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Researchers have implemented inclusive research for over 30 years. This article describes how two research projects collaborated with researchers with disabilities and aligns the description with four attributes of inclusive research developed by a consensus of international experts with and without disabilities. The first project, the Person Experiences Interview Survey (PEIS) Workgroup, reviewed and revised items for a self-report survey of mental health service experiences. The second project describes the peer-led implementation of the Self-Determined Career Design Model (SDCDM) intervention. Four factors facilitated or were barriers to the projects' alignment with inclusive research attributes. First, relationships enhanced capacity to engage in meaningful ways. Second, balance between consistency and adaptability promoted engagement. Third, long-term capacity was enabled by ongoing engagement and peer mentorship. Fourth, time and funds impacted inclusive implementation. Engaging researchers with disabilities meaningfully enhanced the research process and products.

Abstract A persistent cooling trend in the subpolar North Atlantic known as the North Atlantic Warming Hole (NAWH) has appeared in sea surface temperature (SST) observations since 1870, and the reasons for its persistence in an era of rapid anthropogenic global warming remain elusive. Here we investigate the response of the atmosphere to the NAWH in a set of model experiments, and further examine the associated feedback mechanisms. In one experiment, the observed warming hole is imposed upon the present-day climatology, and in another we run a sensitivity experiment, shifting the location of the warming hole southward of its observed location to limit its direct interaction with the jet stream. Surprisingly, the response of the jet stream and surface circulation is relatively insensitive to the latitude of the NAWH within the basin. However, the capacity for the atmospheric response to invoke a positive feedback onto the SST forcing does depend on proximity to the midlatitude jet stream. These results distinctly differ from similar coarser resolution experiments but align with observed patterns, highlighting the importance of eddies in determining the response of the midlatitude atmosphere to persistent SST forcing. These findings therefore augment our understanding of the long-term persistence of the NAWH.

Abstract Background Metastatic prostate cancer remains a therapeutic challenge. Based on data of the STAMPEDE trial, patients with a low metastatic burden showed prolonged failure-free and overall survival when treated with prostate radio therapy (RT) in addition to standard of care (SOC). The objective of this study was to determine the cost-effectiveness of additional prostate RT compared to SOC alone for following subgroups: non-regional lymph node (NRLN) metastases, up to three bone metastases and four or more bone metastases. Methods A partitioned survival model was implemented with clinical data from STAMPEDE trial. Analyses were performed from a United States healthcare system perspective. Costs for treatment and adverse events were derived from Medicare coverage. Utilities for health states were derived from public databases and literature. Outcome measurements included incremental costs, effectiveness, and cost-effectiveness ratio. The willingness-to-pay threshold was set to USD 100,000 per quality-adjusted life year (QALY). Results Additional RT led to 0.92 incremental QALYs with increased costs of USD 26,098 with an incremental cost-effectiveness ratio (ICER) of USD 28,452/QALY for patients with only NRLN metastases and 3.83 incremental QALYs with increased costs of USD 153,490 with an ICER of USD 40,032/QALY for patients with up to three bone metastases. Sensitivity analysis showed robustness of the model regarding various parameters. In probabilistic sensitivity analysis using Monte Carlo simulation with 10,000 iterations, additional RT was found as the cost-effective strategy in over 96% for both subgroups iterations at a willingness-to-pay threshold of USD 100,000/QALYs. Conclusions Additional RT is cost-effective in patients with only NRLN metastases and up to three metastases compared to SOC.

Primary Sjögren’s disease (pSD) is a systemic autoimmune disease that has the strongest female predilection of all autoimmune diseases. The underlying mechanisms that govern this sexual dimorphism, however, remain poorly understood. We hypothesized that pSD females would exhibit more robust disease as compared to males, and that Tlr7 controls distinct disease manifestations in males and females. Using a well-established pSD mouse model, we harvested exocrine glands, and pulmonary and renal tissue from males and females and quantified the inflammation present. We then collected salivary glands, spleens, and cervical lymph nodes and performed flow cytometry to assess immune populations implicated in disease. We also harvested sera to examine total and autoreactive antibodies. Our data revealed that pSD mice displayed sex-biased disease, as pSD females showed decreased dacryoadenitis, but increased nephritis as compared to males. Moreover, females exhibited increased proportions of germinal center B cells and CD4+ activated/memory T cells in the periphery. Additionally, salivary gland immune populations were altered in a sex-dependent manner in pSD. Females with pSD also displayed elevated total and autoreactive IgG as compared to males. Additionally, splenic B cell Tlr7 expression was increased in females. We next generated pSD mice that lacked Tlr7 systemically and found that ablation of Tlr7 was primarily protective in pSD females, while Tlr7-deficient pSD males showed heightened disease. Thus, pSD mice display sex-biased disease and these dichotomous manifestations are governed by Tlr7 activation. This study identifies Tlr7 as a druggable target for pSD, and highlights the importance of studying pSD disease mechanisms in both sexes.

Abstract Background In recent years, the subspecialty of neuropalliative care has emerged with the goal of improving the quality of life of patients suffering from neurological disease, though gaps remain in neuropalliative care education and training. E-learning has been described as a way to deliver interactive and facilitated lower-cost learning to address global gaps in medical care. We describe here the development of a novel, international, hybrid, and asynchronous curriculum with both self-paced modules and class-based lectures on neuropalliative care topics designed for the neurologist interested in palliative care, the palliative care physician interested in caring for neurological patients, and any other physician or advanced care providers interested in neuropalliative care. Methods The course consisted of 12 modules, one per every four weeks, beginning July 2022. Each module is based on a case and relevant topics. Course content was divided into three streams (Neurology Basics, Palliative Care Basics, and Neuropalliative Care Essentials) of which two were optional and one was mandatory, and consisted of classroom sessions, webinars, and an in-person skills session. Evaluation of learners consisted of multiple choice questions and written assignments for each module. Evaluation of the course was based on semi-structured qualitative interviews conducted with both educator and learner, the latter of which will be published separately. Audio files were transcribed and underwent thematic analysis. For the discussion of the results, Khan’s e-learning framework was used. Results Ten of the 12 participating educators were interviewed. Of the educators, three identified as mid-career and seven as senior faculty, ranging from six to 33 years of experience. Nine of ten reported an academic affiliation and all reported association with a teaching hospital. Themes identified from the educators’ evaluations were: bridging the global gap, getting everybody on board, defining the educational scope, investing extensive hours of voluntary time and resources, benefiting within and beyond the curriculum, understanding the learner’s experience, creating a community of shared learning, adapting future teaching and learning strategies, and envisioning long term sustainability. Conclusions The first year of a novel, international, hybrid, and asynchronous neuropalliative care curriculum has been completed, and its educators have described both successes and avenues for improvement. Further research is planned to assess this curriculum from the learner perspective.

Abstract The modification of fertile stamens into sterile staminodes has occurred independently many times in the flowering plant lineage. In the genus Aquilegia (columbine) and its closest relatives, the two stamen whorls closest to the carpels have been converted to staminodes. In Aquilegia, the only genetic analyses of staminode development have been reverse genetic approaches revealing that B-class floral identity genes are involved. A. jonesii, the only species of columbine where staminodes have reverted to fertile stamens, allows us to explore the genetic architecture of staminode development using a forward genetic approach. We performed QTL analysis using an outcrossed F2 population between A. jonesii and a horticultural variety that makes fully developed staminodes, A. coerulea ‘Origami’. Our results reveal a polygenic basis for staminode loss where the two staminode whorls are under some level of independent control. We also discovered that staminode loss in A. jonesii is not complete, in which staminode-like traits sometimes occur in the inner fertile stamens, potentially representing a fading boundary of gene expression. The QTLs identified in this study provide a map to guide future reverse genetic and functional studies examining the genetic basis and evolutionary significance of this trait.

Abstract The full data set of the Daya Bay reactor neutrino experiment is used to probe the effect of the charged current non-standard interactions (CC-NSI) on neutrino oscillation experiments. Two different approaches are applied and constraints on the corresponding CC-NSI parameters are obtained with the neutrino flux taken from the Huber-Mueller model with a 5% uncertainty. For the quantum mechanics-based approach (QM-NSI), the constraints on the CC-NSI parameters ϵ eα and ϵ eα s $$ {\epsilon}_{e\alpha}^s $$ are extracted with and without the assumption that the effects of the new physics are the same in the production and detection processes, respectively. The approach based on the weak effective field theory (WEFT-NSI) deals with four types of CC-NSI represented by the parameters [ε X ] eα . For both approaches, the results for the CC-NSI parameters are shown for cases with various fixed values of the CC-NSI and the Dirac CP-violating phases, and when they are allowed to vary freely. We find that constraints on the QM-NSI parameters ϵ eα and ϵ eα s $$ {\epsilon}_{e\alpha}^s $$ from the Daya Bay experiment alone can reach the order O $$ \mathcal{O} $$ (0.01) for the former and O $$ \mathcal{O} $$ (0.1) for the latter, while for WEFT-NSI parameters [ε X ] eα , we obtain O $$ \mathcal{O} $$ (0.1) for both cases.

Women are disproportionately affected by symptoms of angina with nonobstructive coronary arteries (ANOCA) which is associated with significant mortality and economic impact. Although distinct endotypes of ANOCA have been defined, it is underdiagnosed and is often incompletely characterized when identified. Patients are often unresponsive to traditional therapeutic options, which are typically antianginal, and the current ability to guide treatment modification by specific pathways is limited. Studies have associated specific genetic loci, transcriptomic features, and biomarkers with ANOCA. Such panomic data, in combination with known imaging and invasive diagnostic techniques, should be utilized to define more precise pathophysiologic subtypes of ANOCA in women, which will in turn help to identify targeted, effective therapies. A precision medicine-based approach to managing ANOCA incorporating these techniques in women has the potential to significantly improve their clinical care.

Objectives: We recently introduced a frameless, navigated, robot-driven laser tool for depth electrode implantation as an alternative to frame-based procedures. This method has only been used in cadaver and non-recovery studies. This is the first study to test the robot-driven laser tool in an in vivo recovery animal study.Methods: A preoperative computed tomography (CT) scan was conducted to plan trajectories in sheep specimens. Burr hole craniotomies were performed using a frameless, navigated, robot-driven laser tool. Depth electrodes were implanted after cut-through detection was confirmed. The electrodes were cut at the skin level postoperatively. Postoperative imaging was performed to verify accuracy. Histopathological analysis was performed on the bone, dura, and cortex samples.Results: Fourteen depth electrodes were implanted in two sheep specimens. Anesthetic protocols did not show any intraoperative irregularities. One sheep was euthanized on the same day of the procedure while the other sheep remained alive for 1 week without neurological deficits. Postoperative MRI and CT showed no intracerebral bleeding, infarction, or unintended damage. The average bone thickness was 6.2 mm (range 4.1–8.0 mm). The angulation of the planned trajectories varied from 65.5° to 87.4°. The deviation of the entry point performed by the frameless laser beam ranged from 0.27 mm to 2.24 mm. The histopathological analysis did not reveal any damage associated with the laser beam.Conclusion: The novel robot-driven laser craniotomy tool showed promising results in this first in vivo recovery study. These findings indicate that laser craniotomies can be performed safely and that cut-through detection is reliable.

The karyotype of an organism is the set of gross features that characterize the way the genome is packaged into separate chromosomes. It has been known for decades that different taxonomic groups often have distinct karyotypic features, but whether selective forces act to maintain these differences over evolutionary timescales is an open question. In this paper we analyze a database of karyotype features and sperm head morphology in 103 mammal species with spatulate sperm heads and 90 sauropsid species (birds and non-avian reptiles) with vermiform heads. We find that mammal species with a larger head area have more chromosomes, while sauropsid species with longer heads have a wider range of chromosome lengths. These results remain significant after controlling for genome size, so sperm head morphology is the relevant variable. This suggest that post-copulatory sexual selection, by acting on sperm head shape, can influence genome architecture.

Abstract Dramatic improvements in measuring genetic variation across agriculturally relevant populations (genomics) must be matched by improvements in identifying and measuring relevant trait variation in such populations across many environments (phenomics). Identifying the most critical opportunities and challenges in genome to phenome (G2P) research is the focus of this paper. Previously (Genome Biol, 23(1):1–11, 2022), we laid out how Agricultural Genome to Phenome Initiative (AG2PI) will coordinate activities with USA federal government agencies expand public–private partnerships, and engage with external stakeholders to achieve a shared vision of future the AG2PI. Acting on this latter step, AG2PI organized the “Thinking Big: Visualizing the Future of AG2PI” two-day workshop held September 9–10, 2022, in Ames, Iowa, co-hosted with the United State Department of Agriculture’s National Institute of Food and Agriculture (USDA NIFA). During the meeting, attendees were asked to use their experience and curiosity to review the current status of agricultural genome to phenome (AG2P) work and envision the future of the AG2P field. The topic summaries composing this paper are distilled from two 1.5-h small group discussions. Challenges and solutions identified across multiple topics at the workshop were explored. We end our discussion with a vision for the future of agricultural progress, identifying two areas of innovation needed: (1) innovate in genetic improvement methods development and evaluation and (2) innovate in agricultural research processes to solve societal problems. To address these needs, we then provide six specific goals that we recommend be implemented immediately in support of advancing AG2P research.

Mitochondria provide cells with energy and regulate the cellular metabolism. Almost all mitochondrial proteins are nuclear-encoded, translated on ribosomes in the cytoplasm, and subsequently transferred to the different subcellular compartments of mitochondria. Here, we developed OptoMitoImport, an optogenetic tool to control the import of proteins into the mitochondrial matrix via the presequence pathway on demand. OptoMitoImport is based on a two-step process: first, light-induced cleavage by a TEV protease cuts off a plasma membrane-anchored fusion construct in close proximity to a mitochondrial targeting sequence; second, the mitochondrial targeting sequence preceding the protein of interest recruits to the outer mitochondrial membrane and imports the protein fused to it into mitochondria. Upon reaching the mitochondrial matrix, the matrix processing peptidase cuts off the mitochondrial targeting sequence and releases the protein of interest. OptoMitoImport is available as a two-plasmid system as well as a P2A peptide or IRES sequence-based bicistronic system. Fluorescence studies demonstrate the release of the plasma membrane-anchored protein of interest through light-induced TEV protease cleavage and its localization to mitochondria. Cell fractionation experiments confirm the presence of the peptidase-cleaved protein of interest in the mitochondrial fraction. The processed product is protected from proteinase K treatment. Depletion of the membrane potential across the inner mitochondria membrane prevents the mitochondrial protein import, indicating an import of the protein of interest by the presequence pathway. These data demonstrate the functionality of OptoMitoImport as a generic system with which to control the post-translational mitochondrial import of proteins via the presequence pathway.

The Module-0 Demonstrator is a single-phase 600 kg liquid argon time projection chamber operated as a prototype for the DUNE liquid argon near detector. Based on the ArgonCube design concept, Module-0 features a novel 80k-channel pixelated charge readout and advanced high-coverage photon detection system. In this paper, we present an analysis of an eight-day data set consisting of 25 million cosmic ray events collected in the spring of 2021. We use this sample to demonstrate the imaging performance of the charge and light readout systems as well as the signal correlations between the two. We also report argon purity and detector uniformity measurements and provide comparisons to detector simulations.

Abstract Apical extracellular matrices (aECMs) are complex extracellular compartments that form important interfaces between animals and their environment. In the adult C. elegans cuticle, layers are connected by regularly spaced columnar structures known as struts. Defects in struts result in swelling of the fluid-filled medial cuticle layer (‘blistering’, Bli). Here we show that three cuticle collagens BLI-1, BLI-2, and BLI-6, play key roles in struts. BLI-1 and BLI-2 are essential for strut formation whereas activating mutations in BLI-6 disrupt strut formation. BLI-1, BLI-2, and BLI-6 precisely colocalize to arrays of puncta in the adult cuticle, corresponding to struts, initially deposited in diffuse stripes adjacent to cuticle furrows. They eventually exhibit tube-like morphology, with the basal ends of BLI-containing struts contact regularly spaced holes in the cuticle. Genetic interaction studies indicate that BLI strut patterning involves interactions with other cuticle components. Our results reveal strut formation as a tractable example of precise aECM patterning at the nanoscale.

IntroductionHeart failure with preserved ejection fraction (HFpEF) is a complex disease process influenced by metabolic disorders, systemic inflammation, myocardial fibrosis, and microvascular dysfunction. The goal of our study is to identify potential relationships between plasma biomarkers and cardiac magnetic resonance (CMR) imaging markers in patients with HFpEF.MethodsNineteen subjects with HFpEF and 15 age-matched healthy controls were enrolled and underwent multiparametric CMR and plasma biomarker analysis using the Olink® Cardiometabolic Panel (Olink Proteomics, Uppsala, Sweden). Partial least squares discriminant analysis (PLS-DA) was used to characterize CMR and biomarker variables that differentiate the subject groups into two principal components. Orthogonal projection to latent structures by partial least squares (OPLS) analysis was used to identify biomarker patterns that correlate with myocardial perfusion reserve (MPR) and extracellular volume (ECV) mapping.ResultsA PLS-DA could differentiate between HFpEF and normal controls with two significant components explaining 79% (Q2 = 0.47) of the differences. For OPLS, there were 7 biomarkers that significantly correlated with ECV (R2 = 0.85, Q = 0.53) and 6 biomarkers that significantly correlated with MPR (R2 = 0.92, Q2 = 0.32). Only 1 biomarker significantly correlated with both ECV and MPR.DiscussionPatients with HFpEF have unique imaging and biomarker patterns that suggest mechanisms associated with metabolic disease, inflammation, fibrosis and microvascular dysfunction.

Abstract Background Roughly 40% of those with intellectual/developmental disabilities (IDD) have mental health needs, twice the national average. Unfortunately, outpatient mental health services are often inaccessible, increasing reliance on hospital-based services. While telemental health services hold potential to address this gap, little is known about the effectiveness of telemental health for the diversity of persons with IDD, especially as it relates to crisis prevention and intervention services. Accordingly, the aims of this study are to: (1) compare telemental health versus in-person crisis prevention and intervention services among people with IDD; and (2) understand if outcomes vary across subpopulations, in order to identify potential disparities. Methods This study will take place within START (Systemic, Therapeutic, Assessment, Resources, and Treatment), a national evidence-based model of mental health crisis prevention and intervention for people with IDD. A total of 500 youth and adults, located across nine states, will be randomized 1:1 to telemental health vs. in-person. Participant inclusion criteria are ages 12–45 years, living in a family setting, and newly enrolled (within 90 days) to START. Outcomes will be assessed, using a non-inferiority design, for up to 1 year or until discharge. The intervention is comprised of four components: (1) outreach; (2) consultation/coping skills; (3) intake/assessment; and, (4) 24-hour crisis response. The in-person condition will deliver all components in-person. The telemental health condition will deliver components 1 & 2, via telephonic or other communication technology, and components 3 & 4 in-person. Outcomes include mental health crisis contacts, mental health symptoms, emergency psychiatric service use, perceived quality of mental healthcare, and time to discharge. Discussion To our knowledge, this will be the first trial of a telemental health crisis program for the IDD population. The study will be executed by an interdisciplinary team of experts that includes persons with lived experience of disability. Understanding the benefits of specific telemental health methods has important implications to the design of interventions. This telemental health study offers promise to address disparities in access to mental health care for people with IDD across diverse racial, ethnic, linguistic, and cultural groups. Trial Registration Clinicaltrials.gov ( #NCT05336955 ; Registration Date: 4/20/2022).

Abstract Inter-relationships between pain sensitivity, drug reward, and drug misuse are of considerable interest given that many analgesics exhibit misuse potential. Here we studied rats as they underwent a series of pain- and reward-related tests: cutaneous thermal reflex pain, induction and extinction of conditioned place preference to oxycodone (0.56 mg/kg), and finally the impact of neuropathic pain on reflex pain and reinstatement of conditioned place preference. Oxycodone induced a significant conditioned place preference that extinguished throughout repeated testing. Correlations identified of particular interest included an association between reflex pain and oxycodone-induced behavioral sensitization, and between rates of behavioral sensitization and extinction of conditioned place preference. Multidimensional scaling analysis followed by k-clustering identified three clusters: (1) reflex pain, rate of behavioral sensitization and rate of extinction of conditioned place preference (2) basal locomotion, locomotor habituation, acute oxycodone-stimulated locomotion and rate of change in reflex pain during repeated testing, and (3) magnitude of conditioned place preference. Nerve constriction injury markedly enhanced reflex pain but did not reinstate conditioned place preference. These results suggest that high rates of behavioral sensitization predicts faster rates of extinction of oxycodone seeking/reward, and suggest that cutaneous thermal reflex pain may be predictive of both.

There are a large number of chemicals commercially available, but relatively few have legislated occupational exposure limits. Assessing the hazard and risk posed by most chemicals used in the workplace is therefore challenging, especially for small workplaces. This paper describes the development of an easy-to-use MS Excel spreadsheet-based tool (called CHAP-Risk) designed to assist small businesses to undertake a simple assessment of the health and safety risks posed by the chemicals they use. We developed the CHAP-Risk tool through engaging an expert review panel and undertaking a detailed review of existing tools, and by validating a trial version which was piloted by six workplaces and 59 workers. We received multiple rounds of feedback from key experts and end-users, and in response, through 58 versions, refined CHAP-Risk to produce the final free public-release version of the tool. Workplace participants thought that the CHAP-Risk tool would be useful in improving worker and employers’ understanding of workplace chemical risks. However, because this tool required users to have more in-depth knowledge of workplaces’ processes, there was mixed feedback on its usability: those with OHS training were very positive, while others thought it would be too difficult for shop-floor workers to use.

Currently, West-Nile virus (WNV) is spreading worldwide to colder regions due to climate change. Human mortality and morbidity are prevalent and steadily increasing, associated with costs to public health systems. Therefore, the question of the impact of scientific engagement arises. What trends, barriers, and incentives for research related to global burdens are important in this context? To answer these questions, this study provides detailed insights into the publication patterns of WNV research and interprets them using several parameters, such as absolute and relative publication indices and socioeconomic and epidemiological characteristics. It is shown that national interests combined with regional outbreaks significantly influence publication intensity. Thus, a correlation between national publication volume and the number of WNV cases was observed. In contrast to most life science topics, the scientific interest in WNV significantly decreased after 2006. The USA, as the main actor in WNV research, is at the centre of international networking. Recently, European countries are also getting involved according to their new-emerging outbreaks. The results demonstrate national interest in research activities with a lack of globally focused approaches that are urgently needed to better understand and assess the distribution and characteristics of WNV.HighlightsThere is a correlation between national WNV cases and the number of publications.The declining trend in WNV research does not correspond to the growing prevalence.USA as most-publishing country is also at the centre of networking WNV research.France is the primary network partner for African and Middle Eastern countries.

PurposePeople with developmental disabilities and mental health service experiences have a right to be included in healthcare decisions, including the evaluation of their mental health services and providers. However, few self-report measures address this need. This study aimed to fill this gap by developing and evaluating the content validity, including comprehension, relevance, and comprehensiveness, of the Person Experiences Interview Survey (PEIS) with people with developmental disabilities and mental health experiences.MethodsThe research team established a measurement framework based on the Family Experiences Interview Survey (FEIS), resulting in 21 PEIS items that were written in collaboration with young adults with developmental disabilities and mental health service experiences. Comprehension, relevance, and comprehensiveness were evaluated through cognitive interviews with people with developmental disabilities and mental health service experiences (respondents; n = 9) ages 23–49 years. Comprehensiveness and relevance were also evaluated in focus groups with family caregivers (n = 9) and mental health providers (n = 10) who serve this population. Two researchers independently coded open-ended responses to the PEIS for comprehension. A content validity index (CVI), indicating relevance, was calculated for each participant group for each item, and comprehensiveness was rated for item sets.ResultsFifteen of the 21 items met the criteria of ≥80% comprehension, with 89–100% of responses containing all or some intended information. All items met the CVI ≥80% criterion in at least two of the three groups. In all item sets, between 1 and 4 family members or providers felt one question was missing. Respondents used the response scale in a manner that corresponded with their open-ended descriptions, and family caregivers and providers had positive feedback about the response scale’s visual cues and number of choices. Using these findings, four items were removed and six items were revised, resulting in a 17-item measure.ConclusionThis study presents a novel and promising measure, the Person Experiences Interview Survey (PEIS). It also demonstrates that the employment of accessible methods allows people with developmental disabilities to meaningfully evaluate mental health services and providers. The PEIS shows great promise for application in the field by engaging those directly involved in the evaluation of mental health services and providers.

BackgroundLate gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) imaging is the gold standard for non-invasive myocardial tissue characterisation. However, accurate segmentation of the left ventricular (LV) myocardium remains a challenge due to limited training data and lack of quality control. This study addresses these issues by leveraging generative adversarial networks (GAN)-generated virtual native enhancement (VNE) images to expand the training set and incorporating an automated quality control-driven (QCD) framework to improve segmentation reliability.MethodsA dataset comprising 4,716 LGE images (from 1,363 patients with hypertrophic cardiomyopathy and myocardial infarction) was used for development. To generate additional clinically validated data, LGE data were augmented with a GAN-based generator to produce VNE images. LV was contoured on these images manually by clinical observers. To create diverse candidate segmentations, the QCD framework involved multiple U-Nets, which were combined using statistical rank filters. The framework predicted the Dice Similarity Coefficient (DSC) for each candidate segmentation, with the highest predicted DSC indicating the most accurate and reliable result. The performance of the QCD ensemble framework was evaluated on both LGE and VNE test datasets (309 LGE/VNE images from 103 patients), assessing segmentation accuracy (DSC) and quality prediction (mean absolute error (MAE) and binary classification accuracy).ResultsThe QCD framework effectively and rapidly segmented the LV myocardium (

Heart failure (HF) is a clinical syndrome with a wide variety of clinical presentations, pathophysiologies, and natural histories. HF is becoming more prevalent globally, thus increasing effects on healthcare systems. Cardiac magnetic resonance (CMR) imaging is a valuable tool for better understanding HF and its prognosis. The commonly used reference standard of CMR cine imaging provides accurate assessment of chamber size and function. Phase contrast imaging can be used to assess the degree of valvular regurgitation and complex flow patterns. Stress perfusion imaging can detect subtle areas of ischemia and microvascular dysfunction. Late gadolinium enhancement imaging aids in diagnosing causes of HF and guiding revascularization in ischemic cardiomyopathy. Supported by histological validation, T1 and T2 mapping provides non-invasive information on tissue characteristics in inflammatory and infiltrative cardiomyopathies. CMR also provides various techniques to measure strain in the atria and ventricles at high spatial and temporal resolution. CMR continues to serve as an important modality for the evaluation of HF.

With the recent exception of coronavirus disease 2019 (COVID-19), tuberculosis (TB) causes more deaths globally than any other infectious disease, and approximately 1/3 of the world's population is infected with Mycobacterium tuberculosis (Mtb). However, encouraging progress in TB vaccine development has been reported, with approximately 50% efficacy achieved in Phase 2b clinical testing of an adjuvanted subunit TB vaccine candidate. Nevertheless, current lead vaccine candidates require cold-chain transportation and storage. In addition to temperature stress, vaccines may be subject to several other stresses during storage and transport, including mechanical, photochemical, and oxidative stresses. Optimal formulations should enable vaccine configurations with enhanced stability and decreased sensitivity to physical and chemical stresses, thus reducing reliance on the cold chain and facilitating easier worldwide distribution. In this report, we describe the physicochemical stability performance of three lead thermostable formulations of the ID93 + GLA-SE TB vaccine candidate under various stress conditions. Moreover, we evaluate the impact of thermal stress on the protective efficacy of the vaccine formulations. We find that formulation composition impacts stressed stability performance, and our comprehensive evaluation enables selection of a lead single-vial lyophilized candidate containing the excipient trehalose and Tris buffer for advanced development.

Abstract Breast cancer is one of leading causes of death worldwide in the female population. Deaths from breast cancer could be reduced significantly through earlier and more efficient detection of the disease. Saliva, an oral fluid that contains an abundance of protein biomarkers, has been recognized as a promising diagnostic biofluid that is easy to isolate through non-invasive techniques. Assays on saliva can be performed rapidly and are cost-effective. Therefore, our work aimed to identify salivary biomarkers present in the initial stages of breast cancer, where cell alterations are not yet detectable by histopathological analysis. Using state-of-the-art techniques, we employed a transgenic mouse model of mammary cancer to identify molecular changes in precancerous stage breast cancer through protein analysis in saliva. Through corroborative molecular approaches, we established that proteins related to metabolic changes, inflammatory process and cell matrix degradation are detected in saliva at the onset of tumor development. Our work demonstrated that salivary protein profiles can be used to identify cellular changes associated with precancerous stage breast cancer through non-invasive means even prior to biopsy-evident disease.

The Australian, Chinese, European, Indian, and North American pulsar timing array (PTA) collaborations recently reported, at varying levels, evidence for the presence of a nanohertz gravitational-wave background (GWB). Given that each PTA made different choices in modeling their data, we perform a comparison of the GWB and individual pulsar noise parameters across the results reported from the PTAs that constitute the International Pulsar Timing Array (IPTA). We show that despite making different modeling choices, there is no significant difference in the GWB parameters that are measured by the different PTAs, agreeing within 1 σ . The pulsar noise parameters are also consistent between different PTAs for the majority of the pulsars included in these analyses. We bridge the differences in modeling choices by adopting a standardized noise model for all pulsars and PTAs, finding that under this model there is a reduction in the tension in the pulsar noise parameters. As part of this reanalysis, we “extended” each PTA’s data set by adding extra pulsars that were not timed by that PTA. Under these extensions, we find better constraints on the GWB amplitude and a higher signal-to-noise ratio for the Hellings–Downs correlations. These extensions serve as a prelude to the benefits offered by a full combination of data across all pulsars in the IPTA, i.e., the IPTA’s Data Release 3, which will involve not just adding in additional pulsars but also including data from all three PTAs where any given pulsar is timed by more than a single PTA.

Millisecond pulsars are subject to accelerations in globular clusters (GCs) that manifest themselves in both the first and second spin period time derivatives, and can be used to explore the mass distribution of the potentials they inhabit. Here we report on over 20 yr of pulsar timing observations of five millisecond radio pulsars in the core of the core-collapse GC NGC 6752 with the Parkes (Murriyang) and MeerKAT radio telescopes, which have allowed us to measure the proper motions, positions, and first and second time derivatives of the pulsars. The pulsar timing parameters indicate that all the pulsars in the core experience accelerations and jerks that can be explained only if an amount of nonluminous mass of at least 2.56 × 10 ^3 M _⊙ is present in the core of NGC 6752. On the other hand, our studies highly disfavor the presence of an intermediate-mass black hole at the center of the cluster, with a mass equal to or greater than ∼3000 M _⊙ .

Abstract Background In medical residency, performance observations are considered an important strategy to monitor competence development, provide feedback and warrant patient safety. The aim of this study was to gain insight into whether and how supervisor-resident dyads build a working repertoire regarding the use of observations, and how they discuss and align goals and approaches to observation in particular. Methods We used a qualitative, social constructivist approach to explore if and how supervisory dyads work towards alignment of goals and preferred approaches to performance observations. We conducted semi-structured interviews with supervisor-resident dyads, performing a template analysis of the data thus obtained. Results The supervisory dyads did not frequently communicate about the use of observations, except at the start of training and unless they were triggered by internal or external factors. Their working repertoire regarding the use of observations seemed to be primarily driven by patient safety goals and institutional assessment requirements rather than by providing developmental feedback. Although intended as formative, the institutional test was perceived as summative by supervisors and residents, and led to teaching to the test rather than educating for purposes of competence development. Conclusions To unlock the full educational potential of performance observations, and to foster the development of an educational alliance, it is essential that supervisory dyads and the training institute communicate clearly about these observations and the role of assessment practices of- and for learning, in order to align their goals and respective approaches.

Background Cardiac metabolic abnormalities are present in heart failure. Few studies have followed metabolic changes accompanying diastolic and systolic heart failure in the same model. We examined metabolic changes during the development of diastolic and severe systolic dysfunction in spontaneously hypertensive rats (SHR). Methods and Results We serially measured myocardial glucose uptake rates with dynamic 2‐[18F] fluoro‐2‐deoxy‐d‐glucose positron emission tomography in vivo in 9‐, 12‐, and 18‐month‐old SHR and Wistar Kyoto rats. Cardiac magnetic resonance imaging determined systolic function (ejection fraction) and diastolic function (isovolumetric relaxation time) and left ventricular mass in the same rats. Cardiac metabolomics was performed at 12 and 18 months in separate rats. At 12 months, SHR hearts, compared with Wistar Kyoto hearts, demonstrated increased isovolumetric relaxation time and slightly reduced ejection fraction indicating diastolic and mild systolic dysfunction, respectively, and higher (versus 9‐month‐old SHR decreasing) 2‐[18F] fluoro‐2‐deoxy‐d‐glucose uptake rates (Ki). At 18 months, only few SHR hearts maintained similar abnormalities as 12‐month‐old SHR, while most exhibited severe systolic dysfunction, worsening diastolic function, and markedly reduced 2‐[18F] fluoro‐2‐deoxy‐d‐glucose uptake rates. Left ventricular mass normalized to body weight was elevated in SHR, more pronounced with severe systolic dysfunction. Cardiac metabolite changes differed between SHR hearts at 12 and 18 months, indicating progressive defects in fatty acid, glucose, branched chain amino acid, and ketone body metabolism. Conclusions Diastolic and severe systolic dysfunction in SHR are associated with decreasing cardiac glucose uptake, and progressive abnormalities in metabolite profiles. Whether and which metabolic changes trigger progressive heart failure needs to be established.

Many autoimmune diseases show a striking female sex predilection, including primary Sjögren's disease (pSD). Patients with pSD display exocrine gland pathology, such as salivary hypofunction and salivary and lacrimal gland inflammation. Moreover, many serious systemic disease manifestations are well-documented, including interstitial nephritis, hypergammaglobulinemia and neuropathies. Of note, women and men with pSD display distinct clinical phenotypes. While the underlying reasons for these clinical observations were poorly understood for many years, recent studies provide mechanistic insights into the specific regulatory landscapes that mediate female susceptibility to autoimmunity. We will review factors that contribute to the female sex bias, with an emphasis on those that are most relevant to pSD pathogenesis. Specifically, we will focus on sex hormones in disease, genetic alterations that likely contribute to the significant disease prevalence in females, and studies that provide evidence for the role of the gut microbiota in disease. Lastly, we will discuss therapeutics that are in clinical trials for pSD that may be particularly efficacious in targeting signaling networks that mediate inflammation in a sex-specific manner.

Abstract Background Lapses in professionalism have profound negative effects on patients, health professionals, and society. The connection between unprofessional behaviour during training and later practice requires timely identification and remediation. However, appropriate language to describe unprofessional behaviour and its remediation during residency is lacking. Therefore, this exploratory study aims to investigate which behaviours of GP residents are considered unprofessional according to supervisors and faculty, and how remediation is applied. Methods We conducted eight semi-structured focus group interviews with 55 broadly selected supervisors from four Dutch GP training institutes. In addition, we conducted individual semi-structured interviews with eight designated professionalism faculty members. Interview recordings were transcribed verbatim. Data were coded in two consecutive steps: preliminary inductive coding was followed by secondary deductive coding using the descriptors from the recently developed ‘Four I’s’ model for describing unprofessional behaviours as sensitising concepts. Results Despite the differences in participants’ professional positions, we identified a shared conceptualisation in pinpointing and assessing unprofessional behaviour. Both groups described multiple unprofessional behaviours, which could be successfully mapped to the descriptors and categories of the Four I’s model. Behaviours in the categories ‘Involvement’ and ‘Interaction’ were assessed as mild and received informal, pedagogical feedback. Behaviours in the categories ‘Introspection’ and ‘Integrity’, were seen as very alarming and received strict remediation. We identified two new groups of behaviours; ‘Nervous exhaustion complaints’ and ‘Nine-to-five mentality’, needing to be added to the Four I’s model. The diagnostic phase of unprofessional behaviour usually started with the supervisor getting a ‘sense of alarm’, which was described as either a ‘gut feeling’, ‘a loss of enthusiasm for teaching’ or ‘fuss surrounding the resident’. This sense of alarm triggered the remediation phase. However, the diagnostic and remediation phases did not appear consecutive or distinct, but rather intertwined. Conclusions The processes of identification and remediation of unprofessional behaviour in residents appeared to be intertwined. Identification of behaviours related to lack of introspection or integrity were perceived as the most important to remediate. The results of this research provide supervisors and faculty with an appropriate language to describe unprofessional behaviours among residents, which can facilitate timely identification and remediation.

Summary: WDR5 is a broadly studied, highly conserved key protein involved in a wide array of biological functions. Among these functions, WDR5 is a part of several protein complexes that affect gene regulation via post-translational modification of histones. We collected data from 11 unrelated individuals with six different rare de novo germline missense variants in WDR5; one identical variant was found in five individuals and another variant in two individuals. All individuals had neurodevelopmental disorders including speech/language delays (n = 11), intellectual disability (n = 9), epilepsy (n = 7), and autism spectrum disorder (n = 4). Additional phenotypic features included abnormal growth parameters (n = 7), heart anomalies (n = 2), and hearing loss (n = 2). Three-dimensional protein structures indicate that all the residues affected by these variants are located at the surface of one side of the WDR5 protein. It is predicted that five out of the six amino acid substitutions disrupt interactions of WDR5 with RbBP5 and/or KMT2A/C, as part of the COMPASS (complex proteins associated with Set1) family complexes. Our experimental approaches in Drosophila melanogaster and human cell lines show normal protein expression, localization, and protein-protein interactions for all tested variants. These results, together with the clustering of variants in a specific region of WDR5 and the absence of truncating variants so far, suggest that dominant-negative or gain-of-function mechanisms might be at play. All in all, we define a neurodevelopmental disorder associated with missense variants in WDR5 and a broad range of features. This finding highlights the important role of genes encoding COMPASS family proteins in neurodevelopmental disorders.

PSR J2140−2311B is a 13 ms pulsar discovered in 2001 in a 7.8 hr Green Bank Telescope observation of the core-collapsed globular cluster M30 and predicted to be in a highly eccentric binary orbit. This pulsar has eluded detection since then; therefore, its precise orbital parameters have remained a mystery until now. In this work, we present the confirmation of this pulsar using observations taken with the UHF receivers of the MeerKAT telescope as part of the TRAPUM Large Survey Project. Taking advantage of the beamforming capability of our backends, we have localized it, placing it 1.′2(1) from the cluster center. Our observations have enabled the determination of its orbit: It is highly eccentric ( e = 0.879) with an orbital period of 6.2 days. We also measured the rate of periastron advance, $\dot{\omega }=0.078\pm 0.002\,\deg \,{\mathrm{yr}}^{-1}$ . Assuming that this effect is fully relativistic, general relativity provides an estimate of the total mass of the system, M _TOT = 2.53 ± 0.08 M _⊙ , consistent with the lightest double neutron star systems known. Combining this with the mass function of the system gives the pulsar and companion masses of m _p < 1.43 M _⊙ and m _c > 1.10 M _⊙ , respectively. The massive, undetected companion could either be a massive white dwarf or a neutron star. M30B likely formed as a result of a secondary exchange encounter. Future timing observations will allow the determination of a phase-coherent timing solution, vastly improving our uncertainty in $\dot{\omega }$ and likely enabling the detection of additional relativistic effects, which will determine m _p and m _c .

Machine learning (ML) refers to computational algorithms that iteratively improve their ability to recognize patterns in data. The digitization of our healthcare infrastructure is generating an abundance of data from electronic health records, imaging, wearables, and sensors that can be analyzed by ML algorithms to generate personalized risk assessments and promote guideline-directed medical management. ML's strength in generating insights from complex medical data to guide clinical decisions must be balanced with the potential to adversely affect patient privacy, safety, health equity, and clinical interpretability. This review provides a primer on key advances in ML for cardiovascular disease prevention and how they may impact clinical practice.

Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease characterized by chronic inflammation of exocrine tissue, resulting in loss of tears and saliva. Patients also experience many extra-glandular disease manifestations. Treatment for pSS is palliative, and there are currently no treatments available that target disease etiology. Previous studies in our lab demonstrated that MyD88 is crucial for pSS pathogenesis in the NOD.B10Sn-H2b (NOD.B10) pSS mouse model, although the way in which MyD88-dependent pathways become activated in disease remains unknown. Based on its importance in other autoimmune diseases, we hypothesized that TLR7 activation accelerates pSS pathogenesis. We administered the TLR7 agonist Imiquimod (Imq) or sham treatment to pre-disease NOD.B10 females for 6 weeks. Parallel experiments were performed in age and sex-matched C57BL/10 controls. Imq-treated pSS animals exhibited cervical lymphadenopathy, splenomegaly, and expansion of TLR7-expressing B cells. Robust lymphocytic infiltration of exocrine tissues, kidney and lung was observed in pSS mice following treatment with Imq. TLR7 agonism also induced salivary hypofunction in pSS mice, which is a hallmark of disease. Anti-nuclear autoantibodies, including Ro (SSA) and La (SSB) were increased in pSS mice following Imq administration. Cervical lymph nodes from Imq-treated NOD.B10 animals demonstrated an increase in the percentage of activated/memory CD4+ T cells. Finally, T-bet+ B cells were expanded in the spleens of Imq-treated pSS mice. Thus, activation of TLR7 accelerates local and systemic disease and promotes expansion of T-bet-expressing B cells in pSS.

Hypertrophic cardiomyopathy is the most common genetic heart disease. Biomarkers, molecules measurable in the blood, could inform the clinician by aiding in diagnosis, directing treatment, and predicting outcomes. We present an updated review of circulating biomarkers in hypertrophic cardiomyopathy representing key pathologic processes including wall stretch, myocardial necrosis, fibrosis, inflammation, hypertrophy, and endothelial dysfunction, in addition to their clinical significance.

Polymorphonuclear cells (PMNs) control Streptococcus pneumoniae (pneumococcus) infection through various antimicrobial activities. We previously found that reactive oxygen species (ROS) were required for optimal antibacterial function, however, the NADPH oxidase is known to be dispensable for the ability of PMNs to kill pneumococci. In this study, we explored the role of ROS produced by the mitochondria in PMN antimicrobial defense against pneumococci. We found that the mitochondria are an important source of overall intracellular ROS produced by murine PMNs in response to infection. We investigated the host and bacterial factors involved and found that mitochondrial ROS (MitROS) are produced independent of bacterial capsule or pneumolysin but presence of live bacteria that are in direct contact with PMNs enhanced the response. We further found that MyD88-/- PMNs produced less MitROS in response to pneumococcal infection suggesting that released bacterial products acting as TLR ligands are sufficient for inducing MitROS production in PMNs. To test the role of MitROS in PMN function, we used an opsonophagocytic killing assay and found that MitROS were required for the ability of PMNs to kill pneumococci. We then investigated the role of MitROS in host resistance and found that MitROS are produced by PMNs in response to pneumococcal infection. Importantly, treatment of mice with a MitROS scavenger prior to systemic challenge resulted in reduced survival of infected hosts. In exploring host pathways that control MitROS, we focused on extracellular adenosine, which is known to control PMN anti-pneumococcal activity, and found that signaling through the A2B adenosine receptor inhibits MitROS production by PMNs. A2BR-/- mice produced more MitROS and were significantly more resistant to infection. Finally, we verified the clinical relevance of our findings using human PMNs. In summary, we identified a novel pathway that controls MitROS production by PMNs, shaping host resistance against S. pneumoniae.

BackgroundMechanisms of sex-based differences in outcomes following cardiac resynchronization therapy (CRT) are poorly understood.ObjectiveTo use cardiac magnetic resonance (CMR) to define mechanisms of sex-based differences in outcomes after CRT and describe distinct CMR-based phenotypes of CRT candidates based on sex and non-ischemic/ischemic cardiomyopathy type.Materials and methodsIn a prospective study, sex-based differences in three short-term CRT response measures [fractional change in left ventricular end-systolic volume index 6 months after CRT (LVESVI-FC), B-type natriuretic peptide (BNP) 6 months after CRT, change in peak VO2 6 months after CRT], and long-term survival were evaluated with respect to 39 baseline parameters from CMR, exercise testing, laboratory testing, electrocardiograms, comorbid conditions, and other sources. CMR was also used to quantify the degree of left-ventricular mechanical dyssynchrony by deriving the circumferential uniformity ratio estimate (CURE-SVD) parameter from displacement encoding with stimulated echoes (DENSE) strain imaging. Statistical methods included multivariable linear regression with evaluation of interaction effects associated with sex and cardiomyopathy type (ischemic and non-ischemic cardiomyopathy) and survival analysis.ResultsAmong 200 patients, the 54 female patients (27%) pre-CRT had a smaller CMR-based LVEDVI (p = 0.04), more mechanical dyssynchrony based on the validated CMR CURE-SVD parameter (p = 0.04), a lower frequency of both late gadolinium enhancement (LGE) and ischemic cardiomyopathy (p < 0.0001), a greater RVEF (p = 0.02), and a greater frequency of LBBB (p = 0.01). After categorization of patients into four groups based on cardiomyopathy type (ischemic/non-ischemic cardiomyopathy) and sex, female patients with non-ischemic cardiomyopathy had the lowest CURE-SVD (p = 0.003), the lowest pre-CRT BNP levels (p = 0.01), the lowest post-CRT BNP levels (p = 0.05), and the most favorable LVESVI-FC (p = 0.001). Overall, female patients had better 3-year survival before adjustment for cardiomyopathy type (p = 0.007, HR = 0.45) and after adjustment for cardiomyopathy type (p = 0.009, HR = 0.67).ConclusionCMR identifies distinct phenotypes of female CRT patients with non-ischemic and ischemic cardiomyopathy relative to male patients stratified by cardiomyopathy type. The more favorable short-term response and long-term survival outcomes in female heart failure patients with CRT were associated with lower indexed CMR-based LV volumes, decreased presence of scar associated with prior myocardial infarction and ICM, and greater CMR-based dyssynchrony with the CURE-SVD.

Background: Vagus nerve stimulation (VNS) has gained great importance as a promising therapy for a myriad of diseases. Of particular interest is the therapy of cardiovascular diseases, such as heart failure or atrial fibrillation using selective cardiac VNS. However, there is still a lack of organ-specific anatomical knowledge about the fascicular anatomy and topography of the cardiac branch (CB), which diminishes the therapeutic possibilities for selective cardiac neuromodulation. Here, we established a topographical and anatomical map of the superior cardiac VN in two animal species to dissect cervical and cardiac VN morphology.Methods: Autonomic nerves including superior CBs were harvested from domestic pigs and New Zeeland rabbits followed by imaging with microcomputed tomography (µCT) and 3D rendering. The data were analyzed in terms of relevant topographical and anatomical parameters.Results: Our data showed that cardiac vagal fascicles remained separated from other VN fascicles up to 22.19 mm (IQR 14.02–41.30 mm) in pigs and 7.68 mm (IQR 4.06–12.77 mm) in rabbits from the CB point and then started merging with other fascicles. Exchanges of nerve fascicles between sympathetic trunk (ST) and VN were observed in 3 out of 11 nerves, which might cause additional unwanted effects in unselective VNS. Our 3D rendered digital model of the cardiac fascicles was generated showing that CB first remained on the medial side where it branched off the VN, as also shown in the µCT data of 11 pig nerves, and then migrated towards the ventromedial site the further it was traced cranially.Conclusion: Our data provided an anatomical map of the cardiac vagal branches including cervical VN and ST for future approaches of selective cardiac neurostimulation, indicating the best position of selective cardiac VNS just above the CB point.

Pre-meiotic anthers of monocots accumulate phased, small interfering RNAs (phasiRNAs) that are absent in many well-studied model eudicots. Here, the authors show that such 21-nt phasiRNAs are in fact present in diverse eudicot species including strawberry, in which production is triggered by miR11308.

Invasive species can have severe impacts on ecosystems, economies, and human health. Though the economic impacts of invasions provide important foundations for management and policy, up-to-date syntheses of these impacts are lacking. To produce the most comprehensive estimate of invasive species costs within North America (including the Greater Antilles) to date, we synthesized economic impact data from the recently published InvaCost database. Here, we report that invasions have cost the North American economy at least US$ 1.26 trillion between 1960 and 2017. Economic costs have climbed over recent decades, averaging US$ 2 billion per year in the early 1960s to over US$ 26 billion per year in the 2010s. Of the countries within North America, the United States (US) had the highest recorded costs, even after controlling for research effort within each country ($5.81 billion per cost source in the US). Of the taxa and habitats that could be classified in our database, invasive vertebrates were associated with the greatest costs, with terrestrial habitats incurring the highest monetary impacts. In particular, invasive species cumulatively (from 1960–2017) cost the agriculture and forestry sectors US$ 527.07 billion and US$ 34.93 billion, respectively. Reporting issues (e.g., data quality or taxonomic granularity) prevented us from synthesizing data from all available studies. Furthermore, very few of the known invasive species in North America had reported economic costs. Therefore, while the costs to the North American economy are massive, our US$ 1.26 trillion estimate is likely very conservative. Accordingly, expanded and more rigorous economic cost reports are necessary to provide more comprehensive invasion impact estimates, and then support data-based management decisions and actions towards species invasions.

Estimating velocities in gas liquid flows is of importance in many engineering applications. Hohermuth et al. show that previous bubble velocities obtained from intrusive probes have been underestimated and provide a correction scheme for more accurate velocity measurements.

Abstract Background Resistance and tolerance are two coexisting defense strategies for fighting infections. Resistance is mediated by signaling pathways that induce transcriptional activation of resistance factors that directly eliminate the pathogen. Tolerance refers to adaptations that limit the health impact of a given pathogen burden, without targeting the infectious agent. The key players governing immune tolerance are largely unknown. In Drosophila, the histone H3 lysine 9 (H3K9) methyltransferase G9a was shown to mediate tolerance to virus infection and oxidative stress (OS), suggesting that abiotic stresses like OS may also evoke tolerance mechanisms. In response to both virus and OS, stress resistance genes were overinduced in Drosophila G9a mutants, suggesting an intact but overactive stress response. We recently demonstrated that G9a promotes tolerance to OS by maintaining metabolic homeostasis and safeguarding energy availability, but it remained unclear if this mechanism also applies to viral infection, or is conserved in other species and stress responses. To address these questions, we analyzed publicly available datasets from Drosophila, mouse, and human in which global gene expression levels were measured in G9a-depleted conditions and controls at different time points upon stress exposure. Results In all investigated datasets, G9a attenuates the transcriptional stress responses that confer resistance against the encountered stressor. Comparative analysis of conserved G9a-dependent stress response genes suggests that G9a is an intimate part of the design principles of stress resistance, buffering the induction of promiscuous stress signaling pathways and stress-specific resistance factors. Importantly, we find stress-dependent downregulation of metabolic genes to also be dependent on G9a across all of the tested datasets. Conclusions These results suggest that G9a sets the balance between activation of resistance genes and maintaining metabolic homeostasis, thereby ensuring optimal organismal performance during exposure to diverse types of stress across different species. We therefore propose G9a as a potentially conserved master regulator underlying the widely important, yet poorly understood, concept of stress tolerance.