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This study intends to contribute to the discourse on social protection and crime. The study assessed social protection as a tool for crime prevention, with bias to Owerri municipal local government area of Imo state, Nigeria as a case study. The study employed a qualitative approach which allowed the researcher to explore experiences and perspectives of selected participants. Purposive sampling was considered appropriate for the defined population. In-depth interview and focus group discussion (FGD) served as data collection instruments. A review of available literature, reports, newspaper publications, reports, and various internet sources were exhaustively utilised to gather secondary data.
The study revealed that social protection possesses the potential to prevent crime. The study informed that certain intervention programmes established by the government helped in decreasing crime incidences in the area under study. In addition, the study revealed that social protection enhances wellbeing, empowers people, promotes better living conditions, imbues a sense of belonging and inclusiveness, promotes social stability and does not lead to dependency. However, the study revealed that social protection alone is incapable of eradicating crime.
Many people do not consume as much healthy food as recommended. Nudging has been identified as a promising intervention strategy to increase the consumption of healthy food. The present study analyzed the effects of three body shape nudges (thin, thick, or Giacometti artwork) on food ordering and assessed the mediating role of being aware of the nudge. Students (686) and employees (218) of a German university participated in an online experimental study. After randomization, participants visited a realistic online cafeteria and composed a meal for themselves. Under experimental conditions, participants were exposed to one out of three nudges while choosing dishes: (1) thin body shape, (2) thick body shape, and (3) the Giacometti artwork nudge. The Giacometti nudge resulted in more orders for salad among employees. The thin and thick body shape nudges did not change dish orders. Awareness of the nudge mediated the numbers of calories ordered when using the Giacometti or thin body shape nudges. These findings provide useful insights for health interventions in occupational and public health sectors using nudges. Our study contributes to the research on the Giacometti nudge by showing its effectiveness when participants are aware (it is effective under conditions where it is consciously perceived).
Cancer is a complex disease where resistance to therapies and relapses often pose a serious clinical challenge. The scenario is even more complicated when the cancer type itself is heterogeneous in nature, e.g., lymphoma, a cancer of the lymphocytes which constitutes more than 70 different subtypes. Indeed, the treatment options continue to expand in lymphomas. Herein, we provide insights into lymphoma-specific clinical trials based on cytokine-induced killer (CIK) cell therapy and other pre-clinical lymphoma models where CIK cells have been used along with other synergetic tumor-targeting immune modules to improve their therapeutic potential. From a broader perspective, we will highlight that CIK cell therapy has potential, and in this rapidly evolving landscape of cancer therapies its optimization (as a personalized therapeutic approach) will be beneficial in lymphomas.
Most people use disaster apps infrequently, primarily only in situations of turmoil, when they are physically or emotionally vulnerable. Personal data may be necessary to help them, data protections may be waived. In some circumstances, free movement and liberties may be curtailed for public protection, as was seen in the current COVID pandemic. Consuming and producing disaster data can deepen problems arising at the confluence of surveillance and disaster capitalism, where data has become a tool for solutionist instrumentarian power (Zuboff 2019, Klein 2008) and part of a destructive mode of one world worlding (Law 2015, Escobar 2020). The special use of disaster apps prompts us to ask what role consumer protection could play in safeguarding democratic liberties. Within this work, a set of current approaches are briefly reviewed and two case studies are presented of what we call appropriation or design against datafication. These combine document analysis and literature research with several months of online and field ethnographic observation. The first case study examines disaster app use in response to the 2010 Haiti earthquake, the second explores COVID Contact Tracing in Taiwan in 2020/21. Against this backdrop we ask, ‘how could and how should consumer protection respond to problems of surveillance disaster capitalism?’ Drawing on our work with the is IT ethical? Exchange, a co-designed community platform and knowledge exchange for disaster information sharing, and a Societal Readiness Assessment Framework that we are developing alongside it, we explore how co-design methodologies could help define answers.
Background: Atypical myopathy (AM), an acquired multiple acyl-CoA dehydrogenase deficiency (MADD) in horses, induce changes in mitochondrial metabolism. Only few veterinary laboratories offer diagnostic testing for this disease. Inborn and acquired MADD exist in humans, therefore determination of organic acids (OA) in urine and acylcarnitines (AC) in blood by assays available in medical laboratories can serve as AM diagnostics. The evolution of OA and AC profiles in surviving horses is unreported.
Methods: AC profiles using electrospray ionization tandem mass spectrometry (ESI-MS/MS) and OA in urine using gas chromatography mass spectrometry (GC–MS) were determined in dried blot spots (DBS, n = 7) and urine samples (n = 5) of horses with AM (n = 7) at disease presentation and in longitudinal samples from 3/4 survivors and compared to DBS (n = 16) and urine samples (n = 7) from control horses using the Wilcoxon test.
Results: All short- (C2-C5) and medium-chain (C6-C12) AC in blood differed significantly (p < 0.008) between horses with AM and controls, except for C5:1 (p = 0.45) and C5OH + C4DC (p = 0.06). In AM survivors the AC concentrations decreased over time but were still partially elevated after 7 days. 14/62 (23%) of OA differed significantly between horses with AM and control horses. Concentrations of ethylmalonic acid, 2-hydroxyglutaric acid and the acylglycines (butyryl-, valeryl-, and hexanoylglycine) were highly elevated in the urine of all horses with AM at the day of disease presentation. In AM survivors, concentrations of those metabolites were initially lower and decreased during remission to approach normalization after 7 days.
Conclusion: OA and AC profiling by specialized human medical laboratories was used to diagnose AM in horses. Elevation of specific metabolites were still evident several days after disease presentation, allowing diagnosis via analysis of samples from convalescent animals.
Cultivation of perennials such as Miscanthus x giganteus Greef et Deuter (Mis) combines the provision of ecosystem services and the generation of additional carbon sources for farming. The potential of Mis based fertilisers, regarding immobilisation of inorganic nitrogen (N) and build-up of soil organic matter (SOM), was tested in a field trial. Therefore, a crop rotation of winter barley (Hordeum vulgare L.), mustard (Sinapis alba L.) as catch crop, sugar beet (Beta vulgaris L.) and winter wheat (Triticum aestivum L.) was set up. The tested treatments were a mixture of Cattle Slurry (CS) and Mis, a mixture of CS and Wheat Straw (CS–WS), Cattle Manure (CM) from Mis shredded bedding, CM from WS shredded bedding, a pure CS, Urea Ammonium Nitrate (UAN) and a treatment without any N applied (NoN). When the carbon-rich fertilisers (both mixtures and manures) were applied to cereals, they led to a slight N immobilisation compared to pure CS, whereas differences were mostly not significant. Furthermore, Mis fertilisers were at least as efficient as WS-based organic fertilisers in inducing a contribution of SOM build-up and in reducing inorganic N before winter and thus preventing N losses, whereas differences were mostly not significant.
The epithelial sodium channel (ENaC) is a heterotrimeric ion channel that plays a key role in sodium and water homeostasis in tetrapod vertebrates. In the aldosterone-sensitive distal nephron, hormonally controlled ENaC expression matches dietary sodium intake to its excretion. Furthermore, ENaC mediates sodium absorption across the epithelia of the colon, sweat ducts, reproductive tract, and lung. ENaC is a constitutively active ion channel and its expression, membrane abundance, and open probability (PO) are controlled by multiple intracellular and extracellular mediators and mechanisms [9]. Aberrant ENaC regulation is associated with severe human diseases, including hypertension, cystic fibrosis, pulmonary edema, pseudohypoaldosteronism type 1, and nephrotic syndrome [9].
Suitability of Current Sensors for the Measurement of Switching Currents in Power Semiconductors
(2021)
This paper investigates the impact of current sensors on the measurement of transient currents in fast-switching power semiconductors in a double pulse test (DPT environment. We review previous research that assesses the influence of current sensors on a DPT circuit through mathematical modeling. The developed selection aids can be used to identify suitable current sensors for transient current measurements of fast-switching power semiconductors and to estimate the error introduced by their insertion into the DPT circuit. Afterwards, this analysis is extended by including further elements from real DPT applications to increase the consistency of the error estimation with practical situations and setups. Both methods are compared and their individual advantages and drawbacks are discussed. Finally, a recommendation on when to use which method is derived.
Frequently the main purpose of domestic artifacts equipped with smart sensors is to hide technology, like previous examples of a Smart Mirror show. However, current Smart Homes often fail to provide meaningful IoT applications for all residents’ needs. To design beyond efficiency and productivity, we propose to realize the potential of the traditional artifact for calm and engaging experiences. Therefore, we followed a design case study approach with 22 participants in total. After an initial focus group, we conducted a diary study to examine home routines and developed a conceptual design. The evaluation of our mid-fidelity prototype shows, that we need to study carefully the practices of the residents to leverage the physical material of the artifact to fit the routines. Our Smart Mirror, enhanced by digital qualities, supports meaningful activities and makes the bathroom more appealing. Thereby, we discuss domestic technology design beyond automation.
Recent publications propose concepts of systems that integrate the various services and data sources of everyday food practices. However, this research does not go beyond the conceptualization of such systems. Therefore, there is a deficit in understanding how to combine different services and data sources and which design challenges arise from building integrated Household Information Systems. In this paper, we probed the design of an Integrated Household Information System with 13 participants. The results point towards more personalization, automatization of storage administration and enabling flexible artifact ecologies. Our paper contributes to understanding the design and usage of Integrated Household Information Systems, as a new class of information systems for HCI research.
With the debates on climate change and sustainability, a reduction of the share of cars in the modal split has become increasingly prevalent in both public and academic discourse. Besides some motivational approaches, there is a lack of ICT artifacts that successfully raise the ability of consumers to adopt sustainable mobility patterns. To further understand the requirements and the design of these artifacts within everyday mobility adopted a practice-lens. This lens is helpful to get a broader perspective on the use of ICT artifacts along consumers’ transformational journey towards sustainable mobility practices. Based on 12 retrospective interviews with car-free mobility consumers, we argue that artifacts should not be viewed as ’magic-bullet’ solutions but should accompany the complex transformation of practices in multifaceted ways. Moreover, we highlight in particular the difficulties of appropriating shared infrastructures and aligning own practices with them. This opens up a design space to provide more support for these kinds of material-interactions, to provide access to consumption infrastructures and make them usable, rather than leaving consumers alone with increased motivation.
Background: Staurosporine-dependent single and collective cell migration patterns of breast carcinoma cells MDA-MB-231, MCF-7, and SK-BR-3 were analysed to characterise the presence of drug-dependent migration promoting and inhibiting yin-yang effects. Methods: Migration patterns of various breast cancer cells after staurosporine treatment were investigated using Western blot, cell toxicity assays, single and collective cell migration assays, and video time-lapse. Statistical analyses were performed with Kruskal–Wallis and Fligner–Killeen tests. Results: Application of staurosporine induced the migration of single MCF-7 cells but inhibited collective cell migration. With the exception of low-density SK-BR-3 cells, staurosporine induced the generation of immobile flattened giant cells. Video time-lapse analysis revealed that within the borderline of cell collectives, staurosporine reduced the velocity of individual MDA-MB-231 and SK-BR-3, but not of MCF-7 cells. In individual MCF-7 cells, mainly the directionality of migration became disturbed, which led to an increased migration rate parallel to the borderline, and hereby to an inhibition of the migration of the cell collective as a total. Moreover, the application of staurosporine led to a transient activation of ERK1/2 in all cell lines. Conclusion: Dependent on the context (single versus collective cells), a drug may induce opposite effects in the same cell line.
The synthesis and characterization of a new class of 1,2,4-oxadiazolylpyridinium as a cationic scaffold for fluorinated ionic liquid crystals is herein described. A series of 12 fluorinated heterocyclic salts based on a 1,2,4-oxadiazole moiety, connected through its C(5) or C(3) to an N-alkylpyridinium unit and a perfluoroheptyl chain, differing in the length of the alkyl chain and counterions, has been synthesized. As counterions iodide, bromide and bis(trifluoromethane)sulfonimide have been considered. The synthesis, structure, and liquid crystalline properties of these compounds are discussed on the basis of the tuned structural variables. The thermotropic properties of this series of salts have been investigated by differential scanning calorimetry and polarized optical microscopy. The results showed the existence of an enantiotropic mesomorphic smectic liquid crystalline phase for six bis(trifluoromethane)sulfonimide salts.
BACKGROUND: Humans demonstrate many physiological changes in microgravity for which long-duration head down bed rest (HDBR) is a reliable analog. However, information on how HDBR affects sensory processing is lacking.
OBJECTIVE: We previously showed [25] that microgravity alters the weighting applied to visual cues in determining the perceptual upright (PU), an effect that lasts long after return. Does long-duration HDBR have comparable effects?
METHODS: We assessed static spatial orientation using the luminous line test (subjective visual vertical, SVV) and the oriented character recognition test (PU) before, during and after 21 days of 6° HDBR in 10 participants. Methods were essentially identical as previously used in orbit [25].
RESULTS: Overall, HDBR had no effect on the reliance on visual relative to body cues in determining the PU. However, when considering the three critical time points (pre-bed rest, end of bed rest, and 14 days post-bed rest) there was a significant decrease in reliance on visual relative to body cues, as found in microgravity. The ratio had an average time constant of 7.28 days and returned to pre-bed-rest levels within 14 days. The SVV was unaffected.
CONCLUSIONS: We conclude that bed rest can be a useful analog for the study of the perception of static self-orientation during long-term exposure to microgravity. More detailed work on the precise time course of our effects is needed in both bed rest and microgravity conditions.
Animal models are often needed in cancer research but some research questions may be answered with other models, e.g., 3D replicas of patient-specific data, as these mirror the anatomy in more detail. We, therefore, developed a simple eight-step process to fabricate a 3D replica from computer tomography (CT) data using solely open access software and described the method in detail. For evaluation, we performed experiments regarding endoscopic tumor treatment with magnetic nanoparticles by magnetic hyperthermia and local drug release. For this, the magnetic nanoparticles need to be accumulated at the tumor site via a magnetic field trap. Using the developed eight-step process, we printed a replica of a locally advanced pancreatic cancer and used it to find the best position for the magnetic field trap. In addition, we described a method to hold these magnetic field traps stably in place. The results are highly important for the development of endoscopic tumor treatment with magnetic nanoparticles as the handling and the stable positioning of the magnetic field trap at the stomach wall in close proximity to the pancreatic tumor could be defined and practiced. Finally, the detailed description of the workflow and use of open access software allows for a wide range of possible uses.
We analyze short-term effects of free hospitalization insurance for the poorest quintile of the population in the province of Khyber Pakhtunkhwa, Pakistan. First, we exploit that eligibility is based on an exogenous poverty score threshold and apply a regression discontinuity design. Second, we exploit imperfect rollout and compare insured and uninsured households using propensity score matching. With both methods we fail to detect significant effects on the incidence of hospitalization. Whereas the program did not meaningfully increase the quantity of health care consumed, insured households more often choose private hospitals, indicating a shift towards higher perceived quality of care.
The molecular weight properties of lignins are one of the key elements that need to be analyzed for a successful industrial application of these promising biopolymers. In this study, the use of 1H NMR as well as diffusion-ordered spectroscopy (DOSY NMR), combined with multivariate regression methods, was investigated for the determination of the molecular weight (Mw and Mn) and the polydispersity of organosolv lignins (n = 53, Miscanthus x giganteus, Paulownia tomentosa, and Silphium perfoliatum). The suitability of the models was demonstrated by cross validation (CV) as well as by an independent validation set of samples from different biomass origins (beech wood and wheat straw). CV errors of ca. 7–9 and 14–16% were achieved for all parameters with the models from the 1H NMR spectra and the DOSY NMR data, respectively. The prediction errors for the validation samples were in a similar range for the partial least squares model from the 1H NMR data and for a multiple linear regression using the DOSY NMR data. The results indicate the usefulness of NMR measurements combined with multivariate regression methods as a potential alternative to more time-consuming methods such as gel permeation chromatography.
Intimate swabs taken for examination in sexual assault cases typically yield mixtures of sperm and epithelial cell types. While powerful, differential extraction protocols to overcome such cell type mixtures by separate lysis of epithelial cells and spermatozoa can still prove ineffective, in particular if only few sperm cells are present or if swabs contain sperm from more than one individual leading to complex low level DNA mixtures. A means to avoid such mixtures consists in the analysis of single micromanipulated sperm cells. However, the quantity of DNA from single sperm cells is not sufficient for conventional STR analysis. Here, we describe a simple method for micromanipulating individual sperm cells from intimate swabs and show that whole genome amplification can generate sufficient amounts of DNA from single cells for subsequent DNA profiling. We recovered over 80% of alleles of haploid autosomal STR profiles from the majority of individual sperm cells. Furthermore, we demonstrate that in mixtures of sperm from two contributors, Y-STR and X-STR profiles of individual sperm cells can be used to sort the haploid autosomal profiles to develop the diploid consensus STR profiles of the individual donors. Finally, by analysing single sperm cells from mock sexual assault swabs with one or two sperm donors, we showed that our protocols enabled the identification of the unknown male contributors.
Soil nutrient depletion threatens global food security and has been seriously underestimated for potassium (K) and several micronutrients. This is particularly the case for highly weathered soils in tropical countries, where classical soluble fertilizers are often not affordable or not accessible. One way to replenish macro- and micronutrients are ground silicate rock powders (SRPs). Rock forming silicate minerals contain most nutrients essential for higher plants, yet slow and inconsistent weathering rates have restricted their use in the past. Recent findings, however, challenge past agronomic objections which insufficiently addressed the factorial complexity of the weathering process. This review therefore first presents a framework with the most relevant factors for the weathering of SRPs through which several outcomes of prior studies can be explained. A subsequent analysis of 48 crop trials reveals the potential as alternative K source and multi-nutrient soil amendment for tropical soils, whereas the benefits for temperate soils are currently inconclusive. Beneficial results prevail for mafic and ultramafic rocks like basalts and rocks containing nepheline or glauconite. Several rock modifications are highly efficient in increasing the agronomic effectiveness of SRPs. Enhanced weathering of SRPs could additionally sequester substantial amounts of CO2 from the atmosphere and silicon (Si) supply can induce a broad spectrum of plant biotic and abiotic stress resistance. Recycling massive amounts of rock residues from domestic mining industries could furthermore resolve serious disposal challenges and improve fertilizer self-sufficiency. In conclusion, under the right circumstances, SRPs could not only advance low-cost and regional soil sustaining crop production but contribute to various sustainable development goals.
Different analyses and feasibility studies have been conducted on the plant extracts of thyme (Thymus vulgaris), European horse chestnut (Aesculus hippocastanum), Nordmann fir (Abies nordmanniana), and snowdrop (Galanthus elwesii) to evaluate bio‐based alternatives to common petrol‐based stabilisers. For this purpose, in this study, plant extracts were incorporated into poly‐lactic acid films (PLA) at different concentrations. The films’ UV absorbance and migration into packed food was analysed via photometric assays (ABTS radical cation scavenging capacity assay, β‐carotene assay) and GC–MS analysis. Furthermore, the synergistic antioxidant effects of various combinations of extracts and isolated active compounds were determined. This way, antioxidant effects can be increased, allowing for a highly effective use of resources. All extracts were successfully incorporated into PLA films and showed notable photoabsorbing effects, while no migration risk was observed. Depending on extract combinations, high synergistic effects of up to 726% can be utilised to improve the effectiveness of bio‐based extracts. This applies particularly to tomato paste and Aesculus hippocastanum extracts, which overall show high synergistic and antioxidant effects in combination with each other and with isolated active compounds. The study shows that it is possible to create safe bio‐based antioxidant films which show even improved properties when using highlighted target combinations.
The ability to discriminate between different ionic species, termed ion selectivity, is a key feature of ion channels and forms the basis for their physiological function. Members of the degenerin/epithelial sodium channel (DEG/ENaC) superfamily of trimeric ion channels are typically sodium selective, but to a surprisingly variable degree. While acid-sensing ion channels (ASICs) are weakly sodium selective (sodium:potassium ratio ∼10:1), ENaCs show a remarkably high preference for sodium over potassium (>500:1). This discrepancy may be expected to originate from differences in the pore-lining second transmembrane segment (M2). However, these show a relatively high degree of sequence conservation between ASICs and ENaCs, and previous functional and structural studies could not unequivocally establish that differences in M2 alone can account for the disparate degrees of ion selectivity. By contrast, surprisingly little is known about the contributions of the first transmembrane segment (M1) and the preceding pre-M1 region. In this study, we used conventional and noncanonical amino acid-based mutagenesis in combination with a variety of electrophysiological approaches to show that the pre-M1 and M1 regions of mASIC1a channels are major determinants of ion selectivity. Mutational investigations of the corresponding regions in hENaC show that these regions contribute less to ion selectivity, despite affecting ion conductance. In conclusion, our work suggests that the remarkably different degrees of sodium selectivity in ASICs and ENaCs are achieved through different mechanisms. These results further highlight how M1 and pre-M1 are likely to differentially affect pore structure in these related channels.
Risk-based authentication (RBA) aims to strengthen password-based authentication rather than replacing it. RBA does this by monitoring and recording additional features during the login process. If feature values at login time differ significantly from those observed before, RBA requests an additional proof of identification. Although RBA is recommended in the NIST digital identity guidelines, it has so far been used almost exclusively by major online services. This is partly due to a lack of open knowledge and implementations that would allow any service provider to roll out RBA protection to its users. To close this gap, we provide a first in-depth analysis of RBA characteristics in a practical deployment. We observed N=780 users with 247 unique features on a real-world online service for over 1.8 years. Based on our collected data set, we provide (i) a behavior analysis of two RBA implementations that were apparently used by major online services in the wild, (ii) a benchmark of the features to extract a subset that is most suitable for RBA use, (iii) a new feature that has not been used in RBA before, and (iv) factors which have a significant effect on RBA performance. Our results show that RBA needs to be carefully tailored to each online service, as even small configuration adjustments can greatly impact RBA's security and usability properties. We provide insights on the selection of features, their weightings, and the risk classification in order to benefit from RBA after a minimum number of login attempts.
Cytokine-induced killer (CIK) cells are an ex vivo expanded heterogeneous cell population with an enriched NK-T phenotype (CD3+CD56+). Due to the convenient and relatively inexpensive expansion capability, together with low incidence of graft versus host disease (GVHD) in allogeneic cancer patients, CIK cells are a promising candidate for immunotherapy. It is well known that natural killer group 2D (NKG2D) plays an important role in CIK cell-mediated antitumor activity; however, it remains unclear whether its engagement alone is sufficient or if it requires additional co-stimulatory signals to activate the CIK cells. Likewise, the role of 2B4 has not yet been identified in CIK cells. Herein, we investigated the individual and cumulative contribution of NKG2D and 2B4 in the activation of CIK cells. Our analysis suggests that (a) NKG2D (not 2B4) is implicated in CIK cell (especially CD3+CD56+ subset)-mediated cytotoxicity, IFN-γ secretion, E/T conjugate formation, and degranulation; (b) NKG2D alone is adequate enough to induce degranulation, IFN-γ secretion, and LFA-1 activation in CIK cells, while 2B4 only provides limited synergy with NKG2D (e.g., in LFA-1 activation); and (c) NKG2D was unable to costimulate CD3. Collectively, we conclude that NKG2D engagement alone suffices to activate CIK cells, thereby strengthening the idea that targeting the NKG2D axis is a promising approach to improve CIK cell therapy for cancer patients. Furthermore, CIK cells exhibit similarities to classical invariant natural killer (iNKT) cells with deficiencies in 2B4 stimulation and in the costimulation of CD3 with NKG2D. In addition, based on the current data, the divergence in receptor function between CIK cells and NK (or T) cells can be assumed, pointing to the possibility that molecular modifications (e.g., using chimeric antigen receptor technology) on CIK cells may need to be customized and optimized to maximize their functional potential.
The clear-sky radiative effect of aerosol–radiation interactions is of relevance for our understanding of the climate system. The influence of aerosol on the surface energy budget is of high interest for the renewable energy sector. In this study, the radiative effect is investigated in particular with respect to seasonal and regional variations for the region of Germany and the year 2015 at the surface and top of atmosphere using two complementary approaches.
First, an ensemble of clear-sky models which explicitly consider aerosols is utilized to retrieve the aerosol optical depth and the surface direct radiative effect of aerosols by means of a clear-sky fitting technique. For this, short-wave broadband irradiance measurements in the absence of clouds are used as a basis. A clear-sky detection algorithm is used to identify cloud-free observations. Considered are measurements of the short-wave broadband global and diffuse horizontal irradiance with shaded and unshaded pyranometers at 25 stations across Germany within the observational network of the German Weather Service (DWD). The clear-sky models used are the Modified MAC model (MMAC), the Meteorological Radiation Model (MRM) v6.1, the Meteorological–Statistical solar radiation model (METSTAT), the European Solar Radiation Atlas (ESRA), Heliosat-1, the Center for Environment and Man solar radiation model (CEM), and the simplified Solis model. The definition of aerosol and atmospheric characteristics of the models are examined in detail for their suitability for this approach.
Second, the radiative effect is estimated using explicit radiative transfer simulations with inputs on the meteorological state of the atmosphere, trace gases and aerosol from the Copernicus Atmosphere Monitoring Service (CAMS) reanalysis. The aerosol optical properties (aerosol optical depth, Ångström exponent, single scattering albedo and asymmetry parameter) are first evaluated with AERONET direct sun and inversion products. The largest inconsistency is found for the aerosol absorption, which is overestimated by about 0.03 or about 30 % by the CAMS reanalysis. Compared to the DWD observational network, the simulated global, direct and diffuse irradiances show reasonable agreement within the measurement uncertainty. The radiative kernel method is used to estimate the resulting uncertainty and bias of the simulated direct radiative effect. The uncertainty is estimated to −1.5 ± 7.7 and 0.6 ± 3.5 W m−2 at the surface and top of atmosphere, respectively, while the annual-mean biases at the surface, top of atmosphere and total atmosphere are −10.6, −6.5 and 4.1 W m−2, respectively.
The retrieval of the aerosol radiative effect with the clear-sky models shows a high level of agreement with the radiative transfer simulations, with an RMSE of 5.8 W m−2 and a correlation of 0.75. The annual mean of the REari at the surface for the 25 DWD stations shows a value of −12.8 ± 5 W m−2 as the average over the clear-sky models, compared to −11 W m−2 from the radiative transfer simulations. Since all models assume a fixed aerosol characterization, the annual cycle of the aerosol radiation effect cannot be reproduced. Out of this set of clear-sky models, the largest level of agreement is shown by the ESRA and MRM v6.1 models.
Mebendazole Mediates Proteasomal Degradation of GLI Transcription Factors in Acute Myeloid Leukemia
(2021)
The prognosis of elderly AML patients is still poor due to chemotherapy resistance. The Hedgehog (HH) pathway is important for leukemic transformation because of aberrant activation of GLI transcription factors. MBZ is a well-tolerated anthelmintic that exhibits strong antitumor effects. Herein, we show that MBZ induced strong, dose-dependent anti-leukemic effects on AML cells, including the sensitization of AML cells to chemotherapy with cytarabine. MBZ strongly reduced intracellular protein levels of GLI1/GLI2 transcription factors. Consequently, MBZ reduced the GLI promoter activity as observed in luciferase-based reporter assays in AML cell lines. Further analysis revealed that MBZ mediates its anti-leukemic effects by promoting the proteasomal degradation of GLI transcription factors via inhibition of HSP70/90 chaperone activity. Extensive molecular dynamics simulations were performed on the MBZ-HSP90 complex, showing a stable binding interaction at the ATP binding site. Importantly, two patients with refractory AML were treated with MBZ in an off-label setting and MBZ effectively reduced the GLI signaling activity in a modified plasma inhibitory assay, resulting in a decrease in peripheral blood blast counts in one patient. Our data prove that MBZ is an effective GLI inhibitor that should be evaluated in combination to conventional chemotherapy in the clinical setting.