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Human-induced changes in the environment have increased the number of stressors impacting aquatic organism. In the light of climate change and plastic pollution, thermal stress and microplastics (MP) have become two of the most intensively studied stressors in aquatic ecosystems. Previous studies, however, mostly evaluated the impacts of thermal and MP stress in isolation, thereby neglecting joint effects.
To examine the combined effects of both, we exposed the freshwater mussel Dreissena polymorpha to irregular polystyrene MP (6.4, 160, 4000, 100,000 p mL−1) at either 14, 23 or 27 °C for 14 days and analyzed mortality, mussel activity and clearance rate, energy reserves, oxidative stress and the immunological state. Further, we exposed the mussels to diatomite (natural particle equivalent, 100,000 p mL−1) at each of the three water temperatures to compare MP and natural particle toxicity.
An increase in water temperature has a pronounced effect on D. polymorpha and significantly affects the activity, energy reserves, oxidative stress and immune function. In contrast, the effects by MP are limited to a change in the antioxidative capacity without any interactive effects between MP and thermal exposure. The comparison of the MP with a diatomite exposure revealed only limited influence of the particle type on the response of D. polymorpha to high concentrations of suspended particles.
The results indicate that MPs have minor effects on a freshwater mussel compared to thermal stress, neither alone nor as interactive effect. Limited MP toxicity could be based on adaptation mechanism of dreissenids to suspended solids. Nonetheless, MP may contribute to environmental impacts of multiple anthropogenic stressors, especially if their levels increase in the future. Therefore, we suggest integrating MP into the broader context of multiple stressor studies to understand and assess their joint impacts on freshwater ecosystems.
Endocrine disrupting chemicals (EDCs) are man-made compounds interfering with hormone signaling and thereby adversely affecting human health. Recent reports provide evidence for the presence of EDCs in commercially available bottled water, including steroid receptor agonists and antagonists. However, since these findings are based on biological data the causative chemicals remain unidentified and, therefore, inaccessible for toxicological evaluation. Thus, the aim of this study is to assess the antiestrogenic and antiandrogenic activity of bottled water and to identify the causative steroid receptor antagonists. We evaluated the antiestrogenic and antiandrogenic activity of 18 bottled water products in reporter gene assays for human estrogen receptor alpha and androgen receptor. Using nontarget high-resolution mass spectrometry (LTQ-Orbitrap Velos), we acquired corresponding analytical data. We combined the biological and chemical information to determine the exact mass of the tentative steroid receptor antagonist. Further MS(n) experiments elucidated the molecule's structure and enabled its identification. We detected significant antiestrogenicity in 13 of 18 products. 16 samples were antiandrogenic inhibiting the androgen receptor by up to 90%. Nontarget chemical analysis revealed that out of 24520 candidates present in bottled water one was consistently correlated with the antagonistic activity. By combining experimental and in silico MS(n) data we identified this compound as di(2-ethylhexyl) fumarate (DEHF). We confirmed the identity and biological activity of DEHF and additional isomers of dioctyl fumarate and maleate using authentic standards. Since DEHF is antiestrogenic but not antiandrogenic we conclude that additional, yet unidentified EDCs must contribute to the antagonistic effect of bottled water. Applying a novel approach to combine biological and chemical analysis this is the first study to identify so far unknown EDCs in bottled water. Notably, dioctyl fumarates and maleates have been overlooked by science and regulation to date. This illustrates the need to identify novel toxicologically relevant compounds to establish a more holistic picture of the human exposome.
Background: The ERGO2 (Ernaehrungsumstellung bei Patienten mit Rezidiv eines Glioblastoms) MR-spectroscopic imaging (MRSI) subtrial investigated metabolism in patients randomized to calorically restricted ketogenic diet/intermittent fasting (crKD-IF) versus standard diet (SD) in addition to re-irradiation (RT) for recurrent malignant glioma. Intracerebral concentrations of ketone bodies (KB), intracellular pH (pHi), and adenosine triphosphate (ATP) were non-invasively determined. Methods: 50 patients were randomized (1:1): Group A keeping a crKD-IF for nine days, and Group B a SD. RT was performed on day 4-8. Twenty-three patients received an extended MRSI-protocol (1H decoupled 31P MRSI with 3D chemical shift imaging (CSI) and 2D 1H point-resolved spectroscopy (PRESS)) at a 3T scanner at baseline and on day 6. Voxels were selected from the area of recurrent tumor and contralateral hemisphere. Spectra were analyzed with LCModel, adding simulated signals of 3-hydroxybutyrate (βOHB), acetone (Acn) and acetoacetate (AcAc) to the standard basis set. Results: Acn was the only reliably MRSI-detectable KB within tumor tissue and/or normal appearing white matter (NAWM). It was detected in 4/11 patients in Group A and in 0/8 patients in Group B. MRSI results showed no significant depletion of ATP in tumor tissue of patients at day 6 during crKD-IF, even though there were a significant difference in ketone serum levels between Group A and B at day 6 and a decline in fasting glucose in Group A from baseline to day 6. The tumor specific alkaline pHi was maintained. Conclusions: Our metabolic findings suggest that tumor cells maintain energy homeostasis even with reduced serum glucose levels and may generate additional ATP through other sources.r sources.
Background: MicroRNA-21 (miR-21) is up-regulated in tumor tissue of patients with malignant diseases, including hepatocellular carcinoma (HCC). Elevated concentrations of miR-21 have also been found in sera or plasma from patients with malignancies, rendering it an interesting candidate as serum/plasma marker for malignancies. Here we correlated serum miR-21 levels with clinical parameters in patients with different stages of chronic hepatitis C virus infection (CHC) and CHC-associated HCC.
Methodology/Principal Findings: 62 CHC patients, 29 patients with CHC and HCC and 19 healthy controls were prospectively enrolled. RNA was extracted from the sera and miR-21 as well as miR-16 levels were analyzed by quantitative real-time PCR; miR-21 levels (normalized by miR-16) were correlated with standard liver parameters, histological grading and staging of CHC. The data show that serum levels of miR-21 were elevated in patients with CHC compared to healthy controls (P<0.001); there was no difference between serum miR-21 in patients with CHC and CHC-associated HCC. Serum miR-21 levels correlated with histological activity index (HAI) in the liver (r = −0.494, P = 0.00002), alanine aminotransferase (ALT) (r = −0.309, P = 0.007), aspartate aminotransferase (r = −0.495, P = 0.000007), bilirubin (r = −0.362, P = 0.002), international normalized ratio (r = −0.338, P = 0.034) and γ-glutamyltransferase (r = −0.244, P = 0.034). Multivariate analysis revealed that ALT and miR-21 serum levels were independently associated with HAI. At a cut-off dCT of 1.96, miR-21 discriminated between minimal and mild-severe necroinflammation (AUC = 0.758) with a sensitivity of 53.3% and a specificity of 95.2%.
Conclusions/Significance: The serum miR-21 level is a marker for necroinflammatory activity, but does not differ between patients with HCV and HCV-induced HCC.
TRIANNI mice carry an entire set of human immunoglobulin V region gene segments and are a powerful tool to rapidly isolate human monoclonal antibodies. After immunizing these mice with DNA encoding the spike protein of SARS-CoV-2 and boosting with spike protein, we identified 29 hybridoma antibodies that reacted with the SARS-CoV-2 spike protein. Nine antibodies neutralize SARS-CoV-2 infection at IC50 values in the subnanomolar range. ELISA-binding studies and DNA sequence analyses revealed one cluster of three clonally related neutralizing antibodies that target the receptor-binding domain and compete with the cellular receptor hACE2. A second cluster of six clonally related neutralizing antibodies bind to the N-terminal domain of the spike protein without competing with the binding of hACE2 or cluster 1 antibodies. SARS-CoV-2 mutants selected for resistance to an antibody from one cluster are still neutralized by an antibody from the other cluster. Antibodies from both clusters markedly reduced viral spread in mice transgenic for human ACE2 and protected the animals from SARS-CoV-2-induced weight loss. The two clusters of potent noncompeting SARS-CoV-2 neutralizing antibodies provide potential candidates for therapy and prophylaxis of COVID-19. The study further supports transgenic animals with a human immunoglobulin gene repertoire as a powerful platform in pandemic preparedness initiatives.
Background: Rare diseases are, by definition, very serious and chronic diseases with a high negative impact on quality of life. Approximately 350 million people worldwide live with rare diseases. The resulting high disease burden triggers health information search, but helpful, high-quality, and up-to-date information is often hard to find. Therefore, the improvement of health information provision has been integrated in many national plans for rare diseases, discussing the telephone as one access option. In this context, this study examines the need for a telephone service offering information for people affected by rare diseases, their relatives, and physicians.
Methods: In total, 107 individuals participated in a qualitative interview study conducted in Germany. Sixty-eight individuals suffering from a rare disease or related to somebody with rare diseases and 39 health care professionals took part. Individual interviews were conducted using a standardized semi-structured questionnaire. Interviews were analysed using the qualitative content analysis, triangulating patients, relatives, and health care professionals. The fulfilment of qualitative data processing standards has been controlled for.
Results: Out of 68 patients and relatives and 39 physicians, 52 and 18, respectively, advocated for the establishment of a rare diseases telephone service. Interviewees expected a helpline to include expert staffing, personal contact, good availability, low technical barriers, medical and psychosocial topics of counselling, guidance in reducing information chaos, and referrals. Health care professionals highlighted the importance of medical topics of counselling—in particular, differential diagnostics—and referrals.
Conclusions: Therefore, the need for a national rare diseases helpline was confirmed in this study. Due to limited financial resources, existing offers should be adapted in a stepwise procedure in accordance with the identified attributes.
Background: Recently, public and political interest has focused on people living with rare diseases and their health concerns. Due to the large number of different types of rare diseases and the sizable number of patients, taking action to improve the life of those affected is gaining importance. In 2013, the federal government of Germany adopted a national action plan for rare diseases, including the call to establish a central information portal on rare diseases (Zentrales Informationsportal über seltene Erkrankungen, ZIPSE).
Objective: The objective of this study, therefore, was to conduct scientific research on how such a portal must be designed to meet the needs of patients, their families, and medical professionals, and to provide high-quality information for information seekers.
Methods: We chose a 3-step procedure to develop a needs-based prototype of a central information portal. In the first step, we determined the information needs of patients with rare diseases, their relatives, and health care professionals by means of qualitative interviews and their content-analytical evaluation. On the basis of this, we developed the basic structure of the portal. In the second step, we identified quality criteria for websites on rare diseases to ensure that the information linked with ZIPSE meets the quality demands. Therefore, we gathered existing criteria catalogs and discussed them in an expert workshop. In the third step, we implemented and tested the developed prototypical information portal.
Results: A portal page was configured and made accessible on the Web. The structure of ZIPSE was based on the findings from 108 qualitative interviews with patients, their relatives, and health care professionals, through which numerous information needs were identified. We placed particularly important areas of information, such as symptoms, therapy, research, and advisory services, on the start page. Moreover, we defined 13 quality criteria, referring to factors such as author information, creation date, and privacy, enabling links with high-quality information. Moreover, 19 users tested all the developed routines based on usability and comprehensibility. Subsequently, we improved the visual presentation of search results and other important search functions.
Conclusions: The implemented information portal, ZIPSE, provides high-quality information on rare diseases from a central point of access. By integrating the targeted groups as well as different experts on medical information during the construction, the website can assure an improved search for information for users. ZIPSE can also serve as a model for other Web-based information systems in the field of rare diseases.
Registered Report Identifier: RR1-10.2196/7425.
The neutron-unbound isotope 13Be has been studied in several experiments using different reactions, different projectile energies, and different experimental setups. There is, however, no real consensus in the interpretation of the data, in particular concerning the structure of the low-lying excited states. Gathering new experimental information, which may reveal the 13Be structure, is a challenge, particularly in light of its bridging role between 12Be, where the N = 8 neutron shell breaks down, and the Borromean halo nucleus 14Be. The purpose of the present study is to investigate the role of bound excited states in the reaction product 12Be after proton knockout from 14B, by measuring coincidences between 12Be, neutrons, and γ rays originating from de-excitation of states fed by neutron decay of 13Be. The 13Be isotopes were produced in proton knockout from a 400 MeV/nucleon 14B beam impinging on a CH2 target. The 12 Be-n relative-energy spectrum d σ /d Ef n was obtained from coincidences between 12Be(g.s.) and a neutron, and also as threefold coincidences by adding γ rays, from the de-excitation of excited states in 12Be. Neutron decay from the first 5/2+ state in 13Be to the 2+ state in 12Be at 2.11 MeV is confirmed. An energy independence of the proton-knockout mechanism is found from a comparison with data taken with a 35 MeV/nucleon 14B beam. A low-lying p-wave resonance in 13Be(1/2−) is confirmed by comparing proton- and neutron-knockout data from 14B and 14Be.
Quasifree one-proton knockout reactions have been employed in inverse kinematics for a systematic study of the structure of stable and exotic oxygen isotopes at the R3B/LAND setup with incident beam energies in the range of 300–450 MeV/u. The oxygen isotopic chain offers a large variation of separation energies that allows for a quantitative understanding of single-particle strength with changing isospin asymmetry. Quasifree knockout reactions provide a complementary approach to intermediate-energy one-nucleon removal reactions. Inclusive cross sections for quasifree knockout reactions of the type AO(p,2p)A−1N have been determined and compared to calculations based on the eikonal reaction theory. The reduction factors for the single-particle strength with respect to the independent-particle model were obtained and compared to state-of-the-art ab initio predictions. The results do not show any significant dependence on proton-neutron asymmetry.