die Emotionserkennung in der Sprachwahrnehmung und Körpersprache. Bislang war nicht bekannt, wie Oxytocin Hirnaktivität während des Sprechens verändert. Wir hypothetisierten, dass dieser Neuromodulator ähnlich wie Dopamin kortiko-basale Schaltkreise bahnen könnte.
Wir führten eine doppelt-verblindete Verhaltens- und funktionelle Kernspintomographiestudie durch, in der 52 gesunde Probanden an zwei getrennten Untersuchungsterminen entweder intranasales Oxytocin oder ein Placebo erhielten. Die Teilnehmer lasen Sätze außerhalb des Kernspintomographen und im Scanner leise oder laut mit entweder neutraler oder fröhlicher Intonation vor.
Die Verabreichung von Oxytocin erhöhte den zweiten Formanten der produzierten Vokale. Höhere Frequenzen dieses akustischen Parameters wurden zuvor mit einer positiven Valenz gesprochener Sprache in Verbindung gebracht; jedoch konnten unabhängige Beurteiler*innen die akustischen Unterschiede in unserem experimentellen Setting nicht konsistent unterscheiden.
Als neuronales Korrelat verstärkte Oxytocin die präparatorische subkortikale Gehirnaktivität im ventralen Pallidum und Striatum. Auch kortikal erhöhte Oxytocin präparatorische Gehirnaktivität in Regionen des dorsalen wie auch des ventralen Sprachverarbeitungsstroms, in sensomotorischen Kortizes und limbischen sowie exekutiven Regionen. In einigen dieser Regionen modulierte der genetische Oxytocin- Rezeptor-Polymorphismus rs53576 die durch die Oxytocin-Verabreichung verursachte Gehirnaktivität. Ähnlich wie Dopamin modulierte Oxytocin außerdem kortiko-basale Schaltkreise, die an der Generierung von fröhlicher Prosodie beteiligt sind. Während der Vorbereitung von Sprache erhöhte der Neuromodulator die funktionelle Konnektivität zwischen dem ventralem Pallidum und dem dorsolateralen präfrontalen Kortex mit einem spiegelbildlichen Profil während des eigentlichen Sprechens, einen Effekt den wir als „gating“ (Bahnung) interpretierten.
Unsere Ergebnisse legen nahe, dass mehrere neuronale Prozesse, die der Sprachproduktion zugrundeliegen, durch Oxytocin moduliert werden. Das Muster ähnelt hierbei dem anderer Neuromodulatoren wie Dopamin. Die vorliegende Arbeit charakterisiert somit erstmals Oxytocineffekte auf die mit Sprachproduktion assoziierte Hirnaktivität und funktionelle Konnektivität.
The STAR collaboration presents jet substructure measurements related to both the momentum fraction and the opening angle within jets in p+p and Au+Au collisions at sNN−−−√=200 GeV. The substructure observables include SoftDrop groomed momentum fraction (zg), groomed jet radius (Rg), and subjet momentum fraction ((zSJ)) and opening angle ((θSJ)). The latter observable is introduced for the first time. Fully corrected subjet measurements are presented for p+p collisions and are compared to leading order Monte Carlo models. The subjet θSJ distributions reflect the jets leading opening angle and are utilized as a proxy for the resolution scale of the medium in Au+Au collisions. We compare data from Au+Au collisions to those from p+p which are embedded in minimum-bias Au+Au events in order to include the effects of detector smearing and the heavy-ion collision underlying event. The subjet observables are shown to be more robust to the background than zg and (Rg).
We observe no significant modifications of the subjet observables within the two highest-energy, back-to-back jets, resulting in a distribution of opening angles and the splittings that are vacuum-like. We also report measurements of the differential di-jet momentum imbalance (AJ) for jets of varying θg. We find no qualitative differences in energy loss signatures for varying angular scales in the range 0.1<θSJ<0.3, leading to the possible interpretation that energy loss in this population of high momentum di-jet pairs, is due to soft medium-induced gluon radiation from a single color-charge as it traverses the medium.
We study the beam-energy and system-size dependence of \phi meson production (using the hadronic decay mode \phi -- K+K-) by comparing the new results from Cu+Cu collisions and previously reported Au+Au collisions at \sqrt{s_NN} = 62.4 and 200 GeV measured in the STAR experiment at RHIC. Data presented are from mid-rapidity (|y|<0.5) for 0.4 < pT < 5 GeV/c. At a given beam energy, the transverse momentum distributions for \phi mesons are observed to be similar in yield and shape for Cu+Cu and Au+Au colliding systems with similar average numbers of participating nucleons. The \phi meson yields in nucleus-nucleus collisions, normalised by the average number of participating nucleons, are found to be enhanced relative to those from p+p collisions with a different trend compared to strange baryons. The enhancement for \phi mesons is observed to be higher at \sqrt{s_NN} = 200 GeV compared to 62.4 GeV. These observations for the produced \phi(s\bar{s}) mesons clearly suggest that, at these collision energies, the source of enhancement of strange hadrons is related to the formation of a dense partonic medium in high energy nucleus-nucleus collisions and cannot be alone due to canonical suppression of their production in smaller systems.
STAR's measurements of directed flow (v1) around midrapidity for π±, K±, K0S, p and p¯ in Au + Au collisions at $\sqrtsNN = 200$ GeV are presented. A negative v1(y) slope is observed for most of produced particles (π±, K±, K0S and p¯). In 5-30% central collisions a sizable difference is present between the v1(y) slope of protons and antiprotons, with the former being consistent with zero within errors. The v1 excitation function is presented. Comparisons to model calculations (RQMD, UrQMD, AMPT, QGSM with parton recombination, and a hydrodynamics model with a tilted source) are made. For those models which have calculations of v1 for both pions and protons, none of them can describe v1(y) for pions and protons simultaneously. The hydrodynamics model with a tilted source as currently implemented cannot explain the centrality dependence of the difference between the v1(y) slopes of protons and antiprotons.
STAR's measurements of directed flow (v1) around midrapidity for π±, K±, K0S, p and p¯ in Au + Au collisions at $\sqrtsNN = 200$ GeV are presented. A negative v1(y) slope is observed for most of produced particles (π±, K±, K0S and p¯). The proton v1(y) slope is found to be much closer to zero compared to antiprotons. A sizable difference is seen between v1 of protons and antiprotons in 5-30% central collisions. The v1 excitation function is presented. Comparisons to model calculations (RQMD, UrQMD, AMPT, QGSM with parton recombination, and a hydrodynamics model with a tilted source) are made. Anti-flow alone cannot explain the centrality dependence of the difference between the v1(y) slopes of protons and antiprotons.
We report measurements of the longitudinal double-spin asymmetry, ALL, for inclusive jet and dijet production in polarized proton-proton collisions at midrapidity and center-of-mass energy s√ = 510 GeV, using the high luminosity data sample collected by the STAR experiment in 2013. These measurements complement and improve the precision of previous STAR measurements at the same center-of-mass energy that probe the polarized gluon distribution function at partonic momentum fraction 0.015 ≲x≲ 0.25. The dijet asymmetries are separated into four jet-pair topologies, which provide further constraints on the x dependence of the polarized gluon distribution function. These measurements are in agreement with previous STAR measurements and with predictions from current next-to-leading order global analyses. They provide more precise data at low dijet invariant mass that will better constraint the shape of the polarized gluon distribution function of the proton.
We report measurements of the longitudinal double-spin asymmetry, ALL, for inclusive jet and dijet production in polarized proton-proton collisions at midrapidity and center-of-mass energy s√ = 510 GeV, using the high luminosity data sample collected by the STAR experiment in 2013. These measurements complement and improve the precision of previous STAR measurements at the same center-of-mass energy that probe the polarized gluon distribution function at partonic momentum fraction 0.015 ≲x≲ 0.25. The dijet asymmetries are separated into four jet-pair topologies, which provide further constraints on the x dependence of the polarized gluon distribution function. These measurements are in agreement with previous STAR measurements and with predictions from current next-to-leading order global analyses. They provide more precise data at low dijet invariant mass that will better constraint the shape of the polarized gluon distribution function of the proton.
Epigenetic regulation of inflammation by microRNAs in post-infectious bronchiolitis obliterans
(2022)
Objectives: Post-infectious bronchiolitis obliterans (PiBO) is a rare, chronic disease initiated by severe infection and followed by perpetuating inflammation and obliteration of the small airways. MicroRNAs (miRNAs) have been proposed to play a central role as epigenetic regulators, which control resolution and prevent the uncontrolled progress of inflammation. The aim of this study was to define biomarkers on the level of post-transcriptional gene regulation in order to characterise PiBO.
Methods: A total of 39 patients with well-defined PiBO and 31 controls from two centres, Barcelona, Spain, and Frankfurt, Germany, were analysed by next-generation sequencing (NGS). The evaluation of the biological targets of the miRNAs was performed by pathway enrichment analysis and protein–protein interaction network analysis respectively.
Results: Patients with PiBO had significantly lower lung function values and increased airway inflammation in induced sputum as indicated by total cell counts, neutrophils, IL-1β, IL-6, IL-8 and TGF-β compared to controls.
Next-generation sequencing analysis revealed a total of 22 dysregulated miRNAs, which passed significance threshold for Padj ≤ 0.001 with 17 being upregulated and 5 being downregulated. Of these dysregulated miRNAs, miR-335-5p, miR-186-5p, miR-30b-5p and miR-30c-5p were further validated using qRT-PCR. Interestingly, these miRNAs are functionally implicated in cytokine–cytokine receptor interaction, TGF-β signalling and FoxO signalling pathway and significantly correlated with lung function values (FEV1).
Conclusion: Our results demonstrate an aberrant miRNA expression profile in PiBO, which impacts pathways responsible for the regulation of inflammation and fibrosis. The defined miRNAs are useful biomarkers and should be assessed as potential target in the field of miRNA therapeutics.
We report measurements of the longitudinal double-spin asymmetry, ALL, for inclusive jet and dijet production in polarized proton-proton collisions at midrapidity and center-of-mass energy s√ = 510 GeV, using the high luminosity data sample collected by the STAR experiment in 2013. These measurements complement and improve the precision of previous STAR measurements at the same center-of-mass energy that probe the polarized gluon distribution function at partonic momentum fraction 0.015 ≲x≲ 0.25. The dijet asymmetries are separated into four jet-pair topologies, which provide further constraints on the x dependence of the polarized gluon distribution function. These measurements are in agreement with previous STAR measurements and with predictions from current next-to-leading order global analyses. They provide more precise data at low dijet invariant mass that will better constraint the shape of the polarized gluon distribution function of the proton.
Measurement of cold nuclear matter effects for inclusive J/ψ in p+Au collisions at √sNN = 200 GeV
(2021)
Measurement by the STAR experiment at RHIC of the cold nuclear matter (CNM) effects experienced by inclusive J/ψ at mid-rapidity in p+Au collisions at sNN−−−√ = 200 GeV is presented. Such effects are quantified utilizing the nuclear modification factor, RpAu, obtained by taking a ratio of J/ψ yield in p+Au collisions to that in p+p collisions scaled by the number of binary nucleon-nucleon collisions. The differential J/ψ yield in both p+p and p+Au collisions is measured through the dimuon decay channel, taking advantage of the trigger capability provided by the Muon Telescope Detector in the RHIC 2015 run. Consequently, the J/ψ RpAu is derived within the transverse momentum (pT) range of 0 to 10 GeV/c. A suppression of approximately 30% is observed for pT<2 GeV/c, while J/ψ RpAu becomes compatible with unity for pT greater than 3 GeV/c, indicating the J/ψ yield is minimally affected by the CNM effects at high pT. Comparison to a similar measurement from 0-20% central Au+Au collisions reveals that the observed strong J/ψ suppression above 3 Gev/c is mostly due to the hot medium effects, providing strong evidence for the formation of the quark-gluon plasma in these collisions. Several model calculations show qualitative agreement with the measured J/ψ RpAu, while their agreement with the J/ψ yield in p+p and p+Au collisions is worse.
Measurement of cold nuclear matter effects for inclusive J/ψ in p+Au collisions at √sNN = 200 GeV
(2022)
Measurement by the STAR experiment at RHIC of the cold nuclear matter (CNM) effects experienced by inclusive J/ψ at mid-rapidity in 0-100\% p+Au collisions at sNN−−−√ = 200 GeV is presented. Such effects are quantified utilizing the nuclear modification factor, RpAu, obtained by taking a ratio of J/ψ yield in p+Au collisions to that in p+p collisions scaled by the number of binary nucleon-nucleon collisions. The differential J/ψ yield in both p+p and p+Au collisions is measured through the dimuon decay channel, taking advantage of the trigger capability provided by the Muon Telescope Detector in the RHIC 2015 run. Consequently, the J/ψ RpAu is derived within the transverse momentum (pT) range of 0 to 10 GeV/c. A suppression of approximately 30% is observed for pT<2 GeV/c, while J/ψ RpAu becomes compatible with unity for pT greater than 3 GeV/c, indicating the J/ψ yield is minimally affected by the CNM effects at high pT. Comparison to a similar measurement from 0-20% central Au+Au collisions reveals that the observed strong J/ψ suppression above 3 Gev/c is mostly due to the hot medium effects, providing strong evidence for the formation of the quark-gluon plasma in these collisions. Several model calculations show qualitative agreement with the measured J/ψ RpAu, while their agreement with the J/ψ yields in p+p and p+Au collisions is worse.
We report precision measurements of hypernuclei 3ΛH and 4ΛH lifetimes obtained from Au+Au collisions at \snn = 3.0\,GeV and 7.2\,GeV collected by the STAR experiment at RHIC, and the first measurement of 3ΛH and 4ΛH mid-rapidity yields in Au+Au collisions at \snn = 3.0\,GeV. The lifetimes are measured to be 221±15(stat.)±19(syst.)\,ps for 3ΛH and 218±6(stat.)±13(syst.)\,ps for 4ΛH. The pT-integrated yields of 3ΛH and 4ΛH are presented in different centrality and rapidity intervals. It is observed that the shape of the rapidity distribution of 4ΛH is different for 0--10\% and 10--50\% centrality collisions. Thermal model calculations, using the canonical ensemble for strangeness, describes the 3ΛH yield well, while underestimating the 4ΛH yield. Transport models, combining baryonic mean-field and coalescence (JAM) or utilizing dynamical cluster formation via baryonic interactions (PHQMD) for light nuclei and hypernuclei production, approximately describe the measured 3ΛH and 4ΛH yields.