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WT1 is a true chameleon, both acting as an oncogene and tumor suppressor. As its exact role in leukemogenesis is still ambiguous, research with model systems representing natural conditions surrounding the genetic alterations in WT1 is necessary. In a cohort of 59 leukemia/lymphoma cell lines, we showed aberrant expression for WT1 mRNA, which does not always translate into protein levels. We also analyzed the expression pattern of the four major WT1 protein isoforms in the cell lines and primary AML blasts with/without WT1 mutations and demonstrated that the presence of mutations does not influence these patterns. By introduction of key intronic and exonic sequences of WT1 into a lentiviral expression vector, we developed a unique tool that can stably overexpress the four WT1 isoforms at their naturally occurring tissue-dependent ratio. To develop better cellular model systems for WT1, we sequenced large parts of its gene locus and also other important myeloid risk factor genes and revealed previously unknown alterations. Functionally, inhibition of the nonsense-mediated mRNA decay machinery revealed that under natural conditions, the mutated WT1 alleles go through a robust degradation. These results offer new insights and model systems regarding the characteristics of WT1 in leukemia and lymphoma.

Many cellular processes occur out of equilibrium. This includes site-specific unwinding in supercoiled DNA, which may play an important role in gene regulation. Here, we use the Convex Lens-induced Confinement (CLiC) single-molecule microscopy platform to study these processes with high-throughput and without artificial constraints on molecular structures or interactions. We use two model DNA plasmid systems, pFLIP-FUSE and pUC19, to study the dynamics of supercoiling-induced secondary structural transitions after perturbations away from equilibrium. We find that structural transitions can be slow, leading to long-lived structural states whose kinetics depend on the duration and direction of perturbation. Our findings highlight the importance of out-of-equilibrium studies when characterizing the complex structural dynamics of DNA and understanding the mechanisms of gene regulation.

Secretion analysis is a useful tool in forensic genetics, since it establishes the (cellular) origin of the DNA prior in addition to the identification of the DNA donor. This information can be crucial for the construction of the crime sequence or verification of statements of people involved in the crime. For some secretions, rapid/pretests already exist (blood, semen, urine, and saliva) or can be determined via published methylation analyses or expression analyses (blood, saliva vaginal secretions, menstrual blood, and semen). To discriminate nasal secretion/blood from other secretions (like oral mucosa/saliva, blood, vaginal secretion, menstrual blood, and seminal fluid), assays based on specific methylation patterns at several CpGs were set up in this study. Out of an initial 54 different CpG markers tested, two markers showed a specific methylation value for nasal samples: N21 and N27 with a methylation mean value of 64.4% ± 17.6% and 33.2% ± 8.7%, respectively. Although identification or discrimination was not possible for all nasal samples (due to partial overlap in methylation values to other secretions), 63% and 26% of the nasal samples could be unambiguously identified and distinguished from the other secretions using the CpG marker N21 and N27, respectively. In combination with a blood pretest/rapid test, a third marker (N10) was able to detect nasal cells in 53% of samples. Moreover, the employment of this pretest increases the proportion of identifiable or discriminable nasal secretion samples using marker N27 to 68%. In summary, our CpG assays proved to be promising tools in forensic analysis for the detection of nasal cells in samples from a crime scene.

Wird ein Jobcoach in einem Betrieb hinzugezogen, ist das Arbeitsverhältnis oft so massiv belastet, dass eine Kündigung im Raum steht. Dennoch gelingt es Jobcoaches in den meisten Fällen, dass das Arbeitsverhältnis erhalten bleibt. Dafür müssen sie alle Beteiligten mit ihren unterschiedlichen Interessen, Perspektiven und Bedürfnissen auf einen gemeinsamen Kurs bringen.

Objective Since medication errors can have severe consequences, the development of methods to improve patient safety is becoming increasingly important. The aim of this evaluation was to identify frequent medication errors in oncology as well as characteristic correlations in the various error patterns. In addition, the implementation rate of the proposed pharmaceutical intervention was determined in order to assess the benefit of a clinical pharmacist in the field of oncology. Methods The evaluation was based on a data-set from a national documentation system for medication errors and interventions (DokuPIK) used by hospital pharmacists in the field of oncology from 2008 to 2019, namely 6684 reported cases in oncology, representing about 5% of all reports in DokuPIK. Results The most frequently reported errors were incorrect doses (22% of reported errors), followed by interactions (14%); in 10% of errors the prescription/documentation was incomplete/incorrect. The intervention suggested by the pharmacist was implemented in 97% of the cases. Based on the respective Anatomical Therapeutical Chemical Classification (ATC codes), drugs (or groups of drugs) were identified that were reported frequently in connection with medication errors, namely carboplatin and cyclophosphamide as anticancer drugs pantoprazole as non-anticancer drug. Conclusion Frequently occurring medication errors in the field of oncology were identified, facilitating the development of specific recommendations for action and prevention strategies. The implementation of an electronic prescription software is particularly recommended for the avoidance of dosage errors in chemotherapy.

Despite the implication of aerosols for radiative forcing, there are di erences in aerosol estimates from both, observations and models. This study quanti es di erences between current estimates of aerosol optical depth (AOD) to address two questions: (1) How well do we know the large-scale spatio-temporal pattern of present-day AOD across state-of-the-art data? (2) Has the representation of AOD improved across phases of aerosol-climate model intercomparison projects? To answer these questions, we analyze spatio-temporal patterns of the present-day monthly mean AOD from 94 global datasets. The data is taken from eight satellite retrievals, four aerosol-climate model intercomparison projects, two global reanalyses, one operational ensemble product, one climatology and one merged satellite product covering periods between 1998 and 2019. The evaluation includes new satellite data from SLSTR and aerosol-climate models of CMIP6 and AeroCom-III. The comprehensive data assessment allows us to evaluate the performance of individual products and models concerning di erent spatial and temporal aspects. Our assessment is based on metrics for a detailed investigation with respect to di erent spatio-temporal characteristics of AOD.Our results highlight spatio-temporal di erences in AOD across datasets, were the performance of individual data sets varies with respect to the di erent spatio-temporal metrics assessed. Global mean AOD of individual satellites ranges between -11% to +17% around a satellite mean of 0.14. The ensemble means from the aerosol-climate model intercomparison projects fall within the satellite range, but individual models can di er considerably. Reanalyses and climalologies are typically closer to the satellite mean than aerosol-climate models. No systematic improvement from earlier to later phases of CMIP and AeroCom is found, although some regional biases have been reduced. Compared to the satellite and reanalysis data, all aerosol-climate ensemble means tend to overestimate AOD along extra-tropical storm tracks and underestimate AOD in regions of high aerosol load in South America, South Africa, India, and Southeast Asia. The identi ed di erences may be used to guide further e orts to improve satellite retrievals and model simulations for aerosols. In addition, the uncertainty in observed AOD implies that a model evaluation based on a single satellite product might draw biased conclusions. This underlines the need for continued e orts to improve both model and satellite estimates of AOD to facilitate a better understanding of aerosol e ects in the Earth system. At the same time, our analysis suggests that an assimilation of multiple satellite products for AOD would be bene cial to account for observational uncertainty.Reference: Vogel, A., Alessa, G., Scheele, R., Weber, L., Dubovik, O., North, P., Fiedler, S. (2022). Uncertainty in aerosol optical depth from modern aerosol-climate models, reanalyses, and satellite products. Journal of Geophysical Research: Atmospheres, 127, e2021JD035483. https://doi.org/10.1029/2021JD035483

Despite the implication of aerosols for the radiation budget, there are persistent differences in data for the aerosol optical depth (τ) for 1998–2019. This study presents a comprehensive evaluation of the large‐scale spatio‐temporal patterns of mid‐visible τ from modern data sets. In total, we assessed 94 different global data sets from eight satellite retrievals, four aerosol‐climate model ensembles, one operational ensemble product, two reanalyses, one climatology and one merged satellite product. We include the new satellite data SLSTR and aerosol‐climate simulations from the Coupled Model Intercomparison Project Phase 6 (CMIP6) and the Aerosol Comparisons between Observations and Models Phase 3 (AeroCom‐III). Our intercomparison highlights model differences and observational uncertainty. Spatial mean τ for 60°N – 60°S ranges from 0.124 to 0.164 for individual satellites, with a mean of 0.14. Averaged τ from aerosol‐climate model ensembles fall within this satellite range, but individual models do not. Our assessment suggests no systematic improvement compared to CMIP5 and AeroCom‐I. Although some regional biases have been reduced, τ from both CMIP6 and AeroCom‐III are for instance substantially larger along extra‐tropical storm tracks compared to the satellite products. The considerable uncertainty in observed τ implies that a model evaluation based on a single satellite product might draw biased conclusions. This underlines the need for continued efforts to improve both model and satellite estimates of τ, for example, through measurement campaigns in areas of particularly uncertain satellite estimates identified in this study, to facilitate a better understanding of aerosol effects in the Earth system., Plain Language Summary: Aerosols are known to affect atmospheric processes. For instance, particles emitted during dust storms, biomass burning and anthropogenic activities affect air quality and influence the climate through effects on solar radiation and clouds. Although many studies address such aerosol effects, there is a persistent difference in current estimates of the amount of aerosols in the atmosphere across observations and complex climate models. This study documents the data differences for aerosol amounts, including new estimates from climate‐model simulations and satellite products. We quantify considerable differences across aerosol amount estimates as well as regional and seasonal variations of extended and new data. Further, this study addresses the question to what extent complex climate models have improved over the past decades in light of observational uncertainty., Key Points: Present‐day patterns in aerosol optical depth differ substantially between 94 modern global data sets. The range in spatial means from individual satellites is −11% to +17% of the multi‐satellite mean. Spatial means from climate model intercomparison projects fall within the satellite range but strong regional differences are identified., Hans‐Ertel‐Center for Weather Research, Collaborative Research Centre 1211, Max‐Planck‐Institute for Meteorology

Simple Summary Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults. Despite the emergence of new therapeutic agents in recent years, curation remains challenging, and new and better treatment options are needed. In the present study, we investigated the expression, prognostic significance, and functional role of the Receptor Activator of Nuclear Factor-κB (RANK) in AML. We found that RANK is expressed on leukemic cells in a substantial proportion of AML patients and is associated with a dismal disease course. We further demonstrated that signaling via RANK induces release of factors that favor AML cell survival and confers resistance to chemotherapeutics in AML treatment. Together, our findings identify RANK as novel prognostic marker and putative candidate for therapeutic intervention in AML to enhance response to treatment. Abstract Although treatment options of acute myeloid leukemia (AML) have improved over the recent years, prognosis remains poor. Better understanding of the molecular mechanisms influencing and predicting treatment efficacy may improve disease control and outcome. Here we studied the expression, prognostic relevance and functional role of the tumor necrosis factor receptor (TNFR) family member Receptor Activator of Nuclear Factor (NF)-κB (RANK) in AML. We conducted an experimental ex vivo study using leukemic cells of 54 AML patients. Substantial surface expression of RANK was detected on primary AML cells in 35% of the analyzed patients. We further found that RANK signaling induced the release of cytokines acting as growth and survival factors for the leukemic cells and mediated resistance of AML cells to treatment with doxorubicin and cytarabine, the most commonly used cytostatic compounds in AML treatment. In line, RANK expression correlated with a dismal disease course as revealed by reduced overall survival. Together, our results show that RANK plays a yet unrecognized role in AML pathophysiology and resistance to treatment, and identify RANK as “functional” prognostic marker in AML. Therapeutic modulation of RANK holds promise to improve treatment response in AML patients.

Most children will experience some type of trauma during childhood, and many children suffer from significant adversities. Research in genetics, neuroscience, and epidemiology all provide evidence that these experiences have effects at the molecular, cellular, and organ level, with consequences on physical, emotional, developmental, and behavioral health across the life span. Trauma-informed care translates that science to inform and improve pediatric care and outcomes. To practically address trauma and promote resilience, pediatric clinicians need tools to assess childhood trauma and adversity experiences as well as practical guidance, resources, and interventions. In this clinical report, we summarize current, practical advice for rendering trauma-informed care across varied medical settings.

Objective To evaluate the characteristics and outcomes of pediatric cochlear implant recipients diagnosed with Usher syndrome (US). Study design Retrospective study of consecutive pediatric cochlear implant recipients (1991-2010). Setting Tertiary care children's hospital. Patients Children who received a cochlear implant who were diagnosed with US either before or after implantation. Main outcome measures Electroretinography and ophthalmologic findings, cochlear anatomy based on preoperative imaging, age of independent ambulation, age at implantation, speech perception level, and communication method. Results Approximately 26 (3.7%) of 712 cochlear implant recipients were diagnosed with US based on the results of electroretinography and/or genetic testing. Preoperative imaging revealed no evidence of cochlear malformations. Average age of independent ambulation was 21.9 months (range, 12-30). Average age at implantation was 3.3 years (range, 6 mo to 11.6 yr). Mean follow-up after implantation was 7.8 years (range, 10 mo to 15.6 yr). Open-set speech perception was present in 92% of children, with use of a primarily oral communication mode in 69.2%. Conclusion In this large series of patients with the diagnosis of US who have undergone cochlear implantation, CT and MRI imaging were normal. Significant delay in independent ambulation was present in this population secondary to abnormal vestibular function associated with US Type I. A majority of children developed significant open-set speech perception and oral communication skills. Implantation of US children provides them with the opportunity to develop useful hearing and oral communication.

In quantitative analyses of biological processes, one may use many different scales of models (e.g., spatial or non-spatial, deterministic or stochastic, time-varying or at steady-state) or many different approaches to match models to experimental data (e.g., model fitting or parameter uncertainty/sloppiness quantification with different experiment designs). These different analyses can lead to surprisingly different results, even when applied to the same data and the same model. We use a simplified gene regulation model to illustrate many of these concerns, especially for ODE analyses of deterministic processes, chemical master equation and finite state projection analyses of heterogeneous processes, and stochastic simulations. For each analysis, we employ Matlab and Python software to consider a time-dependent input signal (e.g., a kinase nuclear translocation) and several model hypotheses, along with simulated single-cell data. We illustrate different approaches (e.g., deterministic and stochastic) to identify the mechanisms and parameters of the same model from the same simulated data. For each approach, we explore how uncertainty in parameter space varies with respect to the chosen analysis approach or specific experiment design. We conclude with a discussion of how our simulated results relate to the integration of experimental and computational investigations to explore signal-activated gene expression models in yeast [1] and human cells [2]‡.PACS numbers: 87.10.+e, 87.15.Aa, 05.10.Gg, 05.40.Ca,02.50.-rSubmitted to: Phys. Biol.

The Children's Memorial Hospital cochlear implant team believes an interdisciplinary approach is essential for the implementation of best practices when working with the pediatric cochlear implant population. Over time, we have developed a team model that builds relationships with members of the community to ensure comprehensive care for patients and their families.

Family involvement in planning and choosing services has become a key intervention concept in developmental disability services. This study (N = 547) modeled patterns of family decision making and assessed benefits to persons with developmental disabilities (DDs) and their family members. A latent profile analysis identified 4 classes that were highly involved in decision making (n = 118), involved only in planning (n = 166), involved only in financial decisions (n = 75), and uninvolved (n = 188). Multiple regression analysis indicated that consumers with DD whose family members were highly involved received more services than consumers in other families. A multivariate analysis of covariance indicated that the family members in the highly involved and planning classes experienced more family member satisfaction than others. Findings have implications for practice.

Budding yeast Spc110, a member of γ-tubulin complex receptor family (γ-TuCR), recruits γ-tubulin complexes to microtubule (MT) organizing centers (MTOCs). Biochemical studies suggest that Spc110 facilitates higher-order γ-tubulin complex assembly (Kollman et al., 2010). Nevertheless the molecular basis for this activity and the regulation are unclear. Here we show that Spc110 phosphorylated by Mps1 and Cdk1 activates γ-TuSC oligomerization and MT nucleation in a cell cycle dependent manner. Interaction between the N-terminus of the γ-TuSC subunit Spc98 and Spc110 is important for this activity. Besides the conserved CM1 motif in γ-TuCRs (Sawin et al., 2004), a second motif that we named Spc110/Pcp1 motif (SPM) is also important for MT nucleation. The activating Mps1 and Cdk1 sites lie between SPM and CM1 motifs. Most organisms have both SPM-CM1 (Spc110/Pcp1/PCNT) and CM1-only (Spc72/Mto1/Cnn/CDK5RAP2/myomegalin) types of γ-TuCRs. The two types of γ-TuCRs contain distinct but conserved C-terminal MTOC targeting domains. DOI: http://dx.doi.org/10.7554/eLife.02208.001, eLife digest Microtubules are hollow structures made of proteins that have a central role in cell division and a variety of other important processes within cells. For a cell to divide successfully, the chromosomes containing the genetic information of the cell must be duplicated and then separated so that one copy of each chromosome ends up in each daughter cell. To separate the chromosomes, microtubules extend out from two structures called spindle pole bodies, which are found at either end of the cell, and pull one copy of each chromosome to opposite sides of the cell. Although the individual proteins that make up a microtubule can self-assemble into tubes, this occurs very slowly, so cells employ other molecules to speed up this process. In yeast cells, a protein called gamma-tubulin is recruited to the spindle pole body by the protein Spc110, where it combines with two other proteins to form a complex called the gamma-tubulin small complex. Several of these complexes then join together to form a ring, which probably acts as the platform that microtubules grow from. Recent observations suggested that Spc110 may help to construct this ring, but without revealing how. Now, Lin et al. reveal that Spc110 can regulate microtubule formation by controlling how several gamma-tubulin small complexes bind together, and have identified the exact section of Spc110 that interacts with the complexes. However, the Spc110 must become active before it can perform this role, and it is only activated during certain stages of cell division, through phosphorylation. The structures in Spc110 that bind to the gamma-tubulin small complex in yeast are also found in gamma-tubulin binding receptor proteins in human cells. The work of Lin et al. demonstrates that proteins that are assumed to have passive roles within cells, such as Spc110, often play more active roles instead. DOI: http://dx.doi.org/10.7554/eLife.02208.002

Scholarship over the past three decades has generated considerable insight into the roles of the media, politicians, and law enforcement officials in constructing images of criminal justice; still, that body of research has rarely ventured into the realm of corrections. Filling this void, we drew a sample of 206 newspaper articles on corrections published in the New York Times for the purpose of examining news sources and their quoted statements. Our findings reveal that the New York Times relies heavily on political and government sources who—not surprisingly—express support for the prevailing correctional policies and practices. Whereas the New York Times also quoted sources critical of the government's correctional strategies, the dominance of political sources in the press offers evidence of agenda setting in the debate over corrections.

4 Background: Informal caregiving for cancer patients can be both demanding and burdensome – physically, emotionally, and financially – for many caregivers. Cancer caregivers play a large role in advocating for and administering care for their recipients. The current study aimed to explore if cancer caregivers differ from non-cancer caregivers with regard to communicating with healthcare providers, and need for information about end-of-life care. Methods: Data were used from the 2015 Caregiving in the U.S. (CGUS) dataset, a nationally-representative online probability-based panel study of unpaid adult caregivers. The analysis compared cancer and non-cancer caregivers to determine similarities and differences in characteristics and experiences, with a focus on unmet needs in communication with healthcare providers and end-of-life decision-making. Statistical significance was determined at the p < 0.05 level. Results: Approximately 7% (2.8 million) of caregiver participants in the CGUS study indicate cancer as the primary reason for providing care. Cancer caregivers report higher burden than non-cancer caregivers (62% vs. 38%) and significantly more hours per week caregiving (32.9 vs. 23.9 hours per week). Significantly more cancer caregivers indicate interacting with key providers, agencies, and professionals on behalf of their care recipients: 82% report communicating with healthcare professionals (vs. 62%), 76% monitor/adjust care (vs. 66%), and 62% report advocating for care recipient (vs. 49%). Finally, almost twice the number of cancer caregivers than non-cancer caregivers (40% vs. 21%) report needing more help/information with making end-of-life decisions. Conclusions: These findings indicate the burdensome and demanding role of cancer caregiving. These caregivers play a substantial role in directing, monitoring, and advocating for survivor care. Yet, many need more information about end-of-life care. This suggests a gap in preparation despite the roles provided, and suggest a need to explore strategies to engage patient-provider-caregiver communication about care, particularly end of life care.

Although cognitive appraisal, situational properties, and attributions are important parts of the stress process, few multidimensional measures are available to examine these constructs simultaneously. This paper investigates the properties of the Dimensions of Stress Scale (DSS). The DSS is a brief self-report questionnaire designed to assess appraisals of personal relevance (salience) and control; stressor properties (novelty, duration, and predictability); and self-attributions (causality). The items were derived theoretically, using the cognitive-phenomenological model of stress and the stress literature. Empirical support for the six dimensions (scales) was generated first on a sample of elderly individuals (n= 269) and then replicated on an independent sample of younger individuals (n= 162). In both investigations, the factor structure of five of the scales was shown to approximate a simple structure. Evidence of internal consistency and content validity was also provided. The scales’ construct validity was supported by their relationships with stressor type (e. g., physical health problems, relationships, work, finances, individuals with indeterminate Western Blots, and caregivers of patients with Alzheimer's disease), coping, and depressed mood. The DSS should be useful in examining stressful experiences.

Consumer choice is a key concept in developmental disability intervention, but relatively little quantitative research has focused on the relationship between choice and quality of life. This study used data from Washington state's Division of Developmental Disabilities 2002 National Core Indicators study (Human Services Research Institute, 2001a, 2001b) to examine the relationship between choice and 3 quality-of-life indicators: community inclusion, rights, and opportunities for relationships. Consumers (N = 224) with mild intellectual disabilities participated in the study. Structural equation modeling was used to assess the influence of type of living arrangement and choice on quality of life. Consumers who lived in the community and made more choices had higher scores on quality-of-life indicators. The findings have implications for disability policy, practice, and future research.

The archival profession's attention has been focused on the USMARC Format for Archival and Manuscripts Control (AMC), which is part of the USMARC formats for bibliographic data, to the exclusion of the other two USMARC formats: authorities and holdings. The author examines the implications of adopting the USMARC formats for authorities and holdings by looking at the purposes and structures of the two formats, analyzing how they relate to archival description practice, discussing the changes required for the two formats to meet archival descriptive needs, and exploring strategies for the adoption of the USMARC formats to be used in archival information exchange.

Members of the archival profession have demonstrated an increasing interest in standards-related issues, particularly in archival description standards. The author discusses the concepts, principles, and methodologies associated with archival description standards, first by defining the phrase archival description, and then by introducing similar standards in the library profession as a frame of reference. She summarizes existing archival description standards at three levels (data structure, data content, and data value), reviews reasons to develop and use standards along with obstacles blocking their emergence, and explores possible future developments.