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We estimate the feeddown contributions from decays of unstable A=4 and A=5 nuclei to the final yields of protons, deuterons, tritons, 3He, and 4He produced in relativistic heavy-ion collisions at sNN>2.4 GeV, using the statistical model. The feeddown contribution effects do not exceed 5% at LHC and top RHIC energies due to the large penalty factors involved, but are substantial at intermediate collision energies. We observe large feeddown contributions for tritons, 3He, and 4He at sNN≲10 GeV, where they may account for as much as 70% of the final yield at the lower end of the collision energies considered. Sizable (>10%) effects for deuteron yields are observed at sNN≲4 GeV. The results suggest that the excited nuclei feeddown cannot be neglected in the ongoing and future analysis of light nuclei production at intermediate collision energies, including HADES and CBM experiments at FAIR, NICA at JINR, RHIC beam energy scan and fixed-target programmes, and NA61/SHINE at CERN. We further show that the freeze-out curve in the T-μB plane itself is affected significantly by the light nuclei at high baryochemical potential.
In this paper, we discuss the damping of density oscillations in dense nuclear matter in the temperature range relevant to neutron star mergers. This damping is due to bulk viscosity arising from the weak interaction “Urca” processes of neutron decay and electron capture. The nuclear matter is modelled in the relativistic density functional approach. The bulk viscosity reaches a resonant maximum close to the neutrino trapping temperature, then drops rapidly as temperature rises into the range where neutrinos are trapped in neutron stars. We investigate the bulk viscous dissipation timescales in a post-merger object and identify regimes where these timescales are as short as the characteristic timescale ∼10 ms, and, therefore, might affect the evolution of the post-merger object. Our analysis indicates that bulk viscous damping would be important at not too high temperatures of the order of a few MeV and densities up to a few times saturation density.
This article elucidates the spatial order that underpins the politics of the Anthropocene – the ecological nomos of the earth – and criticizes its imperial origins and legacies. It provides a critical reading of Carl Schmitt’s spatial thought to not only illuminate the spatio-political ontology but also the violence and usurpations that characterize the Anthropocene condition. The article first shows how with the emergence of the ecological nomos seemingly ‘natural’ spaces like the biosphere and the atmosphere became politically charged. This challenges the modernist separation between natural facts and political norms. It then underlines the imperial origins of this nomos by introducing the concept of air-appropriation understood as the colonization of atmospheric space by CO2 emissions. Instead of assuming that the ecological nomos represents a transition from a colonial to an ecological and cosmopolitan world order, focusing on air-appropriation highlights forms of ecological imperialism that go along with the new nomos. Accordingly, the article calls for a just redistribution of ecospace that takes into account the imperial legacies and ongoing effects of air-appropriation.
Objective: To determine the impact of an exercise-based prehabilitation (EBPrehab) program on preand postoperative exercise capacity, functional capacity (FC) and quality of life (QoL) in patients awaiting elective coronary artery bypass graft surgery (CABG).
Design: A two-group randomized controlled trail.
Setting: Ambulatory prehabilitation.
Subjects: Overall 230 preoperative elective CABG-surgery patients were randomly assigned to an intervention (IG, n=88; n=27 withdrew after randomization) or control group (CG, n=115).
Intervention: IG: two-week EBPrehab including supervised aerobic exercise. CG: usual care.
Main measures: At baseline (T1), one day before surgery (T2), at the beginning (T3) and at the end of cardiac rehabilitation (T4) the following measurements were performed: cardiopulmonary exercise test, six-minute walk test (6MWT), Timed-Up-and-Go Test (TUG) and QoL (MacNew questionnaire).
Results: A total of 171 patients (IG, n=81; CG, n=90) completed the study. During EBPrehab no complications occurred. Preoperatively FC (6MWTIG: 443.0±80.1m to 493.5±75.5m, P=0.003; TUGIG: 6.9±2.0 s to 6.1±1.8 s, P=0.018) and QoL (IG: 5.1±0.9 to 5.4±0.9, P<0.001) improved significantly more in IG compared to CG. Similar effects were observed postoperatively in FC (6MWDIG: Δ-64.7m, pT1–T3=0.013; Δ+47.2m, pT1–T4<0.001; TUGIG: Δ+1.4s, pT1–T3=0.003).
Conclusions: A short-term EBPrehab is effective to improve perioperative FC and preoperative QoL in patients with stable coronary artery disease awaiting CABG-surgery.
Simple Summary
The interaction between tumors and immune cells influences tumor fate, i.e., regression, growth, or even metastases. The evaluation of tumor infiltrating lymphocytes (TILs) in human breast cancer has prognostic value. Pet rabbits develop spontaneous mammary carcinomas and have an immune system that is comparable with that of humans, so that they have the potential to provide an animal model for human breast cancer. To further substantiate this similarity, this study examined TILs in 107 pet rabbit mammary carcinomas according to criteria established for human breast cancer. For TIL evaluation routinely stained microscopic sections were examined by light microscopy. Relevant histological and immunohistochemical tumor characteristics were obtained from a data base. Results showed that increased presence of stromal TILs was statistically associated with histological tumor features indicative of a less aggressive biological behavior, i.e., reduced tumor cell proliferation and a lower histological grade. The expression by tumor cells of calponin, a presumed tumor suppressor protein, was also associated with their reduced proliferation and a higher percentage of stromal TILs. Data suggest that higher percentages of stromal TILs may have the potential to serve as favorable prognostic indicator in rabbit mammary carcinomas and support the value of pet rabbits for comparative research.
Abstract
Tumor infiltrating lymphocytes (TILs) serve as prognostic biomarker in human breast cancer. Rabbits have the potential to act as animal model for human breast cancer, and close similarities exist between the rabbit and human immune system. The aim of this study is to characterize TILs in pet rabbit mammary carcinomas and to statistically correlate results with histological and immunohistochemical tumor characteristics. Microscopic evaluation of TILs was performed in hematoxylin and eosin stained sections of 107 rabbit mammary carcinomas according to international guidelines for human breast cancer. Data on histological features of malignancy, estrogen and progesterone receptor status and calponin expression were obtained from the data base. This study revealed a statistical association between stromal TILs in the central tumor (CT) and infiltrative margin. Higher maximal percentages of stromal TILs at the CT were statistically correlated with decreased mitotic count and lower tumor grade. An increased number of calponin positive tumor cells was statistically associated with a lower mitotic count and a higher percentage of stromal TILs. Results suggest that higher percentages of stromal TILs are useful biomarkers that may point toward a favorable prognosis in rabbit mammary carcinomas and support the concept of the use of rabbits for translational research
Degeneration of neurons, such as the inner ear spiral ganglion neurons (SGN), may be decelerated or even stopped by neurotrophic factor treatment, such as brain-derived neurotrophic factor (BDNF), as well as electrical stimulation (ES). In a clinical setting, drug treatment of the SGN could start directly during implantation of a cochlear implant, whereas electrical stimulation begins days to weeks later. The present study was conducted to determine the effects of consecutive BDNF and ES treatments on SGN density and electrical responsiveness. An electrode drug delivery device was implanted in guinea pigs 3 weeks after deafening and five experimental groups were established: two groups received intracochlear infusion of artificial perilymph (AP) or BDNF; two groups were treated with AP respectively BDNF in addition to ES (AP + ES, BDNF + ES); and one group received BDNF from the day of implantation until day 34 followed by ES (BDNF ⇨ ES). Electrically evoked auditory brainstem responses were recorded. After one month of treatment, the tissue was harvested and the SGN density was assessed. The results show that consecutive treatment with BDNF and ES was as successful as the simultaneous combined treatment in terms of enhanced SGN density compared to the untreated contralateral side but not in regard to the numbers of protected cells.
Workaholism and overcommitment are often used as interchangeable constructs describing an individual’s over-involvement toward their own job. Employees with high levels in both constructs are characterized by an excessive effort and attachment to their job, with the incapability to detach from it and negative consequences in terms of poor health and job burnout. However, few studies have simultaneously measured both constructs, and their relationships are still not clear. In this study, we try to disentangle workaholism and overcommitment by comparing them with theoretically related contextual and personal antecedents, as well as their health consequences. We conducted a nonprobability mixed mode research design on 133 employees from different organizations in Italy using both self- and other-reported measures. To test our hypothesis that workaholism and overcommitment are related yet different constructs, we used partial correlations and regression analyses. The results confirm that these two constructs are related to each other, but also outline that overcommitment (and not workaholism) is uniquely related to job burnout, so that overcommitment rather than workaholism could represent the true negative aspect of work drive. Additionally, workaholism is more related to conscientiousness than overcommitment, while overcommitment shows a stronger relationship with neuroticism than workaholism. The theoretical implications are discussed.
This paper provides new geochemical data focusing on valuable elements in the coal, parting, and floor samples in the No. 5 coal seam of the Taiyuan Formation from the Wujiawan mine, Datong coalfield, northern China. The minerals mainly consist of kaolinite, calcite, and pyrite, as well as trace amounts of quartz and illite. The No. 5 coal is enriched in Li, Ga, high field strength elements (HFSEs), and rare earth elements and yttrium (REY) when compared with world hard coals. Of particular interest is the high average concentration of Li (67.66 μg/g), which is around seven times higher than the value for world hard coals. Lithium, Ga, and HFSEs have strong inorganic affinities, whereas REY have organic affinities. The main carrier of Li, Ga, and HFSEs is aluminosilicate minerals, while REY appear to occur with organophosphorus. These HFSEs are enriched, both in the parting and in the adjacent coal samples. This suggests that these elements are likely to leach out during the diagenetic process. The distribution patterns of REY, along with the ratio of Al2O3/TiO2 and the figure of Zr/TiO2 vs. Nb/Y are suggestive of their derivation from felsic parent material. In the northern and eastern part of the Datong coalfield, there are several regions where the Li content is higher than the mineable grade, in particular in the northern Datong coalfield where there is a mine with an Li content of 294.6 μg/g. This is significantly higher than the mineable grade. Therefore, there is a potential for financially viable recovery of Li in these coals of the Datong coalfield.
Virtual reality (VR) headsets offer a large and immersive workspace for displaying visualizations with stereoscopic vision, as compared to traditional environments with monitors or printouts. The controllers for these devices further allow direct three-dimensional interaction with the virtual environment. In this paper, we make use of these advantages to implement a novel multiple and coordinated view (MCV) system in the form of a vertical stack, showing tilted layers of geospatial data. In a formal study based on a use-case from urbanism that requires cross-referencing four layers of geospatial urban data, we compared it against more conventional systems similarly implemented in VR: a simpler grid of layers, and one map that allows for switching between layers. Performance and oculometric analyses showed a slight advantage of the two spatial-multiplexing methods (the grid or the stack) over the temporal multiplexing in blitting. Subgrouping the participants based on their preferences, characteristics, and behavior allowed a more nuanced analysis, allowing us to establish links between e.g., saccadic information, experience with video games, and preferred system. In conclusion, we found that none of the three systems are optimal and a choice of different MCV systems should be provided in order to optimally engage users.
The morbidity and mortality of severely injured patients are commonly affected by multiple factors. Especially, severe chest trauma has been shown to be a significant factor in considering outcome. Contemporaneously, weight-associated endocrinological, haematological, and metabolic deviations from the norm seem to have an impact on the posttraumatic course. Therefore, the aim of this study was to determine the influence of body weight on severely injured patients by emphasizing chest trauma. A total of 338 severely injured patients were included. Multivariate regression analyses were performed on patients with severe chest trauma (AIS ≥ 3) and patients with minor chest trauma (AIS < 3). The influence of body weight on in-hospital mortality was evaluated. Of all the patients, 70.4% were male, the median age was 52 years (IQR 36–68), the overall Injury Severity Score (ISS) was 24 points (IQR 17–29), and a median BMI of 25.1 points (IQR 23–28) was determined. In general, chest trauma was associated with prolonged ventilation, prolonged ICU treatment, and increased mortality. For overweight patients with severe chest trauma, an independent survival benefit was found (OR 0.158; p = 0.037). Overweight seems to have an impact on the mortality of severely injured patients with combined chest trauma. Potentially, a nutritive advantage or still-unknown immunological aspects in these patients affecting the intensive treatment course could be argued.
Focused electron beam induced deposition (FEBID) is a direct-write nanofabrication technique able to pattern three-dimensional magnetic nanostructures at resolutions comparable to the characteristic magnetic length scales. FEBID is thus a powerful tool for 3D nanomagnetism which enables unique fundamental studies involving complex 3D geometries, as well as nano-prototyping and specialized applications compatible with low throughputs. In this focused review, we discuss recent developments of this technique for applications in 3D nanomagnetism, namely the substantial progress on FEBID computational methods, and new routes followed to tune the magnetic properties of ferromagnetic FEBID materials. We also review a selection of recent works involving FEBID 3D nanostructures in areas such as scanning probe microscopy sensing, magnetic frustration phenomena, curvilinear magnetism, magnonics and fluxonics, offering a wide perspective of the important role FEBID is likely to have in the coming years in the study of new phenomena involving 3D magnetic nanostructures.
Importance Coronavirus disease 2019 (COVID-19) continues to cause considerable morbidity and mortality worldwide. Case reports of hospitalized patients suggest that COVID-19 prominently affects the cardiovascular system, but the overall impact remains unknown.
Objective To evaluate the presence of myocardial injury in unselected patients recently recovered from COVID-19 illness.
Design, Setting, and Participants In this prospective observational cohort study, 100 patients recently recovered from COVID-19 illness were identified from the University Hospital Frankfurt COVID-19 Registry between April and June 2020.
Exposure Recent recovery from severe acute respiratory syndrome coronavirus 2 infection, as determined by reverse transcription–polymerase chain reaction on swab test of the upper respiratory tract.
Main Outcomes and Measures Demographic characteristics, cardiac blood markers, and cardiovascular magnetic resonance (CMR) imaging were obtained. Comparisons were made with age-matched and sex-matched control groups of healthy volunteers (n = 50) and risk factor–matched patients (n = 57).
Results Of the 100 included patients, 53 (53%) were male, and the mean (SD) age was 49 (14) years. The median (IQR) time interval between COVID-19 diagnosis and CMR was 71 (64-92) days. Of the 100 patients recently recovered from COVID-19, 67 (67%) recovered at home, while 33 (33%) required hospitalization. At the time of CMR, high-sensitivity troponin T (hsTnT) was detectable (greater than 3 pg/mL) in 71 patients recently recovered from COVID-19 (71%) and significantly elevated (greater than 13.9 pg/mL) in 5 patients (5%). Compared with healthy controls and risk factor–matched controls, patients recently recovered from COVID-19 had lower left ventricular ejection fraction, higher left ventricle volumes, and raised native T1 and T2. A total of 78 patients recently recovered from COVID-19 (78%) had abnormal CMR findings, including raised myocardial native T1 (n = 73), raised myocardial native T2 (n = 60), myocardial late gadolinium enhancement (n = 32), or pericardial enhancement (n = 22). There was a small but significant difference between patients who recovered at home vs in the hospital for native T1 mapping (median [IQR], 1119 [1092-1150] ms vs 1141 [1121-1175] ms; P = .008) and hsTnT (4.2 [3.0-5.9] pg/dL vs 6.3 [3.4-7.9] pg/dL; P = .002) but not for native T2 mapping. None of these measures were correlated with time from COVID-19 diagnosis (native T1: r = 0.07; P = .47; native T2: r = 0.14; P = .15; hsTnT: r = −0.07; P = .50). High-sensitivity troponin T was significantly correlated with native T1 mapping (r = 0.33; P < .001) and native T2 mapping (r = 0.18; P = .01). Endomyocardial biopsy in patients with severe findings revealed active lymphocytic inflammation. Native T1 and T2 were the measures with the best discriminatory ability to detect COVID-19–related myocardial pathology.
Conclusions and Relevance In this study of a cohort of German patients recently recovered from COVID-19 infection, CMR revealed cardiac involvement in 78 patients (78%) and ongoing myocardial inflammation in 60 patients (60%), independent of preexisting conditions, severity and overall course of the acute illness, and time from the original diagnosis. These findings indicate the need for ongoing investigation of the long-term cardiovascular consequences of COVID-19.
Aortic stenosis is the most common valvular disease worldwide. With transcatheter aortic valve replacement (TAVR) being increasingly expanded to lower-risk populations, several challenging issues remain to be solved. The present review aims at discussing modern approaches to such issues as well as the current status of TAVR. TAVR has undergone several developments in the recent years: an increased use of transfemoral access, the development of prostheses in order to adapt to challenging anatomies, improved delivery systems with repositioning features, and outer skirts aiming at reducing paravalvular leak. The indication of TAVR is increasingly being expanded to patients with lower surgical risk. The main clinical trials supporting such expansion are reviewed and the latest data on low-risk patients are discussed. A number of challenges need still to be addressed and are also reviewed in this paper: the need for updated international guidelines including the latest evidence; a reduction of main complications such as permanent pacemaker implantation, paravalvular leak, and stroke (and its potential prevention by using anti-embolic protection devices); the appropriate role of TAVR in patients with concomitant cardiac ischemic disease; and durability of bio-prosthetic implanted valves. Finally, the future perspectives for TAVR use and next device developments are discussed.
Background: Aortic stenosis (AS) is the most prevalent primary heart valve disease and the third most prevalent cardiovascular disease in the world, having a severe and slowly progressive evolution. The implementation of Transcatheter Aortic Valve Implantation (TAVI) is necessary because the population is constantly ageing, and most elderly people have various comorbidities, which places them among patients with high surgical risk. The aim was to report immediate and 9 months follow-up results of first TAVI implantations in the Republic of Moldova.
Material and methods: Three patients with severe symptomatic AS and high surgical risk underwent TAVI implantation using Portico valves.
Results: The mean age was 76.7 ± 1.2 years, 2 women and 1 man. The mean Logistic EuroSCORE II was 5.68 ± 0.67%. Procedural success was achieved in all (100%) patients. After the intervention, it was shown that the GP mean decreased by an average of 20.27±1.61 mmHg, the Vmax of the jet through AoV decreased on average by 2.05±0.19 m/s, and they were maintained all over the nine months follow-up period. Quality of life, using the TASQ (Toronto Aortic Stenosis Quality of Life) questionnaire, was improved by 62.3 ± 2.2 points.
Conclusions: TAVI, as a new minimally invasive method of treatment for aortic valve stenosis appears to be safe, with a low rate of early and late complications in elderly patients at high surgical risk, with good clinical outcomes at 9 months. Its implementation in the Republic of Moldova is welcome in the conditions of continuously ageing population and the prevalence of associated comorbidities.
Relapsing fever (RF) is claimed a neglected arthropod-borne disease caused by a number of diverse human pathogenic Borrelia (B.) species. These RF borreliae are separated into the groups of tick-transmitted species including B. duttonii, B. hermsii, B. parkeri, B. turicatae, B. hispanica, B. persica, B. caucasica, and B. myiamotoi, and the louse-borne Borrelia species B. recurrentis. As typical blood-borne pathogens achieving high cell concentrations in human blood, RF borreliae (RFB) must outwit innate immunity, in particular complement as the first line of defense. One prominent strategy developed by RFB to evade innate immunity involves inactivation of complement by recruiting distinct complement regulatory proteins, e.g., C1 esterase inhibitor (C1-INH), C4b-binding protein (C4BP), factor H (FH), FH-like protein-1 (FHL-1), and factor H-related proteins FHR-1 and FHR-2, or binding of individual complement components and plasminogen, respectively. A number of multi-functional, complement and plasminogen-binding molecules from distinct Borrelia species have previously been identified and characterized, exhibiting considerable heterogeneity in their sequences, structures, gene localization, and their capacity to bind host-derived proteins. In addition, RFB possess a unique system of antigenic variation, allowing them to change the composition of surface-exposed variable major proteins, thus evading the acquired immune response of the human host. This review focuses on the current knowledge of the immune evasion strategies by RFB and highlights the role of complement-interfering and infection-associated molecules for the pathogenesis of RFB.
Drug resistance is an obstacle in the therapy of acute lymphoblastic leukemia (ALL). Whether the physical properties such as the motility of the cells contribute to the survival of ALL cells after drug treatment has recently been of increasing interest, as they could potentially allow the metastasis of solid tumor cells and the migration of leukemia cells. We hypothesized that chemotherapeutic treatment may alter these physical cellular properties. To investigate the motility of chemotherapeutics-treated B-cell ALL (B-ALL) cells, patient-derived B-ALL cells were treated with chemotherapy for 7 days and left for 12 h without chemotherapeutic treatment. Two parameters of motility were studied, velocity and migration distance, using a time-lapse imaging system. The study revealed that compared to non-chemotherapeutically treated B-ALL cells, B-ALL cells that survived chemotherapy treatment after 7 days showed reduced motility. We had previously shown that Tysabri and P5G10, antibodies against the adhesion molecules integrins α4 and α6, respectively, may overcome drug resistance mediated through leukemia cell adhesion to bone marrow stromal cells. Therefore, we tested the effect of integrin α4 or α6 blockade on the motility of chemotherapeutics-treated ALL cells. Only integrin α4 blockade decreased the motility and velocity of two chemotherapeutics-treated ALL cell lines. Interestingly, integrin α6 blockade did not affect the velocity of chemoresistant ALL cells. This study explores the physical properties of the movements of chemoresistant B-ALL cells and highlights a potential link to integrins. Further studies to investigate the underlying mechanism are warranted.
Psoriasis (PsO) is one of the common chronic inflammatory skin diseases. Approximately 3% of the European Caucasian population is affected. Psoriatic arthritis (PsA) is a chronic immune-mediated disease associated with PsO characterized by distinct musculoskeletal inflammation. Due to its heterogeneous clinical manifestations (e.g., oligo- or polyarthritis, enthesitis, dactylitis, and axial inflammation), early diagnosis of PsA is often difficult and delayed. Approximately 30% of PsO patients will develop PsA. The responsible triggers for the transition from PsO only to PsA are currently unclear, and the impacts of different factors (e.g., genetic, environmental) on disease development are currently discussed. There is a high medical need, recently unmet, to specifically detect those patients with an increased risk for the development of clinically evident PsA early to initiate sufficient treatment to inhibit disease progression and avoid structural damage and loss of function or even intercept disease development. Increased neoangiogenesis and enthesial inflammation are hypothesized to be early pathological findings in PsO patients with PsA development. Different disease states describe the transition from PsO to PsA. Two of those phases are of value for early detection of PsA at-risk patients to prevent later development of PsA as changes in biomarker profiles are detectable: the subclinical phase (soluble and imaging biomarkers detectable, no clinical symptoms) and the prodromal phase (imaging biomarkers detectable, unspecific musculoskeletal symptoms such as arthralgia and fatigue). To target the unmet need for early detection of this at-risk population and to identify the subgroup of patients who will transition from PsO to PsA, imaging plays an important role in characterizing patients precisely. Imaging techniques such as ultrasound (US), magnetic resonance imaging (MRI), and computerized tomography (CT) are advanced techniques to detect sensitively inflammatory changes or changes in bone structure. With the use of these techniques, anatomic structures involved in inflammatory processes can be identified. These techniques are complemented by fluorescence optical imaging as a sensitive method for detection of changes in vascularization, especially in longitudinal measures. Moreover, high-resolution peripheral quantitative CT (HR-pQCT) and dynamic contrast-enhanced MRI (DCE-MRI) may give the advantage to identify PsA-related early characteristics in PsO patients reflecting transition phases of the disease.
Physical activity counseling in primary health care is regarded as a useful complementary preventive and therapeutic measure and is advocated by leading public health institutions. This integrative review summarizes the available data on physical activity counseling in primary care in Germany. A systematic literature search in various databases (peer reviewed and grey literature) was carried out for quantitative and qualitative studies on physical activity counseling and use of “Exercise on Prescription”. The 25 studies included show a very high methodological diversity and, in some cases, considerable risks of bias, with limited comparability across studies. Counseling was provided in all studies by physicians. They report frequent physical activity counseling, which is partly confirmed and partly refuted by patient data. The use of “Exercise on Prescription” is at a very low level. Information on the frequency of physical activity counseling in Germany varies depending on data source and is sometimes contradictory. Our review provides a synthesis of various perspectives on routine physical activity counseling in primary care in Germany. Future studies using standardized and validated instruments in representative samples are needed to further knowledge on counseling and to be able to establish trends in prevalence. Strengthening the topics of physical activity and health and physical activity counseling in medical curriculum is strongly recommended.
Nuclear receptor related 1 (Nurr1) is an orphan ligand-activated transcription factor and considered as neuroprotective transcriptional regulator with great potential as therapeutic target for neurodegenerative diseases. However, the collection of available Nurr1 modulators and mechanistic understanding of Nurr1 are limited. Here, we report the discovery of several structurally diverse non-steroidal anti-inflammatory drugs as inverse Nurr1 agonists demonstrating that Nurr1 activity can be regulated bidirectionally. As chemical tools, these ligands enable unraveling the co-regulatory network of Nurr1 and the mode of action distinguishing agonists from inverse agonists. In addition to its ability to dimerize, we observe an ability of Nurr1 to recruit several canonical nuclear receptor co-regulators in a ligand-dependent fashion. Distinct dimerization states and co-regulator interaction patterns arise as discriminating factors of Nurr1 agonists and inverse agonists. Our results contribute a valuable collection of Nurr1 modulators and relevant mechanistic insights for future Nurr1 target validation and drug discovery.
The coronavirus disease 2019 COVID-19 pandemic is rapidly spreading worldwide and is becoming a major public health crisis. Increasing evidence demonstrates a strong correlation between obesity and the COVID-19 disease. We have summarized recent studies and addressed the impact of obesity on COVID-19 in terms of hospitalization, severity, mortality, and patient outcome. We discuss the potential molecular mechanisms whereby obesity contributes to the pathogenesis of COVID-19. In addition to obesity-related deregulated immune response, chronic inflammation, endothelium imbalance, metabolic dysfunction, and its associated comorbidities, dysfunctional mesenchymal stem cells/adipose-derived mesenchymal stem cells may also play crucial roles in fueling systemic inflammation contributing to the cytokine storm and promoting pulmonary fibrosis causing lung functional failure, characteristic of severe COVID-19. Moreover, obesity may also compromise motile cilia on airway epithelial cells and impair functioning of the mucociliary escalators, reducing the clearance of severe acute respiratory syndrome coronavirus (SARS-CoV-2). Obese diseased adipose tissues overexpress the receptors and proteases for the SARS-CoV-2 entry, implicating its possible roles as virus reservoir and accelerator reinforcing violent systemic inflammation and immune response. Finally, anti-inflammatory cytokines like anti-interleukin 6 and administration of mesenchymal stromal/stem cells may serve as potential immune modulatory therapies for supportively combating COVID-19. Obesity is conversely related to the development of COVID-19 through numerous molecular mechanisms and individuals with obesity belong to the COVID-19-susceptible population requiring more protective measures.