Differential Hox expression in murine embryonic stem cell models of normal and malignant hematopoiesis

The Hox family are master transcriptional regulators of developmental processes, including hematopoiesis. The Hox regulators, caudal homeobox factors (Cdx1-4), and Meis1, along with several individual Hox proteins, are implicated in stem cell expansion during embryonic development, with gene dosage playing a significant role in the overall function of the integrated Hox network. To investigate the role of this network in normal and aberrant, early hematopoiesis, we employed an in vitro embryonic stem cell differentiation system, which recapitulates mouse developmental hematopoiesis. Expression profiles of Hox, Pbx1, and Meis1 genes were quantified at distinct stages during the hematopoietic differentiation process and compared with the effects of expressing the leukemic oncogene Tel/PDGFR;2. During normal differentiation the Hoxa cluster, Pbx1 and Meis1 predominated, with a marked reduction in the majority of Hox genes (27/39) and Meis1 occurring during hematopoietic commitment. Only the posterior Hoxa cluster genes (a9, a10, a11, and a13) maintained or increased expression at the hematopoietic colony stage. Cdx4, Meis1, and a subset of Hox genes, including a7 and a9, were differentially expressed after short-term oncogenic (Tel/PDGFR;2) induction. Whereas Hoxa4-10, b1, b2, b4, and b9 were upregulated during oncogenic driven myelomonocytic differentiation. Heterodimers between Hoxa7/Hoxa9, Meis1, and Pbx have previously been implicated in regulating target genes involved in hematopoietic stem cell (HSC) expansion and leukemic progression. These results provide direct evidence that transcriptional flux through the Hox network occurs at very early stages during hematopoietic differentiation and validates embryonic stem cell models for gaining insights into the genetic regulation of normal and malignant hematopoiesis

Toxicity of cancer therapy: what the cardiologist needs to know about angiogenesis inhibitors

Clinical outcomes for patients with a wide range of malignancies have improved substantially over the last two decades. Tyrosine kinase inhibitors (TKIs) are potent signalling cascade inhibitors and have been responsible for significant advances in cancer therapy. By inhibiting vascular endothelial growth factor receptor (VEGFR)-mediated tumour blood vessel growth, VEGFR-TKIs have become a mainstay of treatment for a number of solid malignancies. However, the incidence of VEGFR-TKI-associated cardiovascular toxicity is substantial and previously under-recognised. Almost all patients have an acute rise in blood pressure, and the majority develop hypertension. They are associated with the development of left ventricular systolic dysfunction (LVSD), heart failure and myocardial ischaemia and can have effects on myocardial repolarisation. Attention should be given to rigorous baseline assessment of patients prior to commencing VEGFR-TKIs, with careful consideration of baseline cardiovascular risk factors. Baseline blood pressure measurement, ECG and cardiac imaging should be performed routinely. Hypertension management currently follows national guidelines, but there may be a future role forendothelin-1 antagonism in the prevention or treatment of VEGFR-TKI-associated hypertension. VEGFR-TKI-associated LVSD appears to be independent of dose and is reversible. Patients who develop LVSD and heart failure should be managed with conventional heart failure therapies, but the role of prophylactic therapy is yet to be defined. Serial monitoring of left ventricular function and QT interval require better standardisation and coordinated care. Management of these complex patients requires collaborative, cardio-oncology care to allow the true therapeutic potential from cancer treatment while minimising competing cardiovascular effects

Effect of venting range hood flow rate on size-resolved ultrafine particle concentrations from gas stove cooking

Cooking is the main source of ultrafine particles (UFP) in homes. This study investigated the effect of venting range hood flow rate on size-resolved UFP concentrations from gas stove cooking. The same cooking protocol was conducted 60 times using three venting range hoods operated at six flow rates in twin research houses. Size-resolved particle (10–420 nm) concentrations were monitored using a NanoScan scanning mobility particle sizer (SMPS) from 15 min before cooking to 3 h after the cooking had stopped. Cooking increased the background total UFP number concentrations to 1.3 × 103 particles/cm3 on average, with a mean exposure-relevant source strength of 1.8 × 1012 particles/min. Total particle peak reductions ranged from 25% at the lowest fan flow rate of 36 L/s to 98% at the highest rate of 146 L/s. During the operation of a venting range hood, particle removal by deposition was less significant compared to the increasing air exchange rate driven by exhaust ventilation. Exposure to total particles due to cooking varied from 0.9 to 5.8 × 104 particles/cm3·h, 3 h after cooking ended. Compared to the 36 L/s range hood, higher flow rates of 120 and 146 L/s reduced the first-hour post-cooking exposure by 76% and 85%, respectively. © 2018 Crown Copyright. Published with license by Taylor & Francis Group, LLC

A dedicated haem lyase is required for the maturation of a novel bacterial cytochrome c with unconventional covalent haem binding

In bacterial c-type cytochromes, the haem cofactor is covalently attached via two cysteine residues organized in a haem c-binding motif. Here, a novel octa-haem c protein, MccA, is described that contains only seven conventional haem c-binding motifs (CXXCH), in addition to several single cysteine residues and a conserved CH signature. Mass spectrometric analysis of purified MccA from Wolinella succinogenes suggests that two of the single cysteine residues are actually part of an unprecedented CX15CH sequence involved in haem c binding. Spectroscopic characterization of MccA identified an unusual high-potential haem c with a red-shifted absorption maximum, not unlike that of certain eukaryotic cytochromes c that exceptionally bind haem via only one thioether bridge. A haem lyase gene was found to be specifically required for the maturation of MccA in W. succinogenes. Equivalent haem lyase-encoding genes belonging to either the bacterial cytochrome c biogenesis system I or II are present in the vicinity of every known mccA gene suggesting a dedicated cytochrome c maturation pathway. The results necessitate reconsideration of computer-based prediction of putative haem c-binding motifs in bacterial proteomes

Criteria for the use of omics-based predictors in clinical trials.

The US National Cancer Institute (NCI), in collaboration with scientists representing multiple areas of expertise relevant to 'omics'-based test development, has developed a checklist of criteria that can be used to determine the readiness of omics-based tests for guiding patient care in clinical trials. The checklist criteria cover issues relating to specimens, assays, mathematical modelling, clinical trial design, and ethical, legal and regulatory aspects. Funding bodies and journals are encouraged to consider the checklist, which they may find useful for assessing study quality and evidence strength. The checklist will be used to evaluate proposals for NCI-sponsored clinical trials in which omics tests will be used to guide therapy

Improving Work-Integrated Learning Experiences through the Implementation of a Quality Framework at a Multi-Campus College

Work-integrated learning, commonly referred to as WIL, is a growing curricular experiential education practice integrating academic studies with practical experiences within a workplace setting. WIL is a strategic priority within Canadian and international post-secondary institutions, including Waterville College (a pseudonym), a multi-campus Canadian community college. WIL activities at Waterville College, while an institutional priority, have been identified through an internal review as an area with significant operational weaknesses. This dissertation-in-practice addresses the leadership problem of practice at Waterville College focusing on the inconsistent and unsystematic implementation of WIL. Grounded in principles of distributed and transformational leadership, the dissertation-in-practice examines Waterville College’s organizational context, identifies key change drivers, and poses guiding questions to align the change initiative. Through an analysis informed by the functionalist paradigm and structuralist perspective, a leadership framework for a change initiative is proposed. The change path model guides the planning process supported by an exploration of the rationale behind the proposed change, an assessment of the institution’s readiness for change, and a thorough evaluation of potential solutions. The analysis culminates in a comprehensive change implementation plan emphasizing structured communication with monitoring and evaluation strategies. This dissertation-in-practice offers a systematic approach to align WIL practices with institutional goals, thereby enhancing student outcomes and contributing to graduate employability

Strain-dependent host transcriptional responses to toxoplasma infection are largely conserved in mammalian and avian hosts

Toxoplasma gondii has a remarkable ability to infect an enormous variety of mammalian and avian species. Given this, it is surprising that three strains (Types I/II/III) account for the majority of isolates from Europe/North America. The selective pressures that have driven the emergence of these particular strains, however, remain enigmatic. We hypothesized that strain selection might be partially driven by adaptation of strains for mammalian versus avian hosts. To test this, we examine in vitro, strain-dependent host responses in fibroblasts of a representative avian host, the chicken (Gallus gallus). Using gene expression profiling of infected chicken embryonic fibroblasts and pathway analysis to assess host response, we show here that chicken cells respond with distinct transcriptional profiles upon infection with Type II versus III strains that are reminiscent of profiles observed in mammalian cells. To identify the parasite drivers of these differences, chicken fibroblasts were infected with individual F1 progeny of a Type II x III cross and host gene expression was assessed for each by microarray. QTL mapping of transcriptional differences suggested, and deletion strains confirmed, that, as in mammalian cells, the polymorphic rhoptry kinase ROP16 is the major driver of strain-specific responses. We originally hypothesized that comparing avian versus mammalian host response might reveal an inversion in parasite strain-dependent phenotypes; specifically, for polymorphic effectors like ROP16, we hypothesized that the allele with most activity in mammalian cells might be less active in avian cells. Instead, we found that activity of ROP16 alleles appears to be conserved across host species; moreover, additional parasite loci that were previously mapped for strain-specific effects on mammalian response showed similar strain-specific effects in chicken cells. These results indicate that if different hosts select for different parasite genotypes, the selection operates downstream of the signaling occurring during the beginning of the host's immune response. © 2011 Ong et al

Stoics against stoics in Cudworth's "A Treatise of Freewill"

In his 'A Treatise of Freewill', Ralph Cudworth argues against Stoic determinism by drawing on what he takes to be other concepts found in Stoicism, notably the claim that some things are ‘up to us’ and that these things are the product of our choice. These concepts are central to the late Stoic Epictetus and it appears at first glance as if Cudworth is opposing late Stoic voluntarism against early Stoic determinism. This paper argues that in fact, despite his claim to be drawing on Stoic doctrine, Cudworth uses these terms with a meaning first articulated only later, by the Peripatetic commentator Alexander of Aphrodisias

Sex-related changes in physical performance, wellbeing and neuromuscular function of elite Touch players during a four-day international tournament.

Accepted author manuscript version reprinted, by permission, from International Journal of Sports Physiology and Performance, 2020, 15(8): 1138–1146, https://doi.org/10.1123/ijspp.2019-0594. © Human Kinetics, Inc.Purpose: To examine the within- and between-sex physical performance, wellbeing and neuromuscular function responses across a four-day international touch rugby (Touch) tournament. Methods: Twenty females and twenty-one males completed measures of wellbeing (fatigue, soreness, sleep, mood, stress) and neuromuscular function (countermovement jump (CMJ) height, peak power output (PPO) and peak force (PF)) during a 4-day tournament with internal, external and perceptual loads recorded for all matches. Results: Relative and absolute total, low- (females) and high-intensity distance was lower on day 3 (males and females) (ES = -0.37 to -0.71) compared to day 1. Mean heart rate was possibly to most likely reduced during the tournament (except day 2 males) (ES = -0.36 to -0.74), whilst RPE-TL was consistently higher in females (ES = 0.02 to 0.83). The change in mean fatigue, soreness and overall wellbeing were unclear to most likely lower (ES = -0.33 to -1.90) across the tournament for both sexes, with greater perceived fatigue and soreness in females on days 3-4 (ES = 0.39 to 0.78). Jump height and PPO were possibly to most likely lower across days 2-4 (ES = -0.30 to -0.84), with greater reductions in females (ES = 0.21 to 0.66). Wellbeing, CMJ height, and PF were associated with changes in external, internal and perceptual measures of load across the tournament (2 = -0.37 to 0.39). Conclusions: Elite Touch players experience reductions in wellbeing, neuromuscular function and running performance across a 4-day tournament, with notable differences in fatigue and running between males and females, suggesting sex-specific monitoring and intervention strategies are necessary