The development and initial validation of the White Fragility Scale.

Over the last couple of years, the topic of White fragility has garnered a considerable degree of attention. White fragility is considered a state in which even a minimum amount of racial stress can become intolerable and trigger a range of emotional and behavioral reactions intended to restore a sense of racial comfort (DiAngelo, White fragility: Why it's so hard for White people to talk about racism, 2018, Beacon Press). In effort to measure the expression of White fragility, we developed and evaluated the psychometric properties of the 21-item White Fragility Scale (WFS). Data consisted of two independent samples of White participants recruited from M-Turk (327) and a Midwest University's Psychpool (234). Results from exploratory and confirmatory factor analyses provided evidence for a bifactor model consisting of one general White fragility factor and three specific factors of Emotional Defensiveness, Accommodation of Safety, and Exceptionism. Ancillary bifactor indices supported treating the WFS as a unidimensional measure of White fragility yet also revealed meaningful utility of the Accommodation of Safety subscale. Concurrent validity evidence for the WFS was established through significant associations with modern racism, general and specific dimensions of colorblind racial attitudes, and social dominance orientation. In addition, nonsignificant, near-zero correlations with social desirability provided support for divergent validity. Recommendations for future research involving the WFS are provided as well as practical implications for professionals whose work requires a certain degree of racial stamina. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

IgSF11 regulates osteoclast differentiation through association with the scaffold protein PSD-95.

Osteoclasts are multinucleated, giant cells derived from myeloid progenitors. While receptor activator of NF-κB ligand (RANKL) stimulation is the primary driver of osteoclast differentiation, additional signaling further contributes to osteoclast maturation. Here, we demonstrate that immunoglobulin superfamily member 11 (IgSF11), whose expression increases during osteoclast differentiation, regulates osteoclast differentiation through interaction with postsynaptic density protein 95 (PSD-95), a scaffold protein with multiple protein interaction domains. IgSF11 deficiency in vivo results in impaired osteoclast differentiation and bone resorption but no observed defect in bone formation. Consequently, IgSF11-deficient mice exhibit increased bone mass. Using in vitro osteoclast culture systems, we show that IgSF11 functions through homophilic interactions. Additionally, we demonstrate that impaired osteoclast differentiation in IgSF11-deficient cells is rescued by full-length IgSF11 and that the IgSF11-PSD-95 interaction requires the 75 C-terminal amino acids of IgSF11. Our findings reveal a critical role for IgSF11 during osteoclast differentiation and suggest a role for IgSF11 in a receptor- and signal transduction molecule-containing protein complex.

Comprehensive catalog of dendritically localized mRNA isoforms from sub-cellular sequencing of single mouse neurons.

BACKGROUND: RNA localization involves cis-motifs that are recognized by RNA-binding proteins (RBP), which then mediate localization to specific sub-cellular compartments. RNA localization is critical for many different cell functions, e.g., in neuronal dendrites, localization is a critical step for long-lasting synaptic potentiation. However, there is little consensus regarding which RNAs are localized and the role of alternative isoforms in localization. A comprehensive catalog of localized RNA can help dissect RBP/RNA interactions and localization motifs. Here, we utilize a single cell sub-cellular RNA sequencing approach to profile differentially localized RNAs from individual cells across multiple single cells to help identify a consistent set of localized RNA in mouse neurons. RESULTS: Using independent RNA sequencing from soma and dendrites of the same neuron, we deeply profiled the sub-cellular transcriptomes to assess the extent and variability of dendritic RNA localization in individual hippocampal neurons, including an assessment of differential localization of alternative 3'UTR isoforms. We identified 2225 dendritic RNAs, including 298 cases of 3'UTR isoform-specific localization. We extensively analyzed the localized RNAs for potential localization motifs, finding that B1 and B2 SINE elements are up to 5.7 times more abundant in localized RNA 3'UTRs than non-localized, and also functionally characterized the localized RNAs using protein structure analysis. CONCLUSION: We integrate our list of localized RNAs with the literature to provide a comprehensive list of known dendritically localized RNAs as a resource. This catalog of transcripts, including differentially localized isoforms and computationally hypothesized localization motifs, will help investigators further dissect the genome-scale mechanism of RNA localization.

BET Inhibition Improves NASH and Liver Fibrosis.

Non-alcoholic fatty liver disease (NAFLD) is a leading form of chronic liver disease with large unmet need. Non-alcoholic steatohepatitis (NASH), a progressive variant of NAFLD, can lead to fibrosis, cirrhosis, and hepatocellular carcinoma. To identify potential new therapeutics for NASH, we used a computational approach based on Connectivity Map (CMAP) analysis, which pointed us to bromodomain and extra-terminal motif (BET) inhibitors for treating NASH. To experimentally validate this hypothesis, we tested a small-molecule inhibitor of the BET family of proteins, GSK1210151A (I-BET151), in the STAM mouse NASH model at two different dosing timepoints (onset of NASH and progression to fibrosis). I-BET151 decreased the non-alcoholic fatty liver disease activity score (NAS), a clinical endpoint for assessing the severity of NASH, as well as progression of liver fibrosis and interferon-γ expression. Transcriptional characterization of these mice through RNA-sequencing was consistent with predictions from the CMAP analysis of a human NASH signature and pointed to alterations in molecular mechanisms related to interferon signaling and cholesterol biosynthesis, as well as reversal of gene expression patterns linked to fibrotic markers. Altogether, these results suggest that inhibition of BET proteins may present a novel therapeutic opportunity in the treatment of NASH and liver fibrosis.

PIVOT: platform for interactive analysis and visualization of transcriptomics data.

BACKGROUND: Many R packages have been developed for transcriptome analysis but their use often requires familiarity with R and integrating results of different packages requires scripts to wrangle the datatypes. Furthermore, exploratory data analyses often generate multiple derived datasets such as data subsets or data transformations, which can be difficult to track. RESULTS: Here we present PIVOT, an R-based platform that wraps open source transcriptome analysis packages with a uniform user interface and graphical data management that allows non-programmers to interactively explore transcriptomics data. PIVOT supports more than 40 popular open source packages for transcriptome analysis and provides an extensive set of tools for statistical data manipulations. A graph-based visual interface is used to represent the links between derived datasets, allowing easy tracking of data versions. PIVOT further supports automatic report generation, publication-quality plots, and program/data state saving, such that all analysis can be saved, shared and reproduced. CONCLUSIONS: PIVOT will allow researchers with broad background to easily access sophisticated transcriptome analysis tools and interactively explore transcriptome datasets.

Complete fold annotation of the human proteome using a novel structural feature space.

Recognition of protein structural fold is the starting point for many structure prediction tools and protein function inference. Fold prediction is computationally demanding and recognizing novel folds is difficult such that the majority of proteins have not been annotated for fold classification. Here we describe a new machine learning approach using a novel feature space that can be used for accurate recognition of all 1,221 currently known folds and inference of unknown novel folds. We show that our method achieves better than 94% accuracy even when many folds have only one training example. We demonstrate the utility of this method by predicting the folds of 34,330 human protein domains and showing that these predictions can yield useful insights into potential biological function, such as prediction of RNA-binding ability. Our method can be applied to de novo fold prediction of entire proteomes and identify candidate novel fold families.

The purinergic receptor P2X5 regulates inflammasome activity and hyper-multinucleation of murine osteoclasts.

Excessive bone resorption by osteoclasts (OCs) can result in serious clinical outcomes, including bone loss that may weaken skeletal or periodontal strength. Proper bone homeostasis and skeletal strength are maintained by balancing OC function with the bone-forming function of osteoblasts. Unfortunately, current treatments that broadly inhibit OC differentiation or function may also interfere with coupled bone formation. We therefore identified a factor, the purinergic receptor P2X5 that is highly expressed during the OC maturation phase, and which we show here plays no apparent role in early bone development and homeostasis, but which is required for osteoclast-mediated inflammatory bone loss and hyper-multinucleation of OCs. We further demonstrate that P2X5 is required for ATP-mediated inflammasome activation and IL-1ß production by OCs, and that P2X5-deficient OC maturation is rescued in vitro by addition of exogenous IL-1ß. These findings identify a mechanism by which OCs react to inflammatory stimuli, and may identify purinergic signaling as a therapeutic target for bone loss-related inflammatory conditions.

Coroners' guidelines for health practitioners: help or hindrance?

In Victoria, New South Wales and Queensland, coroners' guidelines have been developed to assist health practitioners in complying with their coronial reporting obligations. These guidelines, which are intended to work hand in hand with the legislation, leading the health practitioner through the law, its interpretation and its application, have been commended for assisting with a more detailed and structured consideration of often complex issues. However, closer scrutiny of these guidelines shows legal inaccuracies and other errors that have the potential to lead health practitioners into error. In circumstances where failure to comply with reporting obligations can constitute a criminal offence as well as professional misconduct, this situation is unacceptable. This article recommends changes to the guidelines to bring them into conformity with the law ensuring that the guidelines operate as a help, and not a hindrance, to health care practitioners.

Medical-setting deaths and the coroner: laws, penalties and guidelines.

We examine the law governing the reporting of medical-setting deaths to the Coroner throughout the Australian states and territories. We use a hypothetical case report to explore the different legal requirements for reporting a medical-setting death and the varying penalties that apply for failing to report a reportable death. It is important for health practitioners to understand the law that applies in the state or territory in which they practice. Knowing when to report a medical-setting death requires not only medical knowledge but also legal analysis. On this basis, we recommend the development of coroners' guidelines in all jurisdictions to assist health practitioners in complying with their coronial reporting obligations.

NoFold: RNA structure clustering without folding or alignment.

Structures that recur across multiple different transcripts, called structure motifs, often perform a similar function-for example, recruiting a specific RNA-binding protein that then regulates translation, splicing, or subcellular localization. Identifying common motifs between coregulated transcripts may therefore yield significant insight into their binding partners and mechanism of regulation. However, as most methods for clustering structures are based on folding individual sequences or doing many pairwise alignments, this results in a tradeoff between speed and accuracy that can be problematic for large-scale data sets. Here we describe a novel method for comparing and characterizing RNA secondary structures that does not require folding or pairwise alignment of the input sequences. Our method uses the idea of constructing a distance function between two objects by their respective distances to a collection of empirical examples or models, which in our case consists of 1973 Rfam family covariance models. Using this as a basis for measuring structural similarity, we developed a clustering pipeline called NoFold to automatically identify and annotate structure motifs within large sequence data sets. We demonstrate that NoFold can simultaneously identify multiple structure motifs with an average sensitivity of 0.80 and precision of 0.98 and generally exceeds the performance of existing methods. We also perform a cross-validation analysis of the entire set of Rfam families, achieving an average sensitivity of 0.57. We apply NoFold to identify motifs enriched in dendritically localized transcripts and report 213 enriched motifs, including both known and novel structures.

Length constraints of multi-domain proteins in metazoans.

The increasing number of annotated genome sequences in public databases has made it possible to study the length distributions and domain composition of proteins at unprecedented resolution. To identify factors that influence protein length in metazoans, we performed an analysis of all domain-annotated proteins from a total of 49 animal species from Ensembl (v.56) or EnsemblMetazoa (v.3). Our results indicate that protein length constraints are not fixed as a linear function of domain count and can vary based on domain content. The presence of repeating domains was associated with relaxation of the constraints that govern protein length. Conversely, for proteins with unique domains, length constraints were generally maintained with increased domain counts. It is clear that mean (and median) protein length and domain composition vary significantly between metazoans and other kingdoms; however, the connections between function, domain content, and length are unclear. We incorporated Gene Ontology (GO) annotation to identify biological processes, cellular components, or molecular functions that favor the incorporation of multi-domain proteins. Using this approach, we identified multiple GO terms that favor the incorporation of multi-domain proteins; interestingly, several of the GO terms with elevated domain counts were not restricted to a single gene family. The findings presented here represent an important step in resolving the complex relationship between protein length, function, and domain content. The comparison of the data presented in this work to data from other kingdoms is likely to reveal additional differences in the regulation of protein length.

Sperm removal and dead or dying patients: a dilemma for emergency departments and intensive care units.

An unexpected consequence of the increase in the use of fertility treatment is that emergency department and intensive care doctors are receiving requests from wives (actual or de facto) of dying or recently deceased men for sperm removal. Legislation in all states and territories regulates removal of sperm from a dying man and, provided that lawful consent is obtained, a doctor can harvest sperm. In several states, including Victoria, harvested sperm cannot be used in a fertilisation procedure without the man's consent, and debate surrounds the issue of consent and how it can be proved. Recent Victorian Law Reform Commission recommendations attempt to streamline the law to make a man's consent the cornerstone of decision making for both harvesting and subsequent use of sperm.

Improving hospital preparedness for radiological terrorism: perspectives from emergency department physicians and nurses.

BACKGROUND: Hospital emergency department (ED) clinicians will play a crucial role in responding to any terrorist incident involving radioactive materials. To date, however, there has been a paucity of research focusing specifically on ED clinicians' perspectives regarding this threat. METHODS: At the request of the Centers for Disease Control and Prevention, researchers at the University of Alabama at Birmingham conducted a series of 10 focus groups (total participants, 77) with ED physicians and nurses at hospitals in 3 US regions. Participants considered a hypothetical "dirty bomb" scenario and discussed their perceptions, concerns, information needs, preferred information sources, and views of current guidance and informational materials. RESULTS: Study participants consistently expressed the view that neither EDs nor hospital facilities are sufficiently prepared for a terrorist event involving radioactive materials. Key clinician concerns included the possibility of the hospital being overwhelmed, safety of loved ones, potential staffing problems, readiness problems, and contamination and self-protection. Participants also expressed a need for additional information, strongly disagreed with aspects of current response guidance, and in some cases indicated they would not carry out current protocols. CONCLUSIONS: This study is the first to examine the views, perceptions, and information needs of hospital ED clinicians regarding radiological terrorism. As such, the findings may be useful in informing current and future efforts to improve hospital preparedness.

Communicating with the public about emerging health threats: lessons from the Pre-Event Message Development Project.

OBJECTIVES: We sought to better understand the challenges of communicating with the public about emerging health threats, particularly threats involving toxic chemicals, biological agents, and radioactive materials. METHODS: At the request of the Centers for Disease Control and Prevention, we formed an interdisciplinary consortium of investigative teams from 4 schools of public health. Over 2 years, the investigative teams conducted 79 focus group interviews with 884 participants and individual cognitive response interviews with 129 respondents, for a total sample of 1013 individuals. The investigative teams systematically compared their results with other published research in public health, risk communication, and emergency preparedness. RESULTS: We found limited public understanding of emerging biological, chemical, and radioactive materials threats and of the differences between them; demand for concrete, accurate, and consistent information about actions needed for protection of self and family; active information seeking from media, local authorities, and selected national sources; and areas in which current emergency messaging can be improved. CONCLUSIONS: The public will respond to a threat situation by seeking protective information and taking self-protective action, underlining the critical role of effective communication in public health emergencies.

The rights and interests of doctors and patients: does the new Victorian Health Professions Registration Act 2005 strike a fair balance?

From July 2007, the Health Professions Registration Act 2005 (Vic) will significantly alter the medical disciplinary process in Victoria. For practitioners: Formal hearings for allegations of serious unprofessional conduct will be heard by the Victorian Civil and Administrative Tribunal (VCAT); There will be no right of appeal from a VCAT decision other than on a point of law; The maximum fine for serious unprofessional conduct will increase from $2000 to $50 000; Performance standards panels (PSPs) will be established to conduct informal hearings, with a power to impose conditions on registration; and Costs of the new system will cause an increase in annual registration fees. For complainants: There are new avenues for conciliation; There is a right to seek a review of certain Medical Practitioners Board of Victoria decisions; and Reasons for a PSP decision will be provided. Despite government argument that these changes will make the health complaints handling system fairer, the new Act has the potential to diminish the rights and interests of doctors.