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Adaptive metasurfaces (MSs) provide immense control over the phase, amplitude and propagation direction of electromagnetic waves. Adopting phase-change materials (PCMs) as an adaptive medium allows us to tune functionality of MSs at the meta-atom length scale providing full control over MS (re-)programmability. Recent experimental progress in the local switching of PCM-based MSs promises to revolutionize adaptive photonics. Novel possibilities open new challenges, one of which is a necessity to understand and be able to predict the phase transition behavior at the sub-micrometer scale. A meta-atom can be switched by a local deposition of heat using optical or electrical pulses. The deposited energy is strongly inhomogeneous and the resulting phase transition is spatially non-uniform. The drastic change of the material properties during the phase transition leads to time-dependent changes in the absorption rate and heat conduction near the meta-atom. These necessitate a self-consistent treatment of electromagnetic, thermal and phase transition processes. Here, a self-consistent multiphysics description of an optically induced phase transition in MSs is reported. The developed model is used to analyze local tuning of a perfect absorber. A detailed understanding of the phase transition at the meta-atom length scale will enable a purposeful design of programmable adaptive MSs.

Presents a thermal after-ripening time model for simulating seed dormancy loss of a grass, Bromus tectorum, in the field. Germination data for the thermal after-ripening time model; Changes in water potential; Measurements of seed zone temperature.

Abstract Background There is general consent that empathy is crucial for the physician-patient relationship and thus an important issue in medical education. This comparative study was designed to examine the differences in empathy between first year and final year medical students in Jimma University, Ethiopia. Methods A comparative cross-sectional study among 131 first year and 106 final year medical students was conducted in Jimma University, Ethiopia on academic year 2010/11. The study subjects were selected using simple random sampling technique from the list of the students. Study participation was voluntary. The Balanced Emotional Empathy Scale (BEES) was used for the detection of “heart-reading”, i.e. emotional empathy and the Reading the Mind in the Eyes test (RME-R test) to evaluate “mind-reading”, i.e. cognitive empathy. We performed t-test to compare the mean difference in empathy and RME-R scores between the two groups of students. A linear regression was computed to identify potential factors influencing the BEES and RME-R. Results Out of the total 237 students, 207 (87.3%) were males. The mean age of first year and final year students was 19.3 ± 1.1 and 24.0 ± 1.4 years respectively. First year students have scored 40.6 ± 23.8 while final year students scored 41.5 ± 20.8 mean in the BEES measuring emotional empathy score. However, this difference was not statistically significant (t = −0.30, df = 231, P-value >0.05). Final year students had significantly higher mean cognitive empathy score (17.8 ± 4.5) than first year students (14.4 ± 4.8) [β = 2.7, 95%CI (1.20, 4.13)]. Males had scored lower cognitive [β = −2.5, 95%CI (−4.37, −0.66)] and emotional empathy [β = −12.0, 95%CI (−21.66, −5.46)]. Conclusions Low emotional (BEES) and cognitive empathy sores were found in first year and final year students of Jimma University could have implications on the medical education curricula. Medical education targeted at enhancing emotional empathy and increasing cognitive empathy is required by segmenting with gender for effective physician-patient interaction. The influence of empathy on clinical competence should be studied using more rigorous design.

Abstract Background The PANSS (Positive and Negative Syndrome Scale) is one of the most important rating instruments for patients with schizophrenia. Nevertheless, there is a long and ongoing debate in the psychiatric community regarding its mathematical properties. All 30 items range from 1 to 7 leading to a minimum total score of 30, implying that the PANSS is an interval scale. For such interval scales straightforward calculation of relative changes is not appropriate. To calculate outcome criteria based on a percent change as, e.g., the widely accepted response criterion, the scale has to be transformed into a ratio scale beforehand. Recent publications have already pointed out the pitfall that ignoring the scale level (interval vs. ratio scale) leads to a set of mathematical problems, potentially resulting in erroneous results concerning the efficacy of the treatment. Methods A Pubmed search based on the PRISMA statement of the highest-ranked psychiatric journals (search terms "PANSS" and "response") was carried out. All articles containing percent changes were included and methods of percent change calculation were analysed. Results This systematic literature research shows that the majority of authors (62%) actually appear to use incorrect calculations. In most instances the method of calculation was not described in the manuscript. Conclusions These alarming results underline the need for standardized procedures for PANSS calculations.

Competing Interests: Competing interests: SEM received research funding from CellCentric. MEL, MLG, JSR-S, HAG and EM declare no potential conflicts of interest.

Cancer evolution is a multifaceted process leading to dysregulation of cellular expansion and differentiation through somatic mutations and epigenetic dysfunction. Clonal expansion and evolution is driven by cell-intrinsic and -extrinsic selective pressures, which can be captured with increasing resolution by single-cell and bulk DNA sequencing. Despite the extensive genomic alterations revealed in profiling studies, there remain limited experimental systems to model and perturb evolutionary processes. Here, we integrate multi-recombinase tools for reversible, sequential mutagenesis from premalignancy to leukemia. We demonstrate that inducible Flt3 mutations differentially cooperate with Dnmt3a, Idh2, and Npm1 mutant alleles, and that changing the order of mutations influences cellular and transcriptional landscapes. We next use a generalizable, reversible approach to demonstrate that mutation reversion results in rapid leukemic regression with distinct differentiation patterns depending upon co-occurring mutations. These studies provide a path to experimentally model sequential mutagenesis, investigate mechanisms of transformation and probe oncogenic dependency in disease evolution., Competing Interests: Declaration of interests R.L.L. is on the Supervisory board of Qiagen, a co-founder/board member at Ajax, and is a scientific advisor to Mission Bio, Syndax, Zentalis, Auron, Prelude, and C4 Therapeutics; for each of these entities he receives equity. He has received research support from Calico, Zentalis and Ajax, and has consulted for Incyte, Astra Zeneca and Janssen. A.J.D. is on an advisory board for Morphosys and a consultant for RayThera. S.F.C. is a consultant for Daiichi-Sankyo and Ursamin. He was previously a consultant for Dava Oncology and held equity interest in Imago Biosciences, none of which are directly related to the content of this paper. R.L.B. and L.A.M. have received honoraria from Mission Bio and are members of the Speakers Bureau for Mission Bio. M.P.C. has consulted for Janssen Pharmaceuticals. J.J.T. held a sponsored research project with H3 Biomedicine. P.B.F. has received research funding from Novartis. No other authors report competing interests. R.L.B., A.J.D., L.A.M., and R.L.L. have a pending patent on this work PCT/US2023/066910., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The purpose of this systematic review and meta-analysis was to examine the effects of exercise training on muscle sympathetic nerve activity (MSNA) in humans. Studies included exercise interventions [randomized controlled trials (RCTs), nonrandomized controlled trials (non-RCTs), or pre-to-post intervention] that reported on adults (≥18 yr) where MSNA was directly assessed using microneurography, and relevant outcomes were assessed [MSNA (total activity, burst frequency, burst incidence, amplitude), heart rate, blood pressure (systolic blood pressure, diastolic blood pressure, or mean blood pressure), and aerobic capacity (maximal or peak oxygen consumption)]. Forty intervention studies ( n = 1,253 individuals) were included. RCTs of exercise compared with no exercise illustrated that those randomized to the exercise intervention had a significant reduction in MSNA burst frequency and incidence compared with controls. This reduction in burst frequency was not different between individuals with cardiovascular disease compared with those without. However, the reduction in burst incidence was greater in those with cardiovascular disease [9 RCTs studies, n = 234, mean difference (MD) -21.08 bursts/100 hbs; 95% confidence interval (CI) -16.51, -25.66; I 2 = 63%] compared with those without (6 RCTs, n = 192, MD -10.92 bursts/100 hbs; 95% CI -4.12, -17.73; I 2 = 76%). Meta-regression analyses demonstrated a dose-response relationship where individuals with higher burst frequency and incidence preintervention had a greater reduction in values post-intervention. These findings suggest that exercise training reduces muscle sympathetic nerve activity, which may be valuable for improving cardiovascular health. NEW & NOTEWORTHY This systematic review and meta-analysis suggests exercise training reduces muscle sympathetic nerve activity (MSNA), which may be valuable for improving cardiovascular health. The reduction in burst incidence was greater among individuals with cardiovascular disease when compared with those without; exercise training may be particularly beneficial for individuals with cardiovascular disease. Meta-regression analyses demonstrated a dose-response relationship, where individuals with higher sympathetic activity preintervention had greater reductions in sympathetic activity post-intervention.

Background: At least 1 comorbidity occurs in 80% of patients with rheumatoid arthritis (RA). In addition to cardiovascular comorbidities psychological comorbid conditions are common. The prevalence of depression and anxiety is higher in patients than in the general population. Screening for comorbidities is crucial. A shortage of outpatient specialist care barely allows resources for this. The implementation of team-based care holds the potential to improve the standard of care while simultaneously working against the shortage of care., Objective: The aim of the study was to examine the effects of care on the course of depression and anxiety in patients with seropositive RA and active disease., Material and Methods: A multicenter pragmatic randomized controlled trial was conducted over the course of 1 year with 224 patients. After baseline, five more visits followed. In the intervention group (IG), three were initially carried out by qualified rheumatological assistants. Depression, anxiety and patient satisfaction with outpatient care were looked at in detail., Results: In the IG the anxiety symptoms significantly improved over 12 months (p = 0.036). The proportions of patients with anxiety also significantly changed in the IG (p < 0.001), while there was no change in the control group between baseline and month 12. The values of the depression scale did not differ significantly (p = 0.866). In terms of the information dimension of the satisfaction questionnaire, patients in the IG felt significantly better informed after 6 months (p = 0.013) and 12 months (p = 0.003)., Conclusion: A positive effect of team-based care on the course of depression and anxiety in patients with seropositive RA and active disease could be shown., (© 2023. The Author(s).)

Internal tandem duplication mutations in fms-like tyrosine kinase 3 (FLT3-ITD) are recurrent in acute myeloid leukemia (AML) and increase the risk of relapse. Clinical responses to FLT3 inhibitors (FLT3i) include myeloid differentiation of the FLT3-ITD clone in nearly half of patients through an unknown mechanism. We identified enhancer of zeste homolog 2 (EZH2), a component of polycomb repressive complex 2 (PRC2), as a mediator of this effect using a proteomic-based screen. FLT3i downregulated EZH2 protein expression and PRC2 activity on H3K27me3. FLT3-ITD and loss-of-function mutations in EZH2 are mutually exclusive in human AML. We demonstrated that FLT3i increase myeloid maturation with reduced stem/progenitor cell populations in murine Flt3-ITD AML. Combining EZH1/2 inhibitors with FLT3i increased terminal maturation of leukemic cells and reduced leukemic burden. Our data suggest that reduced EZH2 activity following FLT3 inhibition promotes myeloid differentiation of FLT3-ITD leukemic cells, providing a mechanistic explanation for the clinical observations. These results demonstrate that in addition to its known cell survival and proliferation signaling, FLT3-ITD has a second, previously undefined function to maintain a myeloid stem/progenitor cell state through modulation of PRC2 activity. Our findings support exploring EZH1/2 inhibitors as therapy for FLT3-ITD AML., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Seed banks, the collection of viable seeds in the soil, are particularly important determinants of population survival in highly variable environments. Predictions of increased stochasticity in the amount and timing of precipitation in desert environments raise the question of how seed banks of desert species will respond to climate change, and ultimately, whether these species will persist. Here, we present data from our long-term studies of germination requirements and seed bank dynamics in a rare desert gypsophile perennial, Arctomecon californica (Las Vegas bearpoppy). Arctomecon californica is a relatively short-lived plant that recruits from seed in sequences of unusually favorable years. We used germination experiments, an in situ seed bank study, and a 15-year field seed retrieval study to examine factors affecting seed bank persistence. In the germination study, a majority of seeds remained dormant, despite a wide variety of treatments, suggesting that a large proportion of the seed dispersed each year has cue-nonresponsive dormancy. Our in situ seed bank study showed that seed density varied widely between sites, among transects, and among samples within a transect. The patchiness of seeds in the soil highlights the importance of protecting large areas where A . californica populations are known to have existed in the past. The seed retrieval study provided strong evidence that this species has a long-lived seed bank in which only a small fraction of seeds (roughly 5%) become nondormant each year, allowing seed banks of this species to last up to 20 years without a seed production event. Whether this impressive life-history strategy can maintain the species in the face of climate change depends on the future frequency of the well-timed precipitation that allows for the establishment of new cohorts of adult plants., Competing Interests: The authors declare no conflict of interest., (Published 2023. This article is a U.S. Government work and is in the public domain in the USA. Ecology and Evolution published by John Wiley & Sons Ltd.)

Purpose: DNMT3A mutations confer a poor prognosis in acute myeloid leukemia (AML), but the molecular mechanisms downstream of DNMT3A mutations in disease pathogenesis are not completely understood, limiting targeted therapeutic options. The role of miRNA in DNMT3A-mutant AML pathogenesis is understudied., Experimental Design: DNA methylation and miRNA expression was evaluated in human AML patient samples and in Dnmt3a/Flt3-mutant AML mice. The treatment efficacy and molecular mechanisms of TLR7/8-directed therapies on DNMT3A-mutant AML were evaluated in vitro on human AML patient samples and in Dnmt3a/Flt3-mutant AML mice., Results: miR-196b is hypomethylated and overexpressed in DNMT3A-mutant AML and is associated with poor patient outcome. miR-196b overexpression in DNMT3A-mutant AML is important to maintain an immature state and leukemic cell survival through repression of TLR signaling. The TLR7/8 agonist resiquimod induces dendritic cell-like differentiation with costimulatory molecule expression in DNMT3A-mutant AML cells and provides a survival benefit to Dnmt3a/Flt3-mutant AML mice. The small molecule bryostatin-1 augments resiquimod-mediated AML growth inhibition and differentiation., Conclusions: DNMT3A loss-of-function mutations cause miRNA locus-specific hypomethylation and overexpression important for mutant DNMT3A-mediated pathogenesis and clinical outcomes. Specifically, the overexpression of miR-196b in DNMT3A-mutant AML creates a novel therapeutic vulnerability by controlling sensitivity to TLR7/8-directed therapies., (©2022 American Association for Cancer Research.)

Since the discovery of Paraburkholderia tuberum, an indigenous South African species and one of the first beta-rhizobia described, several other South African rhizobial Paraburkholderia species have been recognized. Here, we investigate the taxonomic status of 31 rhizobial isolates from the root nodules of diverse South African legume hosts in the Core Cape Subregion, which were initially identified as P. tuberum. These isolates originate from the root nodules of genera in the Papilionoideae as well as Vachellia karroo, from the subfamily Caesalpinioideae. Genealogical concordance analysis of five loci allowed delineation of the isolates into two putative species clusters (A and B). Cluster A included P. tuberum STM678 T , suggesting that this monophyletic group represents P. tuberum sensu stricto. Cluster B grouped sister to P. tuberum and included isolates from the Paarl Rock Nature Reserve in the Western Cape Province. Average Nucleotide Identity (ANI) analysis further confirmed that isolates of Cluster A shared high genome similarity with P. tuberum STM678 T compared to Cluster B and other Paraburkholderia species. The members of Cluster B associated with a single species of Podalyria, P. calyptrata. For this new taxon we accordingly propose the name Paraburkholderia podalyriae sp. nov., with the type strain WC7.3b T (= LMG 31413 T ; SARCC 750 T ). Based on our nodA and nifH phylogenies, P. podalyriae sp. nov. and strains of P. tuberum sensu stricto (including one from V. karroo) belong to symbiovar africana, the symbiotic loci of which have a separate evolutionary origin to those of Central and South American Paraburkholderia strains., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

Epigenetic programs are dysregulated in acute myeloid leukemia (AML) and help enforce an oncogenic state of differentiation arrest. To identify key epigenetic regulators of AML cell fate, we performed a differentiation-focused CRISPR screen in AML cells. This screen identified the histone acetyltransferase KAT6A as a novel regulator of myeloid differentiation that drives critical leukemogenic gene-expression programs. We show that KAT6A is the initiator of a newly described transcriptional control module in which KAT6A-catalyzed promoter H3K9ac is bound by the acetyl-lysine reader ENL, which in turn cooperates with a network of chromatin factors to induce transcriptional elongation. Inhibition of KAT6A has strong anti-AML phenotypes in vitro and in vivo, suggesting that KAT6A small-molecule inhibitors could be of high therapeutic interest for mono-therapy or combinatorial differentiation-based treatment of AML., Significance: AML is a poor-prognosis disease characterized by differentiation blockade. Through a cell-fate CRISPR screen, we identified KAT6A as a novel regulator of AML cell differentiation. Mechanistically, KAT6A cooperates with ENL in a "writer-reader" epigenetic transcriptional control module. These results uncover a new epigenetic dependency and therapeutic opportunity in AML. This article is highlighted in the In This Issue feature, p. 587., (©2021 American Association for Cancer Research.)

This study of Astragalus holmgreniorum examines its adaptations to the warm desert environment and whether these adaptations will enable it to persist. Its spring ephemeral hemicryptophyte life-history strategy is unusual in warm deserts. We used data from a 22-year demographic study supplemented with reproductive output, seed bank, and germinant survival studies to examine the population dynamics of this species using discrete-time stochastic matrix modeling. The model showed that A . holmgreniorum is likely to persist in the warm desert in spite of high dormant-season mortality. It relies on a stochastically varying environment with high inter-annual variation in precipitation for persistence, but without a long-lived seed bank, environmental stochasticity confers no advantage. Episodic high reproductive output and frequent seedling recruitment along with a persistent seed bank are adaptations that facilitate its survival. These adaptations place its life-history strategy further along the spectrum from "slower" to "faster" relative to other perennial spring ephemerals. The extinction risk for small populations is relatively high even though mean λ s  > 1 because of the high variance in year quality. This risk is also strongly dependent on seed bank starting values, creating a moving window of extinction risk that varies with population size through time. Astragalus holmgreniorum life-history strategy combines the perennial spring ephemeral life form with features more characteristic of desert annuals. These adaptations permit persistence in the warm desert environment. A promising conclusion is that new populations of this endangered species can likely be established through direct seeding., Competing Interests: The authors declare no conflict of interest., (© 2021 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

Objective: To determine the non-inferiority of nurse-led care (NLC) in patients with anticitrullinated protein antibody (ACPA)-positive and/or rheumatoid factor (RF)-positive rheumatoid arthritis (RA) with active disease who are starting disease-modifying antirheumatic drug therapy, following treat-to-target (T2T) recommendations., Methods: A multicentre, pragmatic randomised controlled trial was conducted to assess clinical effectiveness, anxiety, depression and patient satisfaction following a non-inferiority design. The participants were 224 adults with ACPA/RF-positive RA who were randomly assigned to either NLC or rheumatologist-led care (RLC). The primary outcome was the Disease Activity Score in 28 Joints measured with C reactive protein (DAS28-CRP) assessed at baseline and after 3, 6, 9 and 12 months. A DAS28-CRP difference of 0.6 was set as the non-inferiority margin. Mean differences between the groups were assessed following per-protocol and intention-to-treat strategies., Results: Demographic data and baseline characteristics of patients in the NLC group (n=111) were comparable to those of patients in the RLC group (n=113). The improvement in disease activity (change in DAS28-CRP, primary outcome) over the course of 12 months was significant in both groups (p<0.001). No significant differences were observed between the NLC and RLC groups (p=0.317). Non-inferiority of NLC was shown for the primary outcome and all secondary outcomes., Conclusion: This study supported the non-inferiority of NLC in managing T2T and follow-up care of patients with RA with moderate to high disease activity and poor prognostic factors in addition to RLC., Trial Registration Number: DRKS00013055., Competing Interests: Competing interests: JH, JZ, SEM, TW and UvH: none declared; GG has undertaken consultancies and speakers’ bureau for Abbvie, Lilly, Gilead, Celgene and Novartis; PSK has undertaken consultancies and speakers’ bureau for Abbvie, Chugai, Novartis, Sanofi, Mylan and Lilly. MW has undertaken consultancies and speakers’ bureau for Abbvie, Actelion, Aescu, Amgen, Biogen, BMS, Berlin Chemie, Celgene, Gilead, GSK, Hexal, Janssen, Medac, MSD, Mundipharma, Mylan, Novartis, Pfizer, Riemser, Roche, Sanofi, SOBI and UCB. JW has undertaken consultancies and speakers’ bureau for Janssen, Abbvie, Roche, Chugai and Novartis. FS has undertaken consultancies and speakers’ bureau for Novartis, Abbvie and Gilead. AS has received grants from Pfizer, GSK and Novartis, and has undertaken consultancies and speakers’ bureau for GSK and Roche. DMO has received grants from Novartis and Sandoz Hexal and has undertaken consultancies and speakers’ bureau for Abbvie, Amgen, BMS, Chugai, Lilly, Mylan, Novartis, Pfizer, Sandoz Hexal and Sanofi. KH has undertaken consultancies and speakers’ bureau for Abbvie, Chugai, Novartis, Lilly, Celgene, UCB, Sandoz Hexal, Sanofi and Gilead., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose of Review: Clonal heterogeneity is a significant obstacle to successful treatment of patients with acute myeloid leukemia (AML). Here, we review new advances in the understanding of genetic heterogeneity in AML using single-cell DNA-sequencing technology., Recent Findings: New genomics and immunologic discovery tools have provided single-cell resolution maps of the clonal architecture of AML. The use of these technologies reveals the mutational landscape of AML at diagnosis, during treatment, and at relapse has an enormous degree of clonal complexity and diversity that is poised to adapt and evolve under environmental pressures., Summary: AML is a complex ecosystem of competing and cooperating clones undergoing constant evolution and selection.

Previous studies have recognized South and Central/Latin American mimosoid legumes in the genera Mimosa, Piptadenia and Calliandra as hosts for various nodulating Paraburkholderia species. Several of these species have been validly named in the last two decades, e.g., P. nodosa, P. phymatum, P. diazotrophica, P. piptadeniae, P. ribeironis, P. sabiae and P. mimosarum. There are still, however, a number of diverse Paraburkholderia strains associated with these legumes that have an unclear taxonomic status. In this study, we focus on 30 of these strains which originate from the root nodules of Brazilian and Mexican Mimosa species. They were initially identified as P. tuberum and subsequently placed into a symbiovar (sv. mimosae) based on their host preferences. A polyphasic approach for the delineation of these strains was used, consisting of genealogical concordance analysis (using atpD, gyrB, acnA, pab and 16S rRNA gene sequences), together with comparisons of Average Nucleotide Identity (ANI), DNA G+C content ratios and phenotypic characteristics with those of the type strains of validly named Paraburkholderia species. Accordingly, these 30 strains were delineated into two distinct groups, of which one is conspecific with 'P. atlantica' CNPSo 3155 T and the other new to Science. We propose the name Paraburkholderia youngii sp. nov. with type strain JPY169 T (= LMG 31411 T ; SARCC751 T ) for this novel species., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

Cheatgrass (Bromus tectorum L.) is an invasive annual grass (Poaceae) that has colonized large portions of the Intermountain West. Cheatgrass stand failures have been observed throughout the invaded region, the cause of which may be related to the presence of several species of pathogenic fungi in the soil or surface litter. In this metabarcoding study, we compared the fungal communities between sites that have and have not experienced stand failure. Samples were taken from the soil and surface litter near Winnemucca, Nevada, and in Skull Valley, Utah. Our results show distinct fungal communities associated with stand failure based on both geography and sample type. In both the Winnemucca and Skull Valley surface litter, there was an elevated abundance of the endophyte Ramimonilia apicalis in samples that had experienced a stand failure. Winnemucca surface litter stand failure samples had an increased abundance of a potential pathogen in the genus Comoclathris. Skull Valley surface litter stand failure samples had an increased abundance of an undescribed new species in the Rustroemiaceae family which is responsible for the so-called bleach blonde syndrome in cheatgrass, while the soils had an increased abundance of potential pathogens in the genera Olpidium and Monosporascus., (© 2021 The Authors. MicrobiologyOpen published by John Wiley & Sons Ltd.)

Myeloid malignancies, including acute myeloid leukaemia (AML), arise from the expansion of haematopoietic stem and progenitor cells that acquire somatic mutations. Bulk molecular profiling has suggested that mutations are acquired in a stepwise fashion: mutant genes with high variant allele frequencies appear early in leukaemogenesis, and mutations with lower variant allele frequencies are thought to be acquired later 1-3 . Although bulk sequencing can provide information about leukaemia biology and prognosis, it cannot distinguish which mutations occur in the same clone(s), accurately measure clonal complexity, or definitively elucidate the order of mutations. To delineate the clonal framework of myeloid malignancies, we performed single-cell mutational profiling on 146 samples from 123 patients. Here we show that AML is dominated by a small number of clones, which frequently harbour co-occurring mutations in epigenetic regulators. Conversely, mutations in signalling genes often occur more than once in distinct subclones, consistent with increasing clonal diversity. We mapped clonal trajectories for each sample and uncovered combinations of mutations that synergized to promote clonal expansion and dominance. Finally, we combined protein expression with mutational analysis to map somatic genotype and clonal architecture with immunophenotype. Our findings provide insights into the pathogenesis of myeloid transformation and how clonal complexity evolves with disease progression.

Background: Opioids can have adverse effects on casualties in hemorrhagic shock. In 2014, the Committee on Tactical Combat Casualty Care (CoTCCC) recommended the use of ketamine at the point of injury (POI). Despite these recommendations the adherence is moderate at best. Poor use may stem from a lack of access to use ketamine during training. The United States Special Operations Command (USSOCOM) is often in a unique position, they maintain narcotics for use during all training events and operations. The goal of this work is to demonstrate that ketamine is safe and effective in both training and operational environments., Methods: This was a retrospective, observational performance improvement project within United States Special Operations Command and Air Combat Command that included the US Army's 75th Ranger Regiment, 160th Special Operations Aviation Regiment, and US Air Force Pararescue. Descriptive statistics were used to calculate the doses per administration to include the interquartile range (IQR), standard deviation (SD) and the range of likely doses using a 95% confidence interval (CI). A Wilcoxon signed-rank test was used to compare the mean pre-ketamine pain scores to the mean post-ketamine on a 0-to-10 pain scale., Results: From July 2010 to October 2017, there was a total of 34 patients; all were male. A total of 22 (64.7%) received intravenous ketamine and 12 (35.3%) received intramuscular ketamine and 8 (23.5%) received intranasal ketamine. The mean number of ketamine doses via all routes administered to patients was 1.88 (SD 1.094) and the mean total dose of all ketamine administration was 90.29mg (95% CI, 70.09-110.49). The mean initial dose of all ketamine administration was 47.35mg (95% CI, 38.52-56.18). The median preketamine pain scale for casualties was noted to be 8.0 (IQR 3) and the median post-ketamine pain scale was 0.0 (IQR 3)., Conclusion: Ketamine appears to be safe and effective for use during military training accidents. Military units should consider allowing their medics to carry and use as needed., (2020.)

Premise: Adaptive seed dispersal mechanisms are fundamental to plant fitness, but dispersal advantage is scale-dependent. We tested the hypothesis that informed dispersal in response to an environmental cue enables dispersal by wind on a local scale for Astragalus holmgreniorum, a desert species restricted to swales and wash skirts with overland flow, but prevents longer-distance dispersal by water into unfavorable wash habitats., Methods: Pod biomechanics in A. holmgreniorum lead to major shape modifications with changes in moisture content. We performed laboratory experiments to examine the interaction of pod shape with wind and water, and conducted field experiments in A. holmgreniorum habitat evaluating the roles of wind, water, and seed predators on dispersal., Results: Dry pods exhibit a flattened crescent shape with partial dehiscence that facilitated wind dispersal by ground tumbling and seed scattering in laboratory experiments. Rain simulation experiments showed that even small precipitation events returned wetted pods to their cylindrical shape and opened the dorsal suture, exposing the seeds. In the field experiments, dry pods were moved locally by wind, whereas rain caused pod opening and washing out of seeds in place. Seed predators had minimal effect on pod movement., Conclusions: Astragalus holmgreniorum exhibits pod structural remodeling in response to environmental change in a striking and novel demonstration of informed dispersal. Wind-driven movement of dry pods facilitates local seed dispersal, but rain causes pods to open and release seeds, ensuring that they are not transported out of suitable habitats and into active washes where they would be lost from the seed bank., (© 2020 Botanical Society of America.)

The development and performance of a perforated plate burner (PPB) operating using premixed natural gas and air at engine-relevant inlet temperatures and combustor pressures with thermal powers up to 1 MW is discussed. A significant benefit of using burners with simplified flow fields, such as the PPB, for experimental studies in the laboratory is the potential for decoupling the complex fluid dynamics in typical combustors from the chemical kinetics. The primary motivation for developing this burner was to use it as a source of vitiated flow with negligible swirl for reacting jet in vitiated crossflow experiments. The design methodology for the PPB is described, including plate geometry selection and flashback mitigation features. The stable operation of the PPB within a high-pressure test rig was validated: successful ignition, effective use of red-lines for flashback mitigation, and long duration steady-state operation in both piloted and nonpiloted modes were all observed. Exhaust gas emissions measured using a Fourier-transform infrared (FTIR) spectrometer showed very good performance of the PPB in terms of the combustion efficiency (based on measured CO and UHC), and a stability diagram of the PPB was developed as a function of the equivalence ratio and the PPB hole velocity. FTIR measurements also showed very low levels of NO X in nonpiloted operation that were generally within 3 ppm (reported dry and referenced to 15% O 2 ). The capability for steady-state operation, high combustion efficiency, and low levels of NO X makes this PPB an excellent burner candidate for combustion experiments in the laboratory.

Background: Placebo-controlled trials are an important tool when assessing the efficacy of spinal surgical procedures. The most common spinal surgical procedure in older adults is decompression for lumbar spinal stenosis. Before conducting a placebo-surgical trial on decompression surgery, an investigation of patients' willingness to participate in a placebo-controlled trial of decompression surgery and barriers to participation were explored., Materials: An online survey., Methods: Descriptive analyses of demographic and clinical data, and participants' willingness to participate in a placebo-surgical trial. Logistic regression was used to examine potential predictors of willingness to participate. Two independent researchers performed a coded framework analysis of patients' barriers to participation., Results: 68 patients were invited and 63 participants completed the survey (91.3% response, mean (SD) age 69.5 (10.9) years, 52% females), 71% suffered from moderate to very severe pain. Ten participants (15.9%) were willing to participate in a placebo-controlled trial. Being married was associated with decreased odds of participating (OR: 0.2; 95% CI, 0.05 to 0.8; P = 0.03), while the main barriers were a lack of information about the procedure, reassurance of a positive outcome with participation, and concerns about the risks and benefits of placebo surgery., Conclusions: A minority of patients with lumbar spinal stenosis were willing to participate in a placebo-controlled trial of surgery. The identified barriers indicate that educating eligible patients about: the need for placebo-surgical trials, the personal risks and benefits of participation, and the importance and potential benefits of placebo trials to others, may be crucial to ensure adequate recruitment into the placebo-controlled surgical trial. Conclusions should be read cautiously however, given the small sample size present in this study.

Five strains of Gram-stain-negative, rod-shaped bacteria were isolated from Carmichaelia and Montigena root nodules. Based on 16S rRNA gene phylogeny, they were shown to belong to the genus Mesorhizobium, and to be most closely related to Mesorhizobium jarvisii ATCC 33669 T (100-99.6 % sequence similarity), Mesorhizobium huakuii IAM 14158 T (99.9-99.6 %), Mesorhizobium japonicum MAFF303099 T (99.8-99.6 %) and Mesorhizobium erdmanii USDA 3471 T (99.8-99.5 %). Additionally, the strains formed distinct groups based on housekeeping gene analysis and were most closely related to M. jarvisii ATCC 33669 T (89.6-89.5 and 97.6-97.3 % sequence similarity for glnII and recA, respectively), M. erdmanii USDA 3471 T (94.3-94.0 and 94.9-94.1 %), M. japonicum MAFF303099 T (90.0-89.9 and 96.7-96.2 %) and M. huakuii IAM 14158 T (89.9-90.0 and 95.4-94.9 %). Chemotaxonomic data supported the assignment of the strains to the genus Mesorhizobium and DNA-DNA hybridizations, average nucleotide identity analysis, matrix-assisted laser desorption ionization time-of-flight MS analysis, physiological and biochemical tests differentiated them genotypically and phenotypically from their nearest neighbouring species. Therefore, these strains are considered to represent a novel species, for which the name Mesorhizobium carmichaelinearum sp. nov. is proposed. The type strain is ICMP 18942 T (=MonP1N1 T =LMG 28414 T ).

Given that phosphate supplies may diminish and become uneconomic to mine after 2020, there is a compelling need to develop alternative industries to support the population on Christmas Island. Former mine sites could be turned into productive agricultural land, however, large-scale commercial agriculture has never been attempted, and, given the uniqueness of the island, the diversity of rhizobia prior to introducing legumes needed evaluation. Therefore, 84 rhizobia isolates were obtained from nine different hosts, both crop and introduced legumes, located at seven sites across the island. Based on 16S rRNA and recA gene sequence analysis, the isolates grouped into 13 clades clustering within the genus Bradyrhizobium, Ensifer, Cupriavidus and Rhizobium. According to the sequences of their symbiosis genes nodC and nifH, the isolates were classified into 12 and 11 clades, respectively, and clustered closest to tropical or crop legume isolates. Moreover, the symbiosis gene phylogeny and Multi Locus Sequence Analysis gene phylogeny suggested vertical transmission in the Alpha-rhizobia but horizontal transmission within the Beta-rhizobia. Furthermore, this study provides evidence of a large diversity of endemic rhizobia associated with both crop and introduced legumes, and highlights the necessity of inoculation for common bean, chickpea and soybean on the Island., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

We have shown that antagomiR inhibition of miRNA miR-21 and miR-196b activity is sufficient to ablate MLL-AF9 leukemia stem cells (LSC) in vivo. Here, we used an shRNA screening approach to mimic miRNA activity on experimentally verified miR-196b targets to identify functionally important and therapeutically relevant pathways downstream of oncogenic miRNA in MLL-r AML. We found Cdkn1b (p27 Kip1 ) is a direct miR-196b target whose repression enhanced an embryonic stem cell-like signature associated with decreased leukemia latency and increased numbers of leukemia stem cells in vivo. Conversely, elevation of p27 Kip1 significantly reduced MLL-r leukemia self-renewal, promoted monocytic differentiation of leukemic blasts, and induced cell death. Antagonism of miR-196b activity or pharmacologic inhibition of the Cks1-Skp2-containing SCF E3-ubiquitin ligase complex increased p27 Kip1 and inhibited human AML growth. This work illustrates that understanding oncogenic miRNA target pathways can identify actionable targets in leukemia., (© 2018 Crown copyright. The government of Australia, Canada, or the UK ("the Crown") owns the copyright interests of authors who are government employees. The Crown Copyright is not transferable.)

Nine Gram-negative, rod-shaped bacteria were isolated from Lebeckia ambigua root nodules. All strains were able to nodulate and fix nitrogen with Lebeckia ambigua apart from WSM4178 T , WSM4181 and WSM4182. Based on the 16S rRNA gene phylogeny, all strains were closely related to Paraburkholderia species (98.4-99.9 %), belonging to the Betaproteobacteria class and Burkholderiaceae family. According to 16S rRNA gene phylogeny the closest relative for WSM4174-WSM4177 and WSM4179-WSM4180 was Paraburkholderia tuberum(99.80-99.86 %), for WSM4178 T was Paraburkholderia caledonica (98.42 %) and for WSM4181-WSM4182 was Paraburkholderia graminis (99.79 %). Analysis of the gyrB and recA housekeeping genes supported the assignment of WSM4181-WSM4182 to P. graminis and the other investigated strains could be assigned to the genus Paraburkholderia. The results of DNA-DNA hybridization, physiological and biochemical tests allowed genotypic and phenotypic differentiation of WSM4178 T from the closest validly published Paraburkholderia species. However, WSM4174-WSM4177 and WSM4179-WSM4180 could not reliably be distinguished from its closest neighbour and therefore complete genome comparison was performed between WSM4176 and P. tuberum STM678 T which gave ANI values of 96-97 %. Chemotaxonomic data, including fatty acid profiles and quinone data supported the assignment of the strains to the genus Paraburkholderia. On the basis of genotypic and phenotypic data one novel species, Paraburkholderiafynbosensis sp. nov. (WSM4178 T =LMG 27177 T =HAMBI 3356 T ), is proposed and the isolation of P. tuberum and P. graminis from root nodules of Lebeckia ambigua is reported.

Phaseolus vulgaris (common bean) was introduced to Kenya several centuries ago but the rhizobia that nodulate it in the country remain poorly characterised. To address this gap in knowledge, 178 isolates recovered from the root nodules of P. vulgaris cultivated in Kenya were genotyped stepwise by the analysis of genomic DNA fingerprints, PCR-RFLP and 16S rRNA, atpD, recA and nodC gene sequences. Results indicated that P. vulgaris in Kenya is nodulated by at least six Rhizobium genospecies, with most of the isolates belonging to Rhizobium phaseoli and a possibly novel Rhizobium species. Infrequently, isolates belonged to Rhizobium paranaense, Rhizobium leucaenae, Rhizobium sophoriradicis and Rhizobium aegyptiacum. Despite considerable core-gene heterogeneity among the isolates, only four nodC gene alleles were observed indicating conservation within this gene. Testing of the capacity of the isolates to fix nitrogen (N 2 ) in symbiosis with P. vulgaris revealed wide variations in effectiveness, with ten isolates comparable to Rhizobium tropici CIAT 899, a commercial inoculant strain for P. vulgaris. In addition to unveiling effective native rhizobial strains with potential as inoculants in Kenya, this study demonstrated that Kenyan soils harbour diverse P. vulgaris-nodulating rhizobia, some of which formed phylogenetic clusters distinct from known lineages. The native rhizobia differed by site, suggesting that field inoculation of P. vulgaris may need to be locally optimised., (Copyright © 2018 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Objective: Cochlear explantation for purely elective (e.g. psychological and emotional) reasons is not well studied. Herein, we aim to provide data and expert commentary about elective cochlear implant (CI) removal that may help to guide clinical decision-making and formulate guidelines related to CI explantation., Data Sources: We address these objectives via three approaches: case report of a patient who desired elective CI removal; review of literature and expert discussion by surgeon, audiologist, bioethicist, CI user and member of Deaf community., Review Methods: A systematic review using three scientific online databases was performed. Included articles addressed the benefits and/or complications of cochlear implantation in young children, CI explantation with or without revision surgery and the ethical debate between the medical and Deaf communities on cochlear implantation and explantation., Conclusions: The medical and audiological perspectives identify a host of risks related to implant removal without reimplantation, including risk from surgery, general anaesthesia, cochlear ossification and poor audiometric outcomes. The member of the deaf community and bioethicist argue that physicians need to guide the principles of beneficence, non-maleficence and patient autonomy. Taken together, patient desires should be seen as paramount, if the patient is otherwise fit for surgery and well informed., Implications for Practice: Similar to the case of device implantation, device explantation should be a multidisciplinary and collaborative decision with the patient and the family's desires at the centre. While every case is different, we offer a CI explantation discussion to assist in clinical decision-making, patient counselling and education., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Community settings allow individuals to connect and interact socially with others, and engage in new learning experiences. One type of community setting, public art museums, provide rich, cultural experiences for individuals that are distinctive and often repeated, due to changing exhibits. Unfortunately, for individuals with disabilities, these settings can have a negative impact if the physical environment or the social interactions with docents impede individuals' abilities to function and benefit from this type of community engagement. The principles of universal design (UD) can transform these negative experiences into positive ones that benefit the individuals and the community settings. One public institution of higher education in the United States, Worcester State University in Worcester, Massachusetts has a unique partnership with a nearby art museum. This partnership allowed two separate projects from two health-related professions to be conducted using the principles of UD. One project from the Occupational Therapy Department examined the physical environment in the context of an undergraduate course, and the other project from the Communication and Sciences Department investigated the delivery of docents' presentations for individuals with communication disorders, such as hearing loss. Although each project examined different aspects of the same museum experience, the recommendations benefit all museum visitors and increase community engagement.

We report here the complete genome sequence of Mesorhizobium sophorae ICMP 19535 T This strain was isolated from Sophora microphylla root nodules and can nodulate and fix nitrogen with this host and also with Sophora prostrata , Sophora longicarinata , and Clianthus puniceus The genome consists of 8.05 Mb., (Copyright © 2017 De Meyer et al.)

Competing Interests: Conflict-of-interest disclosure: The author declares no competing financial interests.

Competing Interests: Competing interests: None declared.

Thirteen Gram-negative, aerobic, motile with polar flagella, rod-shaped bacteria were isolated from root nodules of Centrolobium paraense Tul. grown in soils from the Amazon region of Brazil. Growth of strains was observed at temperature range 20-36 °C (optimal 28 °C), pH ranges 5-11 (optimal 6.0-7.0), and 0.1-0.5%NaCl (optimal 0.1-0.3%). Analysis of 16S rRNA gene placed the strains into two groups within Bradyrhizobium. Closest neighbouring species (98.8%) for group I was B. neotropicale while for group II were 12 species with more than 99% of similarity. Multi-locus sequence analysis (MLSA) with dnaK, glnII, recA, and rpoB confirmed B. neotropicale BR 10247 T as the closest type strain for the group I and B. elkanii USDA 76 T and B. pachyrhizi PAC 48 T for group II. Average Nucleotide Identity (ANI) differentiated group I from the B. neotropicale BR 10247 T (79.6%) and group II from B. elkanii USDA 76 T and B. pachyrhizi PAC 48 T (88.1% and 87.9%, respectively). Fatty acid profiles [majority C 16:0 and Summed feature 8 (18:1ω6c/18:1ω7c) for both groups], DNA G + C content, and carbon compound utilization supported the placement of the novel strains in the genus Bradyrhizobium. Gene nodC and nifH of the new strains have in general low similarity with other Bradyrhizobium species. Both groups nodulated plants from the tribes Crotalarieae, Dalbergiae, Genisteae, and Phaseoleae. Based on the presented data, two novel species which the names Bradyrhizobium centrolobii and Bradyrhizobium macuxiense are proposed, with BR 10245 T (=HAMBI 3597 T ) and BR 10303 T (=HAMBI 3602 T ) as the respective-type strains.

Premise of the Study: Invasive species are often initially restricted to a narrow range and may then expand through any of multiple mechanisms including phenotypic plasticity, in situ evolution, or selection on traits preadapted for new habitats. Our study used population genetics to explore possible processes by which the highly selfing invasive annual grass Bromus tectorum has expanded into montane environments., Methods: We used 69 single nucleotide polymorphic (SNP) markers to genotype ca. 20 individuals from each of 38 montane cheatgrass populations from throughout the Intermountain West and to identify characteristic SNP haplotypes and examine their distribution., Key Results: Five invariant SNP haplotypes were dominant in montane cheatgrass populations, making up 59% of genotyped individuals, with each haplotype present in 12 to 21 populations. Four of these were absent or present at low frequency in low elevation populations, while the fifth was also sometimes dominant at low elevation. Sixteen haplotypes made up 78% of all genotyped individuals. These haplotypes were distributed across several haplogroups within the clade that also includes most sagebrush steppe lineages., Conclusions: The wide geographic distribution of several common haplotypes almost completely restricted to montane habitats suggests that dominant lineages in montane populations may possess adaptive syndromes that are preserved through reduced outcrossing rates or negative selection on outcrossed progeny. However, conclusive evidence of such local adaptation requires reciprocal seeding experiments and further characterization of adaptive traits and breeding system characteristics. Other lineages have likely risen to dominance in montane populations through selectively neutral processes., (© 2017 Botanical Society of America.)