Cancer Burden Is Controlled by Mural Cell-ß3-Integrin Regulated Crosstalk with Tumor Cells.

Enhanced blood vessel (BV) formation is thought to drive tumor growth through elevated nutrient delivery. However, this observation has overlooked potential roles for mural cells in directly affecting tumor growth independent of BV function. Here we provide clinical data correlating high percentages of mural-ß3-integrin-negative tumor BVs with increased tumor sizes but no effect on BV numbers. Mural-ß3-integrin loss also enhances tumor growth in implanted and autochthonous mouse tumor models with no detectable effects on BV numbers or function. At a molecular level, mural-cell ß3-integrin loss enhances signaling via FAK-p-HGFR-p-Akt-p-p65, driving CXCL1, CCL2, and TIMP-1 production. In particular, mural-cell-derived CCL2 stimulates tumor cell MEK1-ERK1/2-ROCK2-dependent signaling and enhances tumor cell survival and tumor growth. Overall, our data indicate that mural cells can control tumor growth via paracrine signals regulated by ß3-integrin, providing a previously unrecognized mechanism of cancer growth control.

Alternative donor transplantation for severe aplastic anemia: a comparative study of the SAAWP EBMT.

ABSTRACT: Selecting the most suitable alternative donor becomes challenging in severe aplastic anemia (SAA) when a matched sibling donor (MSD) is unavailable. We compared outcomes in patients with SAA undergoing stem cell transplantation (SCT) from matched unrelated donors (MUD) (n = 1106), mismatched unrelated donors (MMUD) (n = 340), and haploidentical donors (Haplo) (n = 206) registered in the European Society for Blood and Marrow Transplantation database (2012-2021). For Haplo SCT, only those receiving posttransplant cyclophosphamide for graft-versus-host disease (GVHD) prophylaxis were included. Median age was 20 years, and the median time from diagnosis to transplantation 8.7 months. Compared with MUD, MMUD (hazard ratio [HR], 2.93; 95% confidence interval [CI], 1.52-5.6) and Haplo (HR, 5.15; 95% CI, 2.5-10.58) showed significantly higher risks of primary graft failure. MUD had lower rates of acute GVHD compared with MMUD and Haplo (grade 2-4: 13%, 22%, and 19%, respectively; P < .001; grade 3-4: 5%, 9%, and 7%, respectively; P = .028). The 3-year nonrelapse mortality rate was 14% for MUD, 19% for MMUD, and 27% for Haplo (P < .001), whereas overall survival and GVHD and relapse-free survival (GRFS) rates were 81% and 73% for MUD, 74% and 65% for MMUD, and 63% and 54% for Haplo, respectively (P < .001). In addition to donor type, multivariable analysis identified other factors associated with GRFS such as patient age, performance status, and interval between diagnosis and transplantation. For patients with SAA lacking an MSD, our findings support MUDs as the preferable alternative donor option. However, selecting between an MMUD and Haplo donor remains uncertain and requires further exploration.

Genomic asymmetry of the Brassica napus seed: epigenetic contributions of DNA methylation and small RNAs to subgenome bias.

Polyploidy is a persistent phenomenon in angiosperm genome evolution that is hypothesized to have contributed to the diversity of extant flowering plants. Brassica napus, one of the world's most important angiosperm oilseed species, originated from the interspecific hybridization of Brassica rapa (An ) and Brassica oleracea (Cn ). While the trends of genome dominance in transcriptomics are beginning to emerge, less is known about the epigenetic and small RNA landscapes in polyploids during reproductive development. The seed is the pivotal developmental transition into the new sporophytic generation, and experiences substantial epigenetic modifications over time. Here, we investigated the prevalence of bias in the contexts of DNA methylation and small interfering (si)RNA profiles in both subgenomes (An and Cn ), as well as the ancestral fractionated genomes across B. napus seed development. We report ubiquitous Cn subgenome bias of siRNA expression and cytosine methylation, with DNA methylation being particularly abundant on gene promoters in the Cn subgenome. Further, we provide evidence that siRNA transcriptional patterns were conserved within the ancestral triplicated subgenomes of B. napus, but not across the An and Cn subgenomes. We discuss how methylation patterns in the B. napus seed relate to genes, promoter regions, siRNA loci and transposable elements through the lens of genome fractionation and polyploidization. Taken together we provide evidence for epigenetic regulation selectively silencing the Cn subgenome during seed development, and explore the impact of genome fractionation on the epigenetic components of the B. napus seed.

Cord blood transplantation for AML: Comparable LFS in patients with de novo versus secondary AML in CR1, an ALWP/EBMT study.

We investigated whether secondary versus de novo acute myeloid leukaemia (AML) would be associated with poor outcomes in adult acute AML patients in first complete remission (CR1) receiving unrelated cord blood transplantation (CBT). This is a retrospective study from the acute leukaemia working party of the European Society for Blood and Marrow Transplantation. Inclusion criteria included adult at first allogeneic haematopoietic cell transplantation between 2000 and 2021, unrelated single or double unit CBT, AML in CR1, no ex vivo T-cell depletion and no post-transplant cyclophosphamide. The primary end-point of the study was leukaemia-free survival (LFS). A total of 879 patients with de novo (n = 696) or secondary (n = 183) AML met the inclusion criteria. In multivariable analyses, sAML patients had non-significantly different LFS (HR = 0.98, p = 0.86), overall survival (HR = 1.07, p = 0.58), relapse incidence (HR = 0.74, p = 0.09) and non-relapse mortality (HR = 1.26, p = 0.13) than those with de novo AML. Our results demonstrate non-significantly different LFS following CBT in adult patients with secondary versus de novo AML.

Retrospective cohort study of the association between socioeconomic deprivation and incidence of gestational diabetes and perinatal outcomes.

INTRODUCTION: Socioeconomic disparities have been shown to correlate with perinatal mortality and the incidence of type 2 diabetes. Few studies have explored the relationship between deprivation and the incidence of gestational diabetes (GDM). We aimed to identify the relationship between deprivation and incidence of GDM, after adjusting for age, BMI, and ethnicity. We also examined for relationships between deprivation and perinatal outcomes. METHODS: A retrospective cohort analysis of 23,490 pregnancies from a major National Health Service Trust in Northwest London was conducted. The 2019 English Indices of Multiple Deprivation was used to identify the deprivation rank and decile for each postcode. Birthweight centile was calculated from absolute birthweight after adjusting for ethnicity, maternal height, maternal weight, parity, sex and outcome (live birth/stillbirth). Logistic regression and Kendall's Tau were used to identify relationships between variables. RESULTS: After controlling for age, BMI & ethnicity, Index of Multiple Deprivation postcode decile was not associated with an increased risk of developing gestational diabetes. Each increase in decile of deprivation was associated with an increase in birthweight centile by 0.471 (p < 0.001). After adjusting for confounders, age was associated with a 7.1% increased GDM risk (OR: 1.076, p < 0.001); BMI increased risk by 5.81% (OR: 1.059, p < 0.001). There was no significant correlation between Index of Multiple Deprivation rank and perinatal outcomes. DISCUSSION: Our analysis demonstrates that socioeconomic deprivation was not associated with incidence of GDM or adverse perinatal outcomes. Factors such as genetic predisposition and lifestyle habits may likely play a larger role in the development of GDM compared to socioeconomic deprivation alone.

Team Dynamics and Collaborative Problem-Solving for Lunar Construction: Lessons From Complex Construction Scenarios on Earth.

OBJECTIVE: This paper surveys the existing literature surrounding problem-solving and team dynamics in complex and unpredictable scenarios, and evaluates the applicability of studying Earth-based construction teams to identify training needs for Lunar construction crews. BACKGROUND: Lunar and other space exploration construction crews will work in extreme environments and face unpredictable challenges, necessitating real-time problem-solving to address unexpected contingencies. This work will require coordination with Mission Control and autonomous assistants, so crew training must account for multi-agent, distributed teamwork. METHOD: A narrative literature review identified processes, attributes, and skills necessary for the success of Lunar construction teams. We summarized relevant frameworks and synthesized collective findings into over-arching trends and remaining research gaps. RESULTS: While significant literature exists surrounding team performance, very little systematic inquiry has been done with a focus on Lunar construction crews and operations, particularly with respect to dynamic problem-solving and team-based decision-making. Established and standardized metrics for evaluating team performance are lacking, resulting in significant variation in reported outcomes between studies. CONCLUSION: Lunar and other space exploration construction teams will need training that focuses on developing the right approach to team-based problem-solving, rather than on preparing response execution for known contingencies. An investigation of successful Earth-based construction crews may facilitate the development of relevant metrics for training future Lunar construction crews. APPLICATION: Metrics and team training protocols developed for future Lunar construction teams may be adaptable and applicable to a wide range of extreme teams facing uncertain challenges, such as aircrews, surgical teams, first responders, and construction crews.

Global funding for cancer research between 2016 and 2020: a content analysis of public and philanthropic investments.

BACKGROUND: Cancer is a leading cause of disease burden globally, with more than 19·3 million cases and 10 million deaths recorded in 2020. Research is crucial to understanding the determinants of cancer and the effects of interventions, and to improving outcomes. We aimed to analyse global patterns of public and philanthropic investment in cancer research. METHODS: In this content analysis, we searched the UberResearch Dimensions database and Cancer Research UK data for human cancer research funding awards from public and philanthropic funders between Jan 1, 2016, and Dec 31, 2020. Included award types were project and programme grants, fellowships, pump priming, and pilot projects. Awards focused on operational delivery of cancer care were excluded. Awards were categorised by cancer type, cross-cutting research theme, and research phase. Funding amount was compared with global burden of specific cancers, measured by disability-adjusted life-years, years lived with disability, and mortality using data from the Global Burden of Disease study. FINDINGS: We identified 66 388 awards with total investment of about US$24·5 billion in 2016-20. Investment decreased year-on-year, with the largest drop observed between 2019 and 2020. Pre-clinical research received 73·5% of the funding across the 5 years ($18 billion), phase 1-4 clinical trials received 7·4% ($1·8 billion), public health research received 9·4% ($2·3 billion), and cross-disciplinary research received 5·0% ($1·2 billion). General cancer research received the largest investment ($7·1 billion, 29·2% of the total funding). The most highly funded cancer types were breast cancer ($2·7 billion [11·2%]), haematological cancer ($2·3 billion [9·4%]), and brain cancer ($1·3 billion [5·5%]). Analysis by cross-cutting theme revealed that 41·2% of investment ($9·6 billion) went to cancer biology research, 19·6% ($4·6 billion) to drug treatment research, and 12·1% ($2·8 billion) to immuno-oncology. 1·4% of the total funding ($0·3 billion) was spent on surgery research, 2·8% ($0·7 billion) was spent on radiotherapy research, and 0·5% ($0·1 billion) was spent on global health studies. INTERPRETATION: Cancer research funding must be aligned with the global burden of cancer with more equitable funding for cancer research in low-income and middle-income countries (which account for 80% of cancer burden), both to support research relevant to these settings, and build research capacity within these countries. There is an urgent need to prioritise investment in surgery and radiotherapy research given their primacy in the treatment of many solid tumours. FUNDING: None.

Gene expression profiling reveals transcription factor networks and subgenome bias during Brassica napus seed development.

We profiled the global gene expression landscape across the reproductive lifecycle of Brassica napus. Comparative analysis of this nascent amphidiploid revealed the contribution of each subgenome to plant reproduction. Whole-genome transcription factor networks identified BZIP11 as a transcriptional regulator of early B. napus seed development. Knockdown of BZIP11 using RNA interference resulted in a similar reduction in gene activity of predicted gene targets, and a reproductive-lethal phenotype. Global mRNA profiling revealed lower accumulation of Cn subgenome transcripts relative to the An subgenome. Subgenome-specific transcription factor networks identified distinct transcription factor families enriched in each of the An and Cn subgenomes early in seed development. Analysis of laser-microdissected seed subregions further reveal subgenome expression dynamics in the embryo, endosperm and seed coat of early stage seeds. Transcription factors predicted to be regulators encoded by the An subgenome are expressed primarily in the seed coat, whereas regulators encoded by the Cn subgenome were expressed primarily in the embryo. Data suggest subgenome bias are characteristic features of the B. napus seed throughout development, and that such bias might not be universal across the embryo, endosperm and seed coat of the developing seed. Transcriptional networks spanning both the An and Cn genomes of the whole B. napus seed can identify valuable targets for seed development research and that -omics level approaches to studying gene regulation in B. napus can benefit from both broad and high-resolution analyses.

Shooting the messenger: a systematic review investigating extracellular vesicle isolation and characterisation methods and their influence on understanding extracellular vesicles-radiotherapy interactions in glioblastoma.

BACKGROUND: Extracellular vesicles (EVs) hold promise for improving our understanding of radiotherapy response in glioblastoma due to their role in intercellular communication within the tumour microenvironment (TME). However, methodologies to study EVs are evolving with significant variation within the EV research community. METHODS: We conducted a systematic review to critically appraise EV isolation and characterisation methodologies and how this influences our understanding of the findings from studies investigating radiotherapy and EV interactions in glioblastoma. 246 articles published up to 24/07/2023 from PubMed and Web of Science were identified using search parameters related to radiotherapy, EVs, and glioblastoma. Two reviewers evaluated study eligibility and abstracted data. RESULTS: In 26 articles eligible for inclusion (16 investigating the effects of radiotherapy on EVs, five investigating the effect of EVs on radiation response, and five clinical studies), significant heterogeneity and frequent omission of key characterisation steps was identified, reducing confidence that the results are related to EVs and their cargo as opposed to co-isolated bioactive molecules. However, the results are able to clearly identify interactions between EVs and radiotherapy bi-directionally within different cell types within the glioblastoma TME. These interactions facilitate transferable radioresistance and oncogenic signalling, highlighting that EVs are an important component in the variability of glioblastoma radiotherapy response. CONCLUSIONS: Future multi-directional investigations interrogating the whole TME are required to improve subsequent clinical translation, and all studies should incorporate up to date controls and reporting requirements to increase the validity of their findings. This would be facilitated by increased collaboration between less experienced and more experienced EV research groups.

Allocoprobacillus halotolerans gen. nov., sp. nov and Coprobacter tertius sp. nov., isolated from human gut microbiota.

Two novel bacterial isolates were cultured from faecal samples of patients attending the Breast Care clinic at the Norwich and Norfolk University Hospital. Strain LH1062T was isolated from a 58-year-old female diagnosed with invasive adenocarcinoma with ductal carcinoma in situ. Strain LH1063T was isolated from a healthy 51-year-old female. Isolate LH1062T was predicted to be a potential novel genus most closely related to Coprobacillus, whilst LH1063T was predicted to be a novel species belonging to Coprobacter. Both strains were characterized by polyphasic approaches including 16S rRNA gene analysis, core-genome analysis, average nucleotide identity (ANI) comparisons and phenotypic analysis. Initial screening of the 16S rRNA gene of LH1062T returned a nucleotide identity of 93.4 % to Longibaculum muris. For LH1063T, nucleotide identity was a 92.6 % to Coprobacter secundus. Further investigations showed that LH1062T had a genome size of 2.9 Mb and G+C content of 31.3 mol %. LH1063T had a genome size of 3.3Mb and G+C content of 39.2 mol %. Digital DNA-DNA hybridization (dDDH) and ANI values of LH1062T with its closest relative, Coprobacillus cateniformis JCM 10604T, were 20.9 and 79.54 %, respectively. For LH1063T, the dDDH and ANI values with its closest relative, Coprobacter secundus 177T, were 19.3 and 77.81 %, respectively. Phenotypic testing confirmed that LH1062T could not be matched to a known validly published isolate in any database; thereby indicating a novel genus for which the name Allocoprobacillus gen. nov. is now proposed with LH1062T (=DSM 114537T=NCTC 14686T) being the type strain of the proposed novel species Allocoprobacillus halotolerans sp. nov. Strain LH1063T (=DSM 114538T=NCTC 14698T) fits within the genus Coprobacter and, it being the third species within this genus, the name Coprobacter tertius sp. nov. is proposed.

Longitudinal Impacts of Simulated Long-Duration Spaceflight Missions on Operationally Relevant Measures of Human Performance Using a Portable Simulation Platform.

OBJECTIVE: This project quantifies operationally relevant measures of flight performance and workload in a high-fidelity long-duration spaceflight analog, longitudinally across mission duration, using a portable simulation platform. BACKGROUND: Real-time performance measures allow for the objective assessment of task performance and the timely identification of performance degradations. METHODS: Measures of flight performance on a piloted lunar lander task were collected on 32 total crewmembers across 8 simulated space missions of 45 days each (623 total sessions). RESULTS: Mission duration demonstrated a significant effect on measures of flight performance across all campaigns. Flight measures showed a general pattern of peaking in accuracy during the middle-late quartiles of overall mission time, then degrading again towards baseline. On the workload measure, however, a general linear decrease in workload consistent with progressive task learning was observed in both campaigns. CONCLUSION: This investigation demonstrated the disruptive effect of time in mission on some, but not all, aspects of task performance. While mission interval differentially impacted measures of flight accuracy, workload, by contrast, seemed to steadily decrease with in-mission time. APPLICATION: While more work is needed, the observed discrepancy between progression of flight performance and workload assessment highlights the importance of sensitive and specific measurement tools for the tracking of distinct performance metrics.

Cross-Axis Dynamic Field Compensation of Optically Pumped Magnetometer Arrays for MEG.

We present dynamic field compensation (DFC), whereby three-axis field measurements from reference magnetometers are used to dynamically maintain null at the alkali vapor cells of an array of primary sensors that are proximal to a subject's scalp. Precision measurement of the magnetoencephalogram (MEG) by zero-field optically pumped magnetometer (OPM) sensors requires that sensor response is linear and sensor gain is constant over time. OPMs can be operated in open-loop mode, where the measured field is proportional to the output at the demodulated photodiode output, or in closed-loop, where on-board coils are dynamically driven to maintain the internal cell at zero field in the measurement direction. While OPMs can be operated in closed-loop mode along all three axes, this can increase sensor noise and poses engineering challenges. Uncompensated fluctuations in the ambient field along any statically nulled axes perturb the measured field by tipping the measurement axis and altering effective sensor gain - a phenomenon recently referred to as cross-axis projection error (CAPE). These errors are particularly problematic when OPMs are allowed to move in the remnant background field. Sensor gain-errors, if not mitigated, preclude precision measurements with OPMs operating in the presence of ambient field fluctuations within a typical MEG laboratory. In this manuscript, we present the cross-axis dynamic field compensation (DFC) method for maintaining zero field dynamically on all three axes of each sensor in an array of OPMs. Together, DFC and closed-loop operation strongly attenuate errors introduced by CAPE. This method was implemented by using three orthogonal reference sensors together with OPM electronics that permit driving each sensor's transverse field coils dynamically to maintain null field across its OPM measurement cell. These reference sensors can also be used for synthesizing 1st-gradient response to further reduce the effects of fluctuating ambient fields on measured brain activity and compensate for movement within a uniform field. We demonstrate that, using the DFC method, magnetic field measurement errors of less than 0.7% are easily achieved for an array of OPM sensors in the presence of ambient field perturbations of several nT.

ADAMTS-1 and syndecan-4 intersect in the regulation of cell migration and angiogenesis.

ADAMTS-1 is an extracellular protease with critical roles in organogenesis and angiogenesis. Here we demonstrate a functional convergence of ADAMTS-1 and the transmembrane heparan sulfate proteoglycan syndecan-4 in influencing adhesion, migration and angiogenesis. Knockdown of ADAMTS-1 in endothelial cells resulted in a parallel reduction in cell surface syndecan-4, attributable to increased matrix metalloproteinase-9 (MMP9) activity. Knockdown of either ADAMTS-1 or syndecan-4 increased cellular responses to vascular endothelial growth factor A isoform VEGFA164, and increased ex vivo aortic ring microvessel sprouting. On fibronectin, knockdown of either protein enhanced migration and promoted formation of long α5 integrin-containing fibrillar adhesions. However, integrin α5 null cells still showed increased migration in response to ADAMTS-1 and syndecan-4 siRNA treatment. Plating of naïve endothelial cells on cell-conditioned matrix from ADAMTS-1 and syndecan-4 knockdown cells demonstrated that the altered adhesive behaviour was matrix dependent, and this correlated with a lack of expression of fibulin-1: an extracellular matrix co-factor for ADAMTS-1 that is known to inhibit migration. These findings support the notion that ADAMTS-1 and syndecan-4 are functionally interconnected in regulating cell migration and angiogenesis, via collaboration with MMP9 and fibulin-1.This article has an associated First Person interview with the first author of the paper.

Improved outcome of patients with graft-versus-host disease after allogeneic hematopoietic cell transplantation for hematologic malignancies over time: an EBMT mega-file study.

Acute graft-versus-host disease (aGvHD) remains a major threat to successful outcome following allogeneic hematopoietic cell transplantation though advances in prophylaxis and supportive care have been made. The aim of this study is to test whether the incidence and mortality of aGvHD have decreased over time. 102,557 patients with a median age of 47.6 years and with malignancies after first allogeneic sibling or unrelated donor (URD) transplant were studied in the following periods: 1990-1995, 1996-2000, 2001-2005, 2006-2010 and 2011-2015. Findings: 100-day incidences of aGvHD grades II-IV decreased from 40% to 38%, 32%, 29% and 28%, respectively, over calendar time (P<0.001). In multivariate analysis URD, not in complete remission (CR) at transplant or untreated, and female donor for male recipient were factors associated with increased risk whereas the use of ATG/alemtuzumab decreased aGvHD incidence. Median follow-up was 214, 169, 127, 81 and 30 months, respectively, for the periods analyzed. Three-year-survival after aGvHD grades II-IV increased significantly from 38% to 40%, 43%, 44%, and 45%, respectively. In multivariate analysis URD, not in CR at transplant, peripheral blood as stem cell source, female donor for male recipient, and the use of ATG/alemtuzumab were associated with increased mortality whereas reduced-intensity conditioning was linked to lower mortality. Mortality increased with increasing patient age but decreased in the recent cohorts. Our analysis demonstrates that aGvHD has decreased over recent decades and also that the survival rates of patients affected with aGvHD has improved.

Endothelial neuropilin-2 influences angiogenesis by regulating actin pattern development and α5-integrin-p-FAK complex recruitment to assembling adhesion sites.

The ability to form a variety of cell-matrix connections is crucial for angiogenesis to take place. Without stable anchorage to the extracellular matrix (ECM), endothelial cells (ECs) are unable to sense, integrate and disseminate growth factor stimulated responses that drive growth of a vascular bed. Neuropilin-2 (NRP2) is a widely expressed membrane-bound multifunctional non-tyrosine kinase receptor, which has previously been implicated in influencing cell adhesion and migration by interacting with α5-integrin and regulating adhesion turnover. α5-integrin, and its ECM ligand fibronectin (FN) are both known to be upregulated during the formation of neo-vasculature. Despite being descriptively annotated as a candidate biomarker for aggressive cancer phenotypes, the EC-specific roles for NRP2 during developmental and pathological angiogenesis remain unexplored. The data reported here support a model whereby NRP2 actively promotes EC adhesion and migration by regulating dynamic cytoskeletal remodeling and by stimulating Rab11-dependent recycling of α5-integrin-p-FAK complexes to newly assembling adhesion sites. Furthermore, temporal depletion of EC-NRP2 in vivo impairs primary tumor growth by disrupting vessel formation. We also demonstrate that EC-NRP2 is required for normal postnatal retinal vascular development, specifically by regulating cell-matrix adhesion. Upon loss of endothelial NRP2, vascular outgrowth from the optic nerve during superficial plexus formation is disrupted, likely due to reduced FAK phosphorylation within sprouting tip cells.

Stimulation artifact source separation (SASS) for assessing electric brain oscillations during transcranial alternating current stimulation (tACS).

Brain oscillations, e.g. measured by electro- or magnetoencephalography (EEG/MEG), are causally linked to brain functions that are fundamental for perception, cognition and learning. Recent advances in neurotechnology provide means to non-invasively target these oscillations using frequency-tuned amplitude-modulated transcranial alternating current stimulation (AM-tACS). However, online adaptation of stimulation parameters to ongoing brain oscillations remains an unsolved problem due to stimulation artifacts that impede such adaptation, particularly at the target frequency. Here, we introduce a real-time compatible artifact rejection algorithm (Stimulation Artifact Source Separation, SASS) that overcomes this limitation. SASS is a spatial filter (linear projection) removing EEG signal components that are maximally different in the presence versus absence of stimulation. This enables the reliable removal of stimulation-specific signal components, while leaving physiological signal components unaffected. For validation of SASS, we evoked brain activity with known phase and amplitude using 10 Hz visual flickers across 7 healthy human volunteers. 64-channel EEG was recorded during and in absence of 10 Hz AM-tACS targeting the visual cortex. Phase differences between AM-tACS and the visual stimuli were randomized, so that steady-state visually evoked potentials (SSVEPs) were phase-locked to the visual stimuli but not to the AM-tACS signal. For validation, distributions of single-trial amplitude and phase of EEG signals recorded during and in absence of AM-tACS were compared for each participant. When no artifact rejection method was applied, AM-tACS stimulation artifacts impeded assessment of single-trial SSVEP amplitude and phase. Using SASS, amplitude and phase of single trials recorded during and in absence of AM-tACS were comparable. These results indicate that SASS can be used to establish adaptive (closed-loop) AM-tACS, a potentially powerful tool to target various brain functions, and to investigate how AM-tACS interacts with electric brain oscillations.

Exploring the impact of gut microbiota and diet on breast cancer risk and progression.

There is emerging evidence that resident microbiota communities, that is, the microbiota, play a key role in cancer outcomes and anticancer responses. Although this has been relatively well studied in colorectal cancer and melanoma, other cancers, such as breast cancer (BrCa), have been largely overlooked to date. Importantly, many of the environmental factors associated with BrCa incidence and progression are also known to impact the microbiota, for example, diet and antibiotics. Here, we explore BrCa risk factors from large epidemiology studies and microbiota associations, and more recent studies that have directly profiled BrCa patients' gut microbiotas. We also discuss how in vivo studies have begun to unravel the immune mechanisms whereby the microbiota may influence BrCa responses, and finally we examine how diet and specific nutrients are also linked to BrCa outcomes. We also consider future research avenues and important considerations with respect to study design and implementation, and we highlight some of the important unresolved questions, which currently limit our overall understanding of the mechanisms underpinning microbiota-BrCa responses.

Forgoing transesophageal echocardiogram in selected patients with complicated Staphylococcus aureus bacteremia.

Infective endocarditis (IE) has been increasingly recognized as an important complication of Staphylococcus aureus bacteremia (SAB), leading to a low threshold for echocardiography and extended treatment with anti-staphylococcal agents. However, outside of IE, many indications for prolonged anti-staphylococcal therapy courses are present. We sought to determine the frequency in which findings from a transesophageal echocardiogram (TEE) changed clinical SAB management in a large Canadian health region. Residents (> 18 years) with SAB from 2012 to 2014 who underwent transthoracic echocardiogram (TTE) and TEE were assessed. Patients potentially benefiting from an extended course of anti-staphylococcal agents were defined a priori. Patient demographics, treatment (including surgical), and clinical outcomes were extracted and evaluated. Of the 705 episodes of SAB that underwent a screening echocardiogram, 203 episodes underwent both a TTE and TEE, of which 92.1% (187/203) contained an a priori indication for extended anti-staphylococcal therapy. Regardless of TEE results, actual duration of therapy did not differ in SAB episodes that had ≥ 1 extended anti-staphylococcal therapy criteria (36.7 days, IQR 23.4-48.6 vs. 43.8 days, IQR 33.3-49.5, p = 0.17). Additionally, there were no cases in which TEE was utilized as the sole reason to shorten duration of therapy or proceed to surgery for those with SAB. Routine performance of TEE may be unnecessary in all SAB as many patients have pre-existing indications for extended anti-staphylococcal therapy independent of TEE findings. An algorithm to selectively identify cases of SAB that would benefit from TEE can reduce resource and equipment expenditure and patient risks associated with TEE.

3'-(Phenyl alkynyl) analogs of abscisic acid: synthesis and biological activity of potent ABA antagonists.

We report here the synthesis and biological testing of 3'-(phenyl alkynyl) abscisic ABA analogs, a new class of potent ABA antagonists. These ABA analogs incorporate a rigid framework of eight carbon atoms attached at the 3'-carbon atom of ABA that prevents folding of the ABA analog-bound receptor required for ABA signalling. The two-step synthesis is based upon the optimized conversion of natural (S)-ABA to 3'-iodo ABA which can be coupled to phenyl acetylenes using Sonogashira conditions, or to styryl compounds through Suzuki chemistry. The parent 3'-(phenyl alkynyl) ABA analog 7 was obtained in 29% yield, 74% yield based on recovered starting material. In a lentil seed germination assay, compound 7 was found to have more potent activity than other known 3'-substituted ABA antagonists to date. In a structure activity study parasubstituted phenyl alkynyl analogs had comparable activity to the analog 7 while the 3'-styryl ABA 18 was only slightly less active. Analog 7 overcame ABA inhibition of germination and seedling growth in a wide range of mono and dicot plant species, including canola, lentil, soybean, rice, wheat, barley, cannabis and canary seed. 3'-(Phenyl alkynyl) ABA analogs have numerous potential practical agricultural applications including promoting ripening of crops, dormancy breaking of seeds and woody perennials, as well as promoting seed germination, and growth under stress conditions as demonstrated in this report.

Characterization of the acoustic output of single marine-seismic airguns and clusters: The Svein Vaage dataset.

The acoustical output of marine-seismic airguns is determined from recordings of the sound pressure made on hydrophones suspended below a floating barge from which the airguns are also deployed. The signals from multiple types of airguns are considered and each type is operated over a range of deployment depths and chamber pressures. The acoustical output is characterized in terms of a "source waveform" with dimensions of the pressure-times-distance and in an infinite idealized medium, could be divided by the source-receiver distance to give the sound pressure at that receiver. In more realistic environments, the source waveform may be used to predict the pressure at any arbitrary receiver position simply by the application of a time-domain transfer function describing the propagation between the source and receiver. The sources are further characterized by metrics such as the peak source waveform and energy source level. These metrics are calculated in several frequency bands so that the resulting metrics can be used to characterize the acoustical output of the airguns in terms of their utility for seismic image-processing or possible effects on marine life. These characterizations provide reference data for the calibration of models that predict the airguns' acoustical output. They are validated via comparisons of the acoustic pressure measured on far-field hydrophones and predicted using the source waveforms. Comparisons are also made between empirically derived expressions relating the acoustic metrics to the chamber volume, chamber pressure, and deployment depth and similar expressions from the literature.