Search

SUMMARYThrombopoietin (TPO) and its receptor MPL play crucial roles in hematopoietic stem cell (HSC) function and platelet production. However, the precise effects of TPO/MPL signaling on HSC regulation in different hematopoietic niches remain unclear. Here, we investigated the effects of TPO/MPL ablation on marrow and splenic hematopoiesis in TPO-/-and MPL-/-mice during aging. Despite severe thrombocytopenia, TPO-/-and MPL-/-mice did not develop marrow failure during a 2-year follow-up. Marrow and splenic HSCs exhibited different responses to TPO/MPL ablation and exogenous TPO treatment. Splenic niche cells compensated for marrow HSC loss in TPO-/-and MPL-/-mice by upregulating CXCL12 levels. These findings provide new insights into the complex regulation of HSCs by TPO/MPL and reveal a previously unknown link between TPO and CXCL12, two key growth factors for HSC maintenance. Understanding the distinct regulatory mechanisms between marrow and spleen hematopoiesis will help develop novel therapeutic approaches for hematopoietic disorders.

Acute myeloid leukemia (AML) is an aggressive disease with poor outcomes, overwhelmingly due to relapse. Minimal residual disease (MRD), defined as the persistence of leukemic cells after chemotherapy treatment, is thought to be the major cause of relapse. The origins of relapse in AML have been traced to rare therapy-resistant leukemic stem cells (LSCs) that are already present at diagnosis. Effective treatment strategies for long-term remission are lacking, as it has been difficult to eliminate LSCs with conventional therapy. Here, we proposed a new approach based on the chimeric antigen receptor (CAR)-directed T lymphocytes, targeting T-cell immunoglobulin, and mucin domain 3 (TIM-3) to treat MRD in patients with AML. TIM-3 is selected as the target because it is highly expressed on AML blasts and LSCs in most subtypes regardless of the patient's genetic characteristics and treatment course. Moreover, it is absent in the normal hematopoietic stem cells, granulocytes, naïve lymphocytes, and most normal nonhematopoietic tissues. Using a naïve human Fab phage display library, we isolated an anti-human TIM-3 antibody and designed a second-generation anti–TIM-3. Our anti–TIM-3 CAR T cells exhibit potent antileukemic activity against AML cell lines and primary AML blasts, and in the mouse models. More importantly, we demonstrate efficient killing of the primary LSCs directly isolated from the patients. Hence, eradication of the LSCs present in the MRD by anti–TIM-3 CAR T-cell therapy following the first-line treatment may improve the clinical outcomes of patients with AML.

Supplementary figures and methods.

Supplementary Figure 1 from ERG Is a Megakaryocytic Oncogene

Supplementary Figure Legends 1-5 from ERG Is a Megakaryocytic Oncogene

Supplementary Figure 3 from ERG Is a Megakaryocytic Oncogene

Supplementary Figure 2 from ERG Is a Megakaryocytic Oncogene

Supplementary Methods from ERG Is a Megakaryocytic Oncogene

Supplementary Figure 5 from ERG Is a Megakaryocytic Oncogene

ANCA-associated vasculitis is a disease with high morbidity and mortality which has shown to have different phenotypes in different ethnic and racial groups. This disease has been most frequently studied in Caucasians. We studied a group in Southern California where the Hispanics make up half of the population. We believe there will be different phenotypes between the two.A retrospective study of 114 patients was conducted at two tertiary care centers between 2003 and 2019. Demographic data, ICU admission, ANCA antibody status, BVAS on presentation, VDI per the last clinic visit, the number of hospitalizations, the number of follow-up years, and treatment were recorded. We calculated odds ratios for the categorical data and ran independent sample T test for the continuous data with alpha equal to 0.05 for statistical significance.Difference was found in antibody status, disease presentation, morbidity, and age at diagnosis. Hispanics had greater number of AAV flares despite BVAS and VDI being comparable. Caucasians had more frequent follow-up. Hispanics had a 4.39 increase in odds of being admitted to the ICU, a 1.33 increased odds of developing acute respiratory failure, and a 67% increased odds of developing hemoptysis or pulmonary alveolar hemorrhage. Further, Hispanics had a 1.22 increase in odds of having ESRD.Clinicians treating Hispanic patients with AAV should have a high index of suspicion for severe disease in this patient population. Further, epidemiologic and disparities research should be conducted to evaluate the discrepancy in outcomes in these groups. Key Points • This is the first study to examine the phenotype and severity of ANCA associated vasculitis in Southern California, a population which is comprised largely of Hispanics. • Hispanics in this population were found to be more likely to be admitted to the ICU, have more flares, reach end-stage renal disease, have severe pulmonary manifestations, and had fewer outpatient follow-up visits than their Caucasian counterparts. • Clinicians should have a high suspicion for more severe disease in Hispanics in this region when compared to Caucasians. • More research is needed to assess the degree social determinants of health contribute to these findings and if progress can be made with decreasing health disparities between these populations in this disease.

Acute myeloid leukemia (AML) is an aggressive disease with poor outcomes, overwhelmingly due to relapse. Minimal residual disease (MRD), defined as the persistence of leukemic cells after chemotherapy treatment, is thought to be the major cause of relapse. The origins of relapse in AML have been traced to rare therapy-resistant leukemic stem cells (LSCs) that are already present at diagnosis. Effective treatment strategies for long-term remission are lacking, as it has been difficult to eliminate LSCs with conventional therapy. Here, we proposed a new approach based on the chimeric antigen receptor (CAR)-directed T lymphocytes, targeting T-cell immunoglobulin, and mucin domain 3 (TIM-3) to treat MRD in patients with AML. TIM-3 is selected as the target because it is highly expressed on AML blasts and LSCs in most subtypes regardless of the patient's genetic characteristics and treatment course. Moreover, it is absent in the normal hematopoietic stem cells, granulocytes, naïve lymphocytes, and most normal nonhematopoietic tissues. Using a naïve human Fab phage display library, we isolated an anti-human TIM-3 antibody and designed a second-generation anti–TIM-3. Our anti–TIM-3 CAR T cells exhibit potent antileukemic activity against AML cell lines and primary AML blasts, and in the mouse models. More importantly, we demonstrate efficient killing of the primary LSCs directly isolated from the patients. Hence, eradication of the LSCs present in the MRD by anti–TIM-3 CAR T-cell therapy following the first-line treatment may improve the clinical outcomes of patients with AML.

Objective Cardiovascular complications are the leading cause of morbidity and mortality in patients with myeloproliferative neoplasms (MPNs). The acquired kinase mutation JAK2V617F plays a central role in these disorders. Mechanisms responsible for cardiovascular dysfunction in MPNs are not fully understood, limiting the effectiveness of current treatment. Vascular endothelial cells (ECs) carrying the JAK2V617F mutation can be detected in patients with MPNs. The goal of this study was to test the hypothesis that the JAK2V617F mutation alters endothelial function to promote cardiovascular complications in patients with MPNs. Approach and Results We employed murine models of MPN in which the JAK2V617F mutation is expressed in specific cell lineages. When JAK2V617F is expressed in both blood cells and vascular ECs, the mice developed MPN and spontaneous, age‐related dilated cardiomyopathy with an increased risk of sudden death as well as a prothrombotic and vasculopathy phenotype on histology evaluation. In contrast, despite having significantly higher leukocyte and platelet counts than controls, mice with JAK2V617F‐mutant blood cells alone did not demonstrate any cardiac dysfunction, suggesting that JAK2V617F‐mutant ECs are required for this cardiovascular disease phenotype. Furthermore, we demonstrated that the JAK2V617F mutation promotes a pro‐adhesive, pro‐inflammatory, and vasculopathy EC phenotype, and mutant ECs respond to flow shear differently than wild‐type ECs. Conclusions These findings suggest that the JAK2V617F mutation can alter vascular endothelial function to promote cardiovascular complications in MPNs. Therefore, targeting the MPN vasculature represents a promising new therapeutic strategy for patients with MPNs.

Emotions are increasingly incorporated into organisational diversity management initiatives to address some of the challenges said to arise from workforce diversity. Yet few studies have looked at ...

IntroductionNipple-sparing mastectomy (NSM) can be performed for the treatment of breast cancer and risk reduction, but total mammary glandular excision in NSM can be technically challenging. Minimally invasive robot-assisted NSM (RNSM) has the potential to improve the ergonomic challenges of open NSM. Recent studies in RNSM demonstrate the feasibility and safety of the procedure, but this technique is still novel in the USA.Methods and analysisThis is a single-arm prospective pilot study to determine the safety, efficacy and potential risks of RNSM. Up to 12 RNSM will be performed to assess the safety and feasibility of the procedure. Routine follow-up visits and study assessments will occur at 14 days, 30 days, 6 weeks, 6 months and 12 months. The primary outcome is to assess the feasibility of removing the breast gland en bloc using the RNSM technique. To assess safety, postoperative complication information will be collected. Secondary outcomes include defining benefits and challenges of RNSM for both surgeons and patients using surveys, as well as defining the breast and nipple-areolar complex sensation recovery following RNSM. Mainly, descriptive analysis will be used to report the findings.Ethics and disseminationThe RNSM protocol was reviewed and approved by the US Food and Drug Administration using the Investigational Device Exemption mechanism (reference number G200096). In addition, the protocol was registered with ClinicalTrials.gov (NCT04537312) and approved by The Ohio State University Institutional Review Board, reference number 2020C0094 (18 August 2020). The results of this study will be distributed through peer-reviewed journals and presented at surgical conferences.Trial registration numberNCT04537312.

Introduction Although murine models have provided unequivocal evidence that the JAK2V617F mutation is able to cause myeloproliferative neoplasms (MPNs), there is significant heterogeneity in disease phenotypes between different murine models and none has been able to recapitulate both the myeloproliferative phenotype and cardiovascular pathology seen in patients with MPNs. In addition, these murine models were mostly followed for less than 3-9 months and how aging affects MPN disease progression has not been studied. Endothelial cells (ECs) are an essential component of the hematopoietic niche, and they have been shown to express the JAK2V617F mutation in patients with MPNs. In this study, we investigated how MPN progresses in the JAK2V617F-bearing vascular niche during aging. Methods JAK2V617F Flip-Flop (FF1) mice (which carry a Cre-inducible human JAK2V617F gene driven by the human JAK2 promoter) were crossed with Tie2-cre mice to express JAK2V617F specifically in all hematopoietic cells (including HSPCs) and vascular ECs (Tie2FF1). Results The Tie2FF1 mice developed essential thrombocythemia to primary myelofibrosisdisease transformation with extramedullary splenic hematopoiesis during 18-month follow up. No evidence of leukemia transformation was observed in the Tie2FF1 mice. (Figure 1) Hematopoietic colony formation assays, flow cytometry analysis, and in vitro culture experiments revealed that there was a loss of both HSPC number and HSPC function in the marrow of old Tie2FF1 mice during aging, mimicking the advanced phases of myelofibrosis. In contrast, the spleen of old Tie2FF1 mice was able to maintain the expansion of JAK2V617F mutant hematopoiesis during aging and MPN disease progression. (Figure 2) These differences between marrow and spleen hematopoiesis in the old Tie2FF1 mice prompted us to investigate how aging affects the JAK2V617F mutant hematopoiesis differently in the marrow and spleen. We found that, although the JAK2V617F mutant HSCs (Lin -cKit +Sca1 +CD150 +CD48 -) from old Tie2FF1 mice were more proliferative than wild-type HSCs in both the marrow and spleen, mutant marrow HSCs were more apoptotic and senescent than wild-type HSCs in the marrow while mutant spleen HSCs were relatively protected in the spleen. Examination of the hematopoietic vascular niche revealed that marrow ECs (CD45 -CD31 +) were significantly decreased in old Tie2FF1 mice compared to age-matched control mice; in contrast, spleen ECs were significantly expanded and less senescent in old Tie2FF1 mice compared to control mice. Therefore, the different vascular niche function of the marrow and spleen could contribute to the decreased marrow hematopoiesis and expanded splenic hematopoiesis we have observed in the Tie2FF1 mice during aging. (Figure 3) Previously, we reported that the Tie2FF1 mice developed spontaneous heart failure with thrombosis, vasculopathy, and cardiomyopathy at 20wk of age. Here, we followed the cardiovascular function of Tie2FF1 mice during aging. At 18mo of age, the Tie2FF1 mice continued to demonstrate a phenotype of dilated cardiomyopathy with a moderate but significant decrease in left ventricular ejection fraction and an increase in left ventricular volume and mass compared to age-matched control mice. Histology examination revealed spontaneous thrombosis in the right ventricle, pulmonary arteries, both main (epicardial) coronary arteries and scattered coronary arterioles (microvessels) in the old Tie2FF1 mice, while age-matched Tie2-cre control mice had no evidence of spontaneous thrombosis in their heart or lungs. Despite these cardiovascular dysfunctions, there was no difference in body weight nor was there any increased incidence of sudden death between the old Tie2FF1 mice and control mice. These findings suggested that there was a persistent but compensated cardiomyopathy and heart failure in the Tie2FF1 mice during aging. (Figure 4) Conclusion Compared to other MPN murine models reported so far, the Tie2FF1 mice is the first MPN murine model that faithfully recapitulated almost all the key features of the human MPN diseases. Considering the presence of the JAK2V617F mutation in microvascular ECs isolated from patients with MPNs and the recapitulation of all the key features of human MPN diseasesby the Tie2FF1 mice, the roles of endothelial dysfunction in the hematologic and cardiovascular pathogenesis of MPN shall be further investigated. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Megakaryocytes (MKs) is an important component of the hematopoietic niche. Abnormal MK hyperplasia is a hallmark feature of myeloproliferative neoplasms (MPNs). The JAK2V617F mutation is present in hematopoietic cells in a majority of patients with MPNs. Using a murine model of MPN in which the human JAK2V617F gene is expressed specifically in the MK lineage, we show that the JAK2V617F-bearing MKs promote hematopoietic stem cell (HSC) aging, manifesting as myeloid-skewed hematopoiesis with an expansion of CD41+HSCs, a reduced engraftment and self-renewal capacity, and a reduced differentiation capacity. HSCs from 2yr old mice with JAK2V617F-bearing MKs were more proliferative and less quiescent than HSCs from age-matched control mice. Examination of the marrow hematopoietic niche reveals that the JAK2V617F-bearing MKs not only have decreased direct interactions with hematopoietic stem/progenitor cells during aging, but also suppress the vascular niche function during aging. Unbiased RNA expression profiling reveals that HSC aging has a profound effect on MK transcriptomic profiles, while targeted cytokine array shows that the JAK2V617F-bearing MKs can alter the hematopoietic niche through increased levels of pro-inflammatory and anti-angiogenic factors. Therefore, as a hematopoietic niche cell, MKs represent an important connection between the extrinsic and intrinsic mechanisms for HSC aging.Significance StatementThe relative contribution of intrinsic and extrinsic mechanisms to HSC aging remains debated. We find that JAK2V617F mutant MKs can accelerate hematopoietic aging both directly (via decreased MK-HSC interaction) and indirectly (via suppressing vascular niche function). We also show that HSC aging has a profound effect on MK function. Our data suggest that, as a hematopoietic niche cell, MKs represent an important connection between HSC-intrinsic and HSC-extrinsic aging mechanisms.

Despite their ability to adapt to a variety of environments, alpacas suffer from heat stress symptoms when raised in warm and humid regions of the world. Hyperthermia in alpacas not only raises animal welfare concerns, but also decreases productivity. To better understand the relationship between heat stress and alpaca mortality, Taiwanese alpaca facilities were surveyed. Additionally, to address the dearth of experimental research on heat stress reducing amenities in alpacas, an experiment was designed to test the effectiveness of different cooling amenities (water pool, frequent mist spraying, and fans) through temperature, behavioral, location and postural observations of alpacas at the Taipei Zoo during manipulations. Experimental result supports the use of mist sprinklers, water pools, and fans as alpaca cooling amenities, with water pools as being the most effective. Survey result shows a significant portion of alpaca deaths in Taiwan occurred during the summer and that heat stress was a leading cause of death. Furthermore, imported alpacas had a higher mortality rate than those born in Taiwan.

Substance use in adolescents is a public health problem that poses many challenges for health care providers. Adolescents frequently abuse multiple substances simultaneously, further confounding the symptoms and signs of their presentation. Adolescents with substance use disorders often have co-occurring mental health problems predating or resulting from substance use, complicating their diagnoses and treatment. Additionally, many adolescents who use substances do not perceive their own need for treatment or acknowledge their level of functional impairment, which influences their symptom report. In this article, we use case examples to review common drug and alcohol problems present in adolescents and the challenges to diagnosis and treatment. [ Psychiatr Ann. 2019;49(6):263–268.]

Lee, Sandy. 2017. “Beyond the Numbers Game: Diversity in the Encounters of the Professional Workplace.” PhD diss., The University of Melbourne.Feminist concerns about power and its influence on ide...

Much environmental enforcement in the United States has historically relied on either self-reported data or physical, resource-intensive, infrequent inspections. Advances in remote sensing and computer vision, however, have the potential to augment compliance monitoring by detecting early warning signs of noncompliance. We demonstrate a process for rapid identification of significant structural expansion using Planet’s 3 m/pixel satellite imagery products and focusing on Concentrated Animal Feeding Operations (CAFOs) in the US as a test case. Unpermitted building expansion has been a particular challenge with CAFOs, which pose significant health and environmental risks. Using new hand-labeled dataset of 145,053 images of 1,513 CAFOs, we combine state-of-the-art building segmentation with a likelihood-based change-point detection model to provide a robust signal of building expansion (AUC = 0.86). A major advantage of this approach is that it can work with higher cadence (daily to weekly), but lower resolution (3 m/pixel), satellite imagery than previously used in similar environmental settings. It is also highly generalizable and thus provides a near real-time monitoring tool to prioritize enforcement resources in other settings where unpermitted construction poses environmental risk, e.g. zoning, habitat modification, or wetland protection.

Objectives The emergence of a SARS‐CoV‐2 variant with a point mutation in the spike (S) protein, D614G, has taken precedence over the original Wuhan isolate by May 2020. With an increased infection and transmission rate, it is imperative to determine whether antibodies induced against the D614 isolate may cross‐neutralise against the G614 variant. Methods Antibody profiling against the SARS‐CoV‐2 S protein of the D614 variant by flow cytometry and assessment of neutralising antibody titres using pseudotyped lentiviruses expressing the SARS‐CoV‐2 S protein of either the D614 or G614 variant tagged with a luciferase reporter were performed on plasma samples from COVID‐19 patients with known D614G status (n = 44 infected with D614, n = 6 infected with G614, n = 7 containing all other clades: O, S, L, V, G, GH or GR). Results Profiling of the anti‐SARS‐CoV‐2 humoral immunity reveals similar neutralisation profiles against both S protein variants, albeit waning neutralising antibody capacity at the later phase of infection. Of clinical importance, patients infected with either the D614 or G614 clade elicited a similar degree of neutralisation against both pseudoviruses, suggesting that the D614G mutation does not impact the neutralisation capacity of the elicited antibodies. Conclusions Cross‐reactivity occurs at the functional level of the humoral response on both the S protein variants, which suggests that existing serological assays will be able to detect both D614 and G614 clades of SARS‐CoV‐2. More importantly, there should be negligible impact towards the efficacy of antibody‐based therapies and vaccines that are currently being developed., A single point mutation from aspartic acid (D) to glycine (G) at position 614 of the SARS‐CoV‐2 spike (S) protein, termed D614G, has garnered global attention due to the observed increase in transmissibility and infection rate. Given that a majority of the developing antibody‐mediated therapies and serological assays are based on the S antigen of the original Wuhan reference sequence, it is crucial to determine whether humoral immunity acquired from the original SARS‐CoV‐2 isolate is able to induce cross‐detection and cross‐protection against the novel prevailing D614G variant. In this study, we demonstrated an overall equivalent neutralising capacity against both the D614 and G614 pseudoviruses, suggesting negligible impact towards the efficacy of antibody‐based therapies and vaccines that are currently being developed.

Growing health inequities among the increasingly diverse population in Aotearoa New Zealand have prompted responses in the healthcare system. Diversity-related policies and programmes have been developed in some District Health Boards (DHB) to address the issues. The translation of such policy into practice is, however, convoluted by subjective interests and power differentials and thus the outcomes of policies may deviate from their original objectives. In this paper we examine how staff in one DHB translate and implement health equity and diversity initiatives in their everyday practices in hospital settings. In high-level institutional thinking, Māori health equity policy is dictated by the Treaty of Waitangi which sets it apart from the cultural competence focus of programmes for other ethnic groups. Drawing on interviews with clinical staff in the DHB, we reveal how intersecting subject positions, including personal histories and institutional roles, influence the interpretation and enactment of these policies and programmes in ways that blur their distinct agendas. As a result, the paper demonstrates how the politics that underpin agendas that distinctly address equity and diversity, as well as the potential for change in these areas, can be compromised in everyday practice on the hospital floor.

This paper provides a theoretically driven discussion about the need to take the workplace, rather than social group identities, as the point of entry into studying encounters at work. Broadening t...

Introduction Recent studies implicated megakaryocytes (MKs) in regulating hematopoietic stem cell (HSC) function. Abnormal MK hyperplasia is a hallmark feature of myeloproliferative neoplasms (MPNs). In the present study, we investigated the effects of JAK2V617F-bearing MKs on HSC aging in a murine model of MPN during a 2-yr follow up. Methods JAK2V617F Flip-Flop (FF1) mice (which carry a Cre-inducible human JAK2V617F gene driven by the human JAK2 promoter) and Pf4-Cre mice (which express Cre under the promoter of platelet factor 4, a MK-specific gene) were crossed to generate MK lineage-specific human JAK2V617F transgenic mouse line (Pf4 +FF1 +). Results During aging, the Pf4 +FF1 +mice maintained an essential thrombocythemia phenotype with no evidence of transformation to leukemia or myelofibrosis (Figure 1). Myeloid-biased HSCs (Lin -cKit +Sca1 +CD150 +CD48 -CD41 +) were significantly expanded in 1yr old and 2yr old Pf4 +FF1 +mice compared to age-matched control mice, while no difference in myeloid-biased HSC numbers was detected between young (6mo) Pf4 +FF1 +mice and control mice. Competitive repopulation assays and serial transplantation assays showed that HSCs from old Pf4 +FF1 +mice had a reduced engraftment and self-renewal capacity with a skewed differentiation towards the myeloid lineage. Results from the serial transplantation experiments also indicated that the functional decline of HSCs in aged Pf4 +FF1 +mice were HSC-intrinsic and was not reversible. Both cell cycle analysis by Hoechst33342 and Pyronin Y staining and cell proliferation analysis by in vivo BrdU labeling revealed that the JAK2V617F mutant MK niche can promote hematopoietic aging in old Pf4 +FF1 +mice by increasing HSC proliferation/cycling. Taken together, the Pf4 +FF1 +mice demonstrated several hallmarks of accelerated HSC aging.(Figure 2) Next, we examined the hematopoietic microenvironment in the old Pf4 +FF1 + mice. Using whole-mount immunofluorescent staining and confocal imaging, we found that the cKit +HSPCs were located further from MKs in old Pf4 +FF1 +mice compared to old control mice. We also found that CD45 -CD31 +Sca1 - sinusoidal marrow endothelial cell (EC) number (by flow cytometry analysis) and marrow vascular area (by in vivo VE-cadherin staining) were significantly decreased in aged Pf4 +FF1 +mice compared to control mice. Tube formation assays confirmed that conditioned medium from old Pf4 +FF1 +MK culture significantly inhibited EC angiogenesis in vitro. These findings suggest that the JAK2V617F mutant MK niche not only altered its own interaction with HSCs during aging, but also suppressed the vascular niche function to promote HSC aging. (Figure 3) To further understand the mechanisms by which JAK2V617F mutant MKs promote HSC aging, we performed both RNA sequencing and targeted cytokine arrays of wild-type and JAK2V617F mutant MKs from both young (6mo) and old (2yr) Pf4-cre control and Pf4 +FF1 +mice. We found that HSC aging had a profound effect on MK transcriptomic profiles and dysregulated pathways in cell adhesion molecules, MAPK signaling, NF-kappa B signaling, hematopoietic cell lineage, and cytokine-cytokine receptor interaction were highly upregulated in old JAK2V617F mutant MKs compared to young JAK2V617F mutant MKs. FAS ligand, IL-12, tissue inhibitor of metalloproteinases-1, IL-10, IL-6, MIG, macrophage inflammatory protein 1a, GCSF, IL-5, MIP-1g were produced in increased amounts in old mutant MKs compared to old wild-type MKs. Many of these factors are involved in inflammation, angiogenesis, extracellular matrix remodeling, and hematopoiesis regulation. Sensitive PCR assays confirmed that human JAK2 gene was expressed in MKs but not in HSCs in 2yr old Pf4 +FF1 +mice. In vitro co-culture and in vivo co-transplantation assays provided further evidence that the JAK2V617F mutant MKs affected wild-type HSC function directly. Therefore, the hematopoietic aging phenotype we have observed was not caused by any direct effect of the JAK2V617F mutation on HSC function because the Pf4 promoter was 'leaky'. Conclusions Results from this study support that, as a hematopoietic niche cell, MKs represent an important connection between the extrinsic and intrinsic mechanisms for HSC aging in MPNs -- the JAK2V617F-bearing MKs can alter the hematopoietic niche to accelerate HSC aging, and HSC aging in turn can profoundly remodel the niche e.g. by affecting MK transcriptomics. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Background Transposable elements (TEs) make up > 50% of the human genome, and the majority of retrotransposon insertions are truncated and many are located in introns. However, the effects of retrotransposition on the host genes remain incompletely known. Results We report here that insertion of a chimeric L1 (cL1), but not IAP solo LTR, into intron 6 of Axin1 using CRIPSR/Cas9 induced the kinky tail phenotype with ~ 80% penetrance in heterozygous AxincL1 mice. Both penetrant (with kinky tails) and silent (without kinky tails) AxincL1 mice, regardless of sex, could transmit the phenotype to subsequent generations with similar penetrance (~ 80%). Further analyses revealed that a longer Axin1 transcript isoform containing partial cL1-targeted intron was present in penetrant, but absent in silent and wild type mice, and the production of this unique Axin1 transcript appeared to correlate with altered levels of an activating histone modification, H3K9ac. Conclusions The mechanism for AxincL1 mice is different from those previously identified in mice with spontaneous retrotransposition of IAP, e.g., AxinFu and Avy, both of which have been associated with DNA methylation changes. Our data suggest that Axin1 locus is sensitive to genetic and epigenetic alteration by retrotransposons and thus, ideally suited for studying the effects of new retrotransposition events on target gene function in mice. Electronic supplementary material The online version of this article (10.1186/s13100-019-0162-7) contains supplementary material, which is available to authorized users.

This study is intended to propose a framework focusing on how the conception of the artist affects the creation process and how the creation process is understood by the audience. The artist’s creation activities were analyzed through the framework of four steps using case study intended to turn “the feeling of home” to “the visual form of paintings.” The results showed that the approach can be applied to understanding paintings and provides artists with an idea how to concentrate their efforts at the creation stage, the easier to communicate with their audience. In addition, the research framework seems to provide a better way to explore the understanding of how verbal meaning transforms into non-verbal forms, which is clearly worthy of further study.

We describe a comprehensive genomic characterization of adrenocortical carcinoma (ACC). Using this dataset, we expand the catalogue of known ACC driver genes to include PRKAR1A, RPL22, TERF2, CCNE1, and NF1. Genome wide DNA copy-number analysis revealed frequent occurrence of massive DNA loss followed by whole-genome doubling (WGD), which was associated with aggressive clinical course, suggesting WGD is a hallmark of disease progression. Corroborating this hypothesis were increased TERT expression, decreased telomere length, and activation of cell-cycle programs. Integrated subtype analysis identified three ACC subtypes with distinct clinical outcome and molecular alterations which could be captured by a 68-CpG probe DNA-methylation signature, proposing a strategy for clinical stratification of patients based on molecular markers.

Histone modification plays a major role in regulating gene transcription and ensuring the healthy development of an organism. Numerous studies have suggested that histones are dynamically modified during developmental events to control gene expression levels in a temporal and spatial manner. However, the study of histone acetylation dynamics using currently available techniques is hindered by the difficulty of simultaneously measuring acetylation of the numerous potential sites of modification present in histones. Here, we present a methodology that allows us to combine mass spectrometry-based histone analysis with Drosophila developmental genetics. Using this system, we characterized histone acetylation patterns during multiple developmental stages of the fly. Additionally, we utilized this analysis to characterize how treatments with pharmacological agents or environmental changes such as γ-irradiation altered histone acetylation patterns. Strikingly, γ-irradiation dramatically increased the level of acetylation at H3K18, a site linked to DNA repair via nonhomologous end joining. In mutant fly strains deficient in DNA repair proteins, however, this increase in the level of H3K18 acetylation was lost. These results demonstrate the efficacy of our combined mass spectrometry system with a Drosophila model system and provide interesting insight into the changes in histone acetylation during development, as well as the effects of both pharmacological and environmental agents on global histone acetylation.

With the development of the global economy, the cultural and creative industries have become more and more important. The development of the film and television industry has witnessed a steady growth in recent years. The past pure visual entertainment of film and television works has been transformed into the current spiritual consumption and its core attraction to the audience is its creative ideas. With the increasing popularity of video equipment and availability of video equipment for everybody, the ways for artists’ works to stand out lie in the audience’s correct cognition of their ideas, which is exactly the topic discussed in this study. This study is one of the film and television art series studies which construct the research framework of film and television animation. It focuses on viewers and tests cognitive differences of film and television professionals in Taiwan and Chinese Mainland and the general audience for the film. Results: (1) The cognition of microfilm by professionals from Taiwan and Chinese Mainland is obviously different. (2) There are some differences among different genders and occupations in the recognition of microfilm. (3) The research framework can be better applied to the audience’s evaluation of video works.

This study proposed a research framework to study the communication of turning poetry into painting by using 21 paintings with their poetic titles. A total of 57 graduate students participated in the study. Subjects were asked to evaluate the fitness of paintings with their poetic title based on the six functions of communication theory. The results showed that the approach can be applied for evaluating the painting effectively and provide artists with an idea how to concentrate their efforts at the creation stage, and it is easy to communication with audience. In addition, the research framework seems to be a better way to explore the understanding of turning poetry into painting, which is clearly worthy for further research.

The Drosophila melanogaster Genetic Reference Panel (DGRP) is a community resource of 205 sequenced inbred lines, derived to improve our understanding of the effects of naturally occurring genetic variation on molecular and organismal phenotypes. We used an integrated genotyping strategy to identify 4,853,802 single nucleotide polymorphisms (SNPs) and 1,296,080 non-SNP variants. Our molecular population genomic analyses show higher deletion than insertion mutation rates and stronger purifying selection on deletions. Weaker selection on insertions than deletions is consistent with our observed distribution of genome size determined by flow cytometry, which is skewed toward larger genomes. Insertion/deletion and single nucleotide polymorphisms are positively correlated with each other and with local recombination, suggesting that their nonrandom distributions are due to hitchhiking and background selection. Our cytogenetic analysis identified 16 polymorphic inversions in the DGRP. Common inverted and standard karyotypes are genetically divergent and account for most of the variation in relatedness among the DGRP lines. Intriguingly, variation in genome size and many quantitative traits are significantly associated with inversions. Approximately 50% of the DGRP lines are infected with Wolbachia, and four lines have germline insertions of Wolbachia sequences, but effects of Wolbachia infection on quantitative traits are rarely significant. The DGRP complements ongoing efforts to functionally annotate the Drosophila genome. Indeed, 15% of all D. melanogaster genes segregate for potentially damaged proteins in the DGRP, and genome-wide analyses of quantitative traits identify novel candidate genes. The DGRP lines, sequence data, genotypes, quality scores, phenotypes, and analysis and visualization tools are publicly available.

The human X and Y chromosomes evolved from an ordinary pair of autosomes, but millions of years ago genetic decay ravaged the Y chromosome, and only three per cent of its ancestral genes survived. We reconstructed the evolution of the Y chromosome across eight mammals to identify biases in gene content and the selective pressures that preserved the surviving ancestral genes. Our findings indicate that survival was nonrandom, and in two cases, convergent across placental and marsupial mammals. We conclude that the gene content of the Y chromosome became specialized through selection to maintain the ancestral dosage of homologous X-Y gene pairs that function as broadly expressed regulators of transcription, translation and protein stability. We propose that beyond its roles in testis determination and spermatogenesis, the Y chromosome is essential for male viability, and has unappreciated roles in Turner's syndrome and in phenotypic differences between the sexes in health and disease.

In this paper I explore the complex emotions arising from the enactment of an institutional diversity policy and consider the political implications. Neoliberal policies and practices of diversity management have frequently been critiqued for their overly optimistic, depoliticized portrayals of diversity which conceal ongoing injustices. Drawing on research in the Melbourne branch of a multinational professional services firm, however, I highlight how both antagonism and ambivalence are evoked in the implementation of the firm's diversity policy. While managerial discourses normalise different emotional responses to gender and cultural diversity, unanticipated emotions also arise as workers negotiate their multiple identities. These emotions variously activate and placate resistance towards existing inequities and injustices. I therefore argue that both ‘bottom up’ emotions and those managed through ‘top down’ policy have the potential to motivate social change as well as hinder it. The paper extends existing debates in the emotional geographies of policy by challenging the common dichotomy made between the political possibilities of bottom up activism and top down management. By recognising the nuanced affective politics of different diversities learnings can be gleaned from the more successful aspects of diversity to develop policy initiatives able to achieve justice and equality for all disadvantaged groups.

The Mie field calculation of a coated sphere has significance in photonic and biomedical applications, but roundoff errors are often critical. Such pitfalls can be circumvented by arbitrary precision scheme. The extended Mie theory shows spherically symmetric optical heating in laser–liposome interactions. It also predicts a penetrating standing wave in a silver-coated silica microsphere in water under near-infrared irradiation, where a peculiar pattern in the core field is found. The intensity distribution and the dominant mode analysis may be useful to characterize microshells for the near-field applications in nonlinear optics and signal sensitization.

This study mainly investigates the influence of different media presentation forms on viewers’ perception, preference, and viewing time. This study enrolled 15 male and 15 female subjects to participate in the experiment. The independent variables included gender (male and female) and media forms of paintings. The media forms included four factors: original paintings, planar presentation of paintings, screen presentation of paintings, and picture book of paintings. The experimental results showed that, the gender factor did not have significant influence on all the measurement variables. Media forms had significant influence on 4 indices; “viewing paintings arbitrarily,” “paintings reflected a sense of value,” “preference for paintings,” and “viewing time” (p < 0.05). According to the research results of this study, the sense of value reflected by original paintings was the highest, and they were most preferred by viewers. It is advised to provide proper painting titles and good viewing environment during exhibition of paintings to help viewers develop pleasant emotions and further increase their preference for paintings.

A chirally modified nickel catalyst for the enantio-differentiating hydrogenation of β-ketoesters is conventionally prepared by immersing the pre-activated metallic nickel into an aqueous solution of enantiopure tartaric acid (so called “modification step”). During the pre-activation step, nickel precursor is commonly treated with hydrogen gas at elevated temperatures of up to 473 K. The X-ray photoelectron spectral examinations of chirally modified nickel catalysts obtained under the different modification conditions revealed that the chiral modification process itself plays a major role in activating the nickel surface whilst the pre-activation procedure is a less important factor. The corresponding enantio-differentiating hydrogenations of methyl acetoacetate in the liquid phase using the prepared chiral catalysts unambiguously confirmed this conclusion, providing quantitative conversions and high enantioselectivities of up to 90%.

The enantio-differentiating hydrogenation of methyl acetoacetate was carried out over a (R,R)-tartaric acid-NaBr-modified Raney nickel catalyst under low hydrogen pressure. The rate of the supply of hydrogen on the catalyst surface would be an important factor for attaining high enantioselectivity, especially under low hydrogen pressure. A maximum enantioselectivity of 82% was attained under an initial hydrogen pressure of 0.2 MPa at 333 K with a high stirring rate.

Single-walled carbon nanotubes (SWCNTs) greatly enhance photoacoustic effects in aqueous solution of poly(ethylene glycol) via strong near-infrared sensitization and cavity formation. The observed acoustic attenuation and sound speed dispersion reveal polymer entanglement and laser-generated cavitation. Bubble resonance accelerates the sound wave and induces strong nonlinearity. As a versatile nanometer-sized in situ photoacoustic emitter and bubble generator, SWCNTs may find applications in microscopically controlled photoacoustic imaging and low-amplitude shock wave therapy.

The hydrogen–deuterium exchange reactions of methane in a deuterium stream were studied by a pulse experiment over a reduced nickel (Ni1373 prepared from nickel oxide calcined at 1373 K, and Ni773 prepared from nickel oxide calcined at 773 K) and K 2 O promoted reduced nickel (K-Ni1373 and K-Ni773). Ni1373 had a higher exchange activity than Ni773. The effects of the addition of K 2 O resulted in the decrease in the exchange activity due to the inhibition of step defect sites and/or the promotion of the change of nickel crystal structure. High activity of Ni1373 could be due to that the Ni1373 had the surface of a higher Ni(1 0 0)/Ni(1 1 1) ratio.