Myeloid heterogeneity in kidney disease as revealed through single cell RNA sequencing

Kidney disease represents a global health burden of increasing prevalence and is an independent risk factor for cardiovascular disease. Myeloid cells are a major cellular compartment of the immune system; they are found in the healthy kidney and in increased numbers in the damaged and/or diseased kidney, where they act as key players in the progression of injury, inflammation, and fibrosis. They possess enormous plasticity and heterogeneity, adopting different phenotypic and functional characteristics in response to stimuli in the local milieu. Although this inherent complexity remains to be fully understood in the kidney, advances in single-cell genomics promise to change this. Specifically, single-cell RNA sequencing (scRNA-seq) has had a transformative effect on kidney research, enabling the profiling and analysis of the transcriptomes of single cells at unprecedented resolution and throughput, and subsequent generation of cell atlases. Moving forward, combining scRNA- and single-nuclear RNA-seq with greater-resolution spatial transcriptomics will allow spatial mapping of kidney disease of varying etiology to further reveal the patterning of immune cells and nonimmune renal cells. This review summarizes the roles of myeloid cells in kidney health and disease, the experimental workflow in currently available scRNA-seq technologies, and published findings using scRNA-seq in the context of myeloid cells and the kidney

Rubin Observatory LSST Transients and Variable Stars Roadmap

The Vera C. Rubin Legacy Survey of Space and Time holds the potential to revolutionize time domain astrophysics, reaching completely unexplored areas of the Universe and mapping variability time scales from minutes to a decade. To prepare to maximize the potential of the Rubin LSST data for the exploration of the transient and variable Universe, one of the four pillars of Rubin LSST science, the Transient and Variable Stars Science Collaboration, one of the eight Rubin LSST Science Collaborations, has identified research areas of interest and requirements, and paths to enable them. While our roadmap is ever-evolving, this document represents a snapshot of our plans and preparatory work in the final years and months leading up to the survey\u27s first light

Menopause induces changes to the stratum corneum ceramide profile, which are prevented by hormone replacement therapy

Abstract The menopause can lead to epidermal changes that are alleviated by hormone replacement therapy (HRT). We hypothesise that these changes could relate to altered ceramide production, and that oestrogen may have a role in keratinocyte ceramide metabolism. White Caucasian women were recruited into three groups: pre-menopausal (n = 7), post-menopausal (n = 11) and post-menopausal taking HRT (n = 10). Blood samples were assessed for hormone levels, transepidermal water loss was measured to assess skin barrier function, and stratum corneum lipids were sampled from photoprotected buttock skin. Ceramides and sphingomyelins were analysed by ultraperformance liquid chromatography with electrospray ionisation and tandem mass spectrometry. Post-menopausal stratum corneum contained lower levels of ceramides, with shorter average length; changes that were not evident in the HRT group. Serum oestradiol correlated with ceramide abundance and length. Ceramides had shorter sphingoid bases, indicating altered de novo ceramide biosynthesis. Additionally, post-menopausal women had higher sphingomyelin levels, suggesting a possible effect on the hydrolysis pathway. Treatment of primary human keratinocytes with oestradiol (10 nM) increased production of CER[NS] and CER[NDS] ceramides, confirming an effect of oestrogen on cutaneous ceramide metabolism. Taken together, these data show perturbed stratum corneum lipids post-menopause, and a role for oestrogen in ceramide production

The influence of membrane physical properties on microvesicle release in human erythrocytes

Exposure of human erythrocytes to elevated intracellular calcium causes fragments of the cell membrane to be shed as microvesicles. This study tested the hypothesis that microvesicle release depends on microscopic membrane physical properties such as lipid order, fluidity, and composition. Membrane properties were manipulated by varying the experimental temperature, membrane cholesterol content, and the activity of the trans-membrane phospholipid transporter, scramblase. Microvesicle release was enhanced by increasing the experimental temperature. Reduction in membrane cholesterol content by treatment with methyl-β-cyclodextrin also facilitated vesicle shedding. Inhibition of scramblase with R5421 impaired vesicle release. These data were interpreted in the context of membrane characteristics assessed previously by fluorescence spectroscopy with environment-sensitive probes such as laurdan, diphenylhexatriene, and merocyanine 540. The observations supported the following conclusions: 1) calcium-induced microvesicle shedding in erythrocytes relates more to membrane properties detected by diphenylhexatriene than by the other probes; 2) loss of trans-membrane phospholipid asymmetry is required for microvesicle release

Building a patient safety toolkit for use in general practice

Despite 340 000 000 primary care consultations annually in the UK, most of the literature on patient safety has focused on hospital-based services. To improve safety in primary care settings, we must know what methods, tools and indicators are available to measure and monitor patient safety. In collaboration with patient safety experts at the University of Dundee, we were able to identify a number of existing tools, and many of these were adopted for use in the Patient Safety Toolkit

Developing a digital intervention for cancer survivors: an evidence-, theory- and person-based approach

This paper illustrates a rigorous approach to developing digital interventions using an evidence-, theory- and person-based approach. Intervention planning included a rapid scoping review which identified cancer survivors’ needs, including barriers and facilitators to intervention success. Review evidence (N=49 papers) informed the intervention’s Guiding Principles, theory-based behavioural analysis and logic model. The intervention was optimised based on feedback on a prototype intervention through interviews (N=96) with cancer survivors and focus groups with NHS staff and cancer charity workers (N=31). Interviews with cancer survivors highlighted barriers to engagement, such as concerns about physical activity worsening fatigue. Focus groups highlighted concerns about support appointment length and how to support distressed participants. Feedback informed intervention modifications, to maximise acceptability, feasibility and likelihood of behaviour change. Our systematic method for understanding user views enabled us to anticipate and address important barriers to engagement. This methodology may be useful to others developing digital interventions

The Evolution of Early-type Red Galaxies with the GEMS Survey: Luminosity-size and Stellar Mass-size Relations Since z=1

We combine HST/ACS imaging from the GEMS survey with redshifts and rest-frame quantities from COMBO-17 to study the evolution of morphologically early-type galaxies with red colors since z=1. We use a new large sample of 728 galaxies with centrally-concentrated radial profiles (Sersic n>2.5) and rest-frame U-V colors on the red sequence. By appropriate comparison with the local relations from SDSS, we find that the luminosity-size (L-R) and stellar mass-size (M-R) relations evolve in a manner that is consistent with the passive aging of ancient stars. By itself, this result is consistent with a completely passive evolution of the red early-type galaxy population. If instead, as demonstrated by a number of recent surveys, the early-type galaxy population builds up in mass by a factor of 2 since z=1, our results imply that new additions to the early-type galaxy population follow similar L-R and M-R correlations, compared to the older subset of early-type galaxies. Adding early-type galaxies to the red sequence through disk fading appears to be consistent with the data. Through comparison with models, the role of dissipationless merging is limited to <1 major merger on average since z=1 for the most massive galaxies. Predictions from models of gas-rich mergers are not yet mature enough to allow a detailed comparison to our observations. We find tentative evidence that the amount of luminosity evolution depends on galaxy stellar mass, such that the least massive galaxies show stronger luminosity evolution compared to more massive early types. This could reflect a different origin of low-mass early-type galaxies and/or younger stellar populations; the present data is insufficient to discriminate between these possibilities. (abridged)Comment: Submitted to ApJ, 23 pages, Latex using emulateapj5.sty and onecolfloat.sty (included), 10 figures, version with full resolution figures at http://www.astro.umass.edu/~dmac/Papers/ETevol.hires.p

Trial-and-error, Googling and talk: Engineering students taking initiative out of class

A review of the science education literature identifies the importance of outreach in raising public awareness of science while providing students with contextually relevant and meaningful science in ways that enhance their school experiences. The National Virtual School of Emerging Sciences (NVSES) provided just such an opportunity. Established throughout 2012-2014, it enabled 429 secondary students from across Australia to engage with the emerging sciences of Astrophysics and Nanotechnology. Creation of 'virtual' science classrooms allowed small groups of students to connect synchronously twice a week under the guidance of subject specialist teachers. To prepare for this context, teachers modified their face-to-face pedagogies to suit the range of technologies readily accessible in the virtual classroom. This chapter discusses how these different pedagogies were utilised by the NVSES teachers to develop lessons that created unique experiences for students within the virtual classroom environment. Data collected from pre and post student surveys, interviews with the NVSES teachers and access to digitally-recorded lessons demonstrate that while NVSES was highly successful, there were challenges for all involved

Ambient air pollution exposure and full-term birth weight in California

<p>Abstract</p> <p>Background</p> <p>Studies have identified relationships between air pollution and birth weight, but have been inconsistent in identifying individual pollutants inversely associated with birth weight or elucidating susceptibility of the fetus by trimester of exposure. We examined effects of prenatal ambient pollution exposure on average birth weight and risk of low birth weight in full-term births.</p> <p>Methods</p> <p>We estimated average ambient air pollutant concentrations throughout pregnancy in the neighborhoods of women who delivered term singleton live births between 1996 and 2006 in California. We adjusted effect estimates of air pollutants on birth weight for infant characteristics, maternal characteristics, neighborhood socioeconomic factors, and year and season of birth.</p> <p>Results</p> <p>3,545,177 singleton births had monitoring for at least one air pollutant within a 10 km radius of the tract or ZIP Code of the mother's residence. In multivariate models, pollutants were associated with decreased birth weight; -5.4 grams (95% confidence interval -6.8 g, -4.1 g) per ppm carbon monoxide, -9.0 g (-9.6 g, -8.4 g) per pphm nitrogen dioxide, -5.7 g (-6.6 g, -4.9 g) per pphm ozone, -7.7 g (-7.9 g, -6.6 g) per 10 <it>μ</it>g/m³particulate matter under 10 μm, -12.8 g (-14.3 g, -11.3 g) per 10 <it>μ</it>g/m³particulate matter under 2.5 μm, and -9.3 g (-10.7 g, -7.9 g) per 10 <it>μ</it>g/m³of coarse particulate matter. With the exception of carbon monoxide, estimates were largely unchanged after controlling for co-pollutants. Effect estimates for the third trimester largely reflect the results seen from full pregnancy exposure estimates; greater variation in results is seen in effect estimates specific to the first and second trimesters.</p> <p>Conclusions</p> <p>This study indicates that maternal exposure to ambient air pollution results in modestly lower infant birth weight. A small decline in birth weight is unlikely to have clinical relevance for individual infants, and there is debate about whether a small shift in the population distribution of birth weight has broader health implications. However, the ubiquity of air pollution exposures, the responsiveness of pollutant levels to regulation, and the fact that the highest pollution levels in California are lower than those regularly experienced in other countries suggest that precautionary efforts to reduce pollutants may be beneficial for infant health from a population perspective.</p

TLR4 Asp299Gly and Thr399Ile Polymorphisms: No Impact on Human Immune Responsiveness to LPS or Respiratory Syncytial Virus

A broad variety of natural environmental stimuli, genotypic influences and timing all contribute to expression of protective versus maladaptive immune responses and the resulting clinical outcomes in humans. The role of commonly co-segregating Toll-like receptor 4 (TLR4) non-synonymous single nucleotide polymorphisms Asp299Gly and Thr399Ile in this process remains highly controversial. Moreover, what differential impact these polymorphisms might have in at risk populations with respiratory dysfunction, such as current asthma or a history of infantile bronchiolitis, has never been examined. Here we determine the importance of these polymorphisms in modulating LPS and respiratory syncytial virus (RSV)--driven cytokine responses. We focus on both healthy children and those with clinically relevant respiratory dysfunction.To elucidate the impact of TLR4 Asp299Gly and Thr399Ile on cytokine production, we assessed multiple immune parameters in over 200 pediatric subjects aged 7-9. Genotyping was followed by quantification of pro- and anti-inflammatory cytokine responses by fresh peripheral blood mononuclear cells upon acute exposure to LPS or RSV.In contrast to early reports, neither SNP influenced immune responses evoked by LPS exposure or RSV infection, as measured by the intermediate phenotype of pro- and anti-inflammatory cytokine responses to these ubiquitous agents. There is no evidence of altered sensitivity in populations with "at risk" clinical phenotypes.Genomic medicine seeks to inform clinical practice. Determination of the TLR4 Asp299Gly/Thr399Ile haplotype is of no clinical benefit in predicting the nature or intensity of cytokine production in children whether currently healthy or among specific at-risk groups characterized by prior infantile broncholitis or current asthma