Publications by authors named "David Johnston"

296 Publications

TNF receptor agonists induce distinct receptor clusters to mediate differential agonistic activity.

Commun Biol 2021 Jun 23;4(1):772. Epub 2021 Jun 23.

Antibody and Vaccine Group, School of Cancer Sciences, University of Southampton Faculty of Medicine, Southampton, UK.

Monoclonal antibodies (mAb) and natural ligands targeting costimulatory tumor necrosis factor receptors (TNFR) exhibit a wide range of agonistic activities and antitumor responses. The mechanisms underlying these differential agonistic activities remain poorly understood. Here, we employ a panel of experimental and clinically-relevant molecules targeting human CD40, 4-1BB and OX40 to examine this issue. Confocal and STORM microscopy reveal that strongly agonistic reagents induce clusters characterized by small area and high receptor density. Using antibody pairs differing only in isotype we show that hIgG2 confers significantly more receptor clustering than hIgG1 across all three receptors, explaining its greater agonistic activity, with receptor clustering shielding the receptor-agonist complex from further molecular access. Nevertheless, discrete receptor clustering patterns are observed with different hIgG2 mAb, with a unique rod-shaped assembly observed with the most agonistic mAb. These findings dispel the notion that larger receptor clusters elicit greater agonism, and instead point to receptor density and subsequent super-structure as key determinants.
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http://dx.doi.org/10.1038/s42003-021-02309-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222242PMC
June 2021

The early course and treatment of posttraumatic stress disorder in very young children: diagnostic prevalence and predictors in hospital-attending children and a randomized controlled proof-of-concept trial of trauma-focused cognitive therapy, for 3- to 8-year-olds.

J Child Psychol Psychiatry 2021 Jun 14. Epub 2021 Jun 14.

Medical Research Council Cognition and Brain Sciences Unit, University of Cambridge, Cambridge, UK.

Background: The introduction of developmentally adapted criteria for posttraumatic stress disorder (PTSD) has improved the identification of ≤6-year-old children with clinical needs. Across two studies, we assess predictors of the development of PTSD in young children (PTSD-YC), including the adult-led acute stress disorder (ASD) diagnosis, and provide proof of principle for cognitive-focused therapy for this age range, with the aim of increasing treatment options for children diagnosed with PTSD-YC.

Method: Study 1 (N = 105) assessed ASD and PTSD-YC diagnosis in 3- to 8-year-old children within one month and at around three months following attendance at an emergency room. Study 2 (N = 37) was a preregistered (www.isrctn.com/ISRCTN35018680) randomized controlled early-phase trial comparing CBT-3M, a cognitive-focused intervention, to treatment-as-usual (TAU) delivered within the UK NHS to 3- to 8-year-olds diagnosed with PTSD-YC.

Results: In Study 1, the ASD diagnosis failed to identify any young children. In contrast, prevalence of acute PTSD-YC (minus the duration requirement) was 8.6% in the first month post-trauma and 10.1% at 3 months. Length of hospital stay, but no other demographic or trauma-related characteristics, predicted development of later PTSD-YC. Early (within one month) diagnosis of acute PTSD-YC had a positive predictive value of 50% for later PTSD-YC. In Study 2, most children lost their PTSD-YC diagnosis following completion of CBT-3M (84.6%) relative to TAU (6.7%) and CBT-3M was acceptable to recipient families. Effect sizes were also in favor of CBT-3M for secondary outcome measures.

Conclusions: The ASD diagnosis is not fit for purpose in this age-group. There was a strong and encouraging signal of putative efficacy for young children treated using a cognitive-focused treatment for PTSD, and a larger trial of CBT-3M is now warranted.
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http://dx.doi.org/10.1111/jcpp.13460DOI Listing
June 2021

A planetary health model for reducing exposure to faecal contamination in urban informal settlements: Baseline findings from Makassar, Indonesia.

Environ Int 2021 Oct 12;155:106679. Epub 2021 Jun 12.

Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway, Malaysia; International Institute for Global Health, United Nations University, Kuala Lumpur, Malaysia.

Background: The intense interactions between people, animals and environmental systems in urban informal settlements compromise human and environmental health. Inadequate water and sanitation services, compounded by exposure to flooding and climate change risks, expose inhabitants to environmental contamination causing poor health and wellbeing and degrading ecosystems. However, the exact nature and full scope of risks and exposure pathways between human health and the environment in informal settlements are uncertain. Existing models are limited to microbiological linkages related to faecal-oral exposures at the individual level, and do not account for a broader range of human-environmental variables and interactions that affect population health and wellbeing.

Methods: We undertook a 12-month health and environmental assessment in 12 flood-prone informal settlements in Makassar, Indonesia. We obtained caregiver-reported health data, anthropometric measurements, stool and blood samples from children < 5 years, and health and wellbeing data for children 5-14 years and adult respondents. We collected environmental data including temperature, mosquito and rat species abundance, and water and sediment samples. Demographic, built environment and household asset data were also collected. We combined our data with existing literature to generate a novel planetary health model of health and environment in informal settlements.

Results: Across the 12 settlements, 593 households and 2764 participants were enrolled. Two-thirds (64·1%) of all houses (26·3-82·7% per settlement) had formal land tenure documentation. Cough, fever and diarrhoea in the week prior to the survey were reported among an average of 34.3%, 26.9% and 9.7% of children aged < 5 years, respectively; although proportions varied over time, prevalence among these youngest children was consistently higher than among children 5-14 years or adult respondents. Among children < 5 years, 44·3% experienced stunting, 41·1% underweight, 12.4% wasting, and 26.5% were anaemic. There was self- or carer-reported poor mental health among 16.6% of children aged 5-14 years and 13.9% of adult respondents. Rates of potential risky exposures from swimming in waterways, eating uncooked produce, and eating soil or dirt were high, as were exposures to flooding and livestock. Just over one third of households (35.3%) had access to municipal water, and contamination of well water with E. coli and nitrogen species was common. Most (79·5%) houses had an in-house toilet, but no houses were connected to a piped sewer network or safe, properly constructed septic tank. Median monthly settlement outdoor temperatures ranged from 26·2 °C to 29.3 °C, and were on average, 1·1 °C warmer inside houses than outside. Mosquito density varied over time, with Culex quinquefasciatus accounting for 94·7% of species. Framed by a planetary health lens, our model includes four thematic domains: (1) the physical/built environment; (2) the ecological environment; (3) human health; and (4) socio-economic wellbeing, and is structured at individual, household, settlement, and city/beyond spatial scales.

Conclusions: Our planetary health model includes key risk factors and faecal-oral exposure pathways but extends beyond conventional microbiological faecal-oral enteropathogen exposure pathways to comprehensively account for a wider range of variables affecting health in urban informal settlements. It includes broader ecological interconnections and planetary health-related variables at the household, settlement and city levels. It proposes a composite framework of markers to assess water and sanitation challenges and flood risks in urban informal settlements for optimal design and monitoring of interventions.
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http://dx.doi.org/10.1016/j.envint.2021.106679DOI Listing
October 2021

Expanded Genomic Sampling Refines Current Understanding of the Distribution and Evolution of Sulfur Metabolisms in the .

Front Microbiol 2021 19;12:666052. Epub 2021 May 19.

Department of Earth and Planetary Sciences, Harvard University, Cambridge, MA, United States.

The reconstruction of modern and paleo-sulfur cycling relies on understanding the long-term relative contribution of its main actors; these include microbial sulfate reduction (MSR) and microbial sulfur disproportionation (MSD). However, a unifying theory is lacking for how MSR and MSD, with the same enzyme machinery and intimately linked evolutionary histories, perform two drastically different metabolisms. Here, we aim at shedding some light on the distribution, diversity, and evolutionary histories of MSR and MSD, with a focus on the as a test case. The is a diverse and widespread order of bacteria in the (formerly ) phylum primarily composed of sulfate reducing bacteria. Recent culture- and sequence-based approaches have revealed an expanded diversity of organisms and metabolisms within this clade, including the presence of obligate and facultative sulfur disproportionators. Here, we present draft genomes of previously unsequenced species of , substantially expanding the available genomic diversity of this clade. We leverage this expanded genomic sampling to perform phylogenetic analyses, revealing an evolutionary history defined by vertical inheritance of sulfur metabolism genes with numerous convergent instances of transition from sulfate reduction to sulfur disproportionation.
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http://dx.doi.org/10.3389/fmicb.2021.666052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170396PMC
May 2021

Intergenerational transmission of child maltreatment in South Australia, 1986-2017: a retrospective cohort study.

Lancet Public Health 2021 Jul 30;6(7):e450-e461. Epub 2021 Apr 30.

Australian Centre for Precision Health, Cancer Research Institute, University of South Australia, Adelaide, SA, Australia; South Australian Health and Medical Research Institute, Adelaide, SA, Australia.

Background: The extent of intergenerational transmission of child maltreatment is unclear due to methodological limitations in previous studies. In this study, we aimed to examine factors associated with intergenerational transmission of child maltreatment and quantify its extent in a population sample over a 30-year period in South Australia.

Methods: In this retrospective cohort study, we used linked administrative data from the South Australian Birth Registry to identify dyads of mothers and their children both born in South Australia between July 1, 1986, and June 30, 2017. Three child protection system (CPS) outcomes (any CPS involvement, substantiated maltreatment, and time spent in out-of-home care) were computed from data obtained from the South Australian Department for Child Protection. Multivariable Cox regression models were used to estimate hazard ratios (HRs) for child CPS outcomes according to their mother's CPS exposure.

Findings: 38 556 unique mother-child dyads were included. 458 (2·0%) of 23 437 children whose mothers had no CPS involvement in childhood had a substantiated report of maltreatment and 127 (0·5%) spent time in out-of-home care. By comparison, 970 (22·1%) of 4382 children whose mothers experienced substantiated maltreatment in childhood had substantiated maltreatment and 469 (10·7%) spent time in out-of-home care. After adjusting for potential confounders, children of mothers with any CPS involvement in childhood had an increased risk of CPS contact compared with children whose mothers had no CPS involvement; this risk was greatest for children of mothers who had both substantiated maltreatment and spent time in out-of-home care (HR 6·25 [95% CI 5·59-6·98] for any CPS involvement, 13·69 [10·08-16·92] for substantiated maltreatment, and 25·78 [18·23-36·45] for any time in out-of-home care). Risks of child CPS outcomes were substantially increased for children of mothers who had a first CPS notification under the age of 1 year or who had any CPS notification at age 13-17 years.

Interpretation: Children are at high risk of maltreatment if their mother experienced maltreatment as a child. Assisting survivors of childhood maltreatment, particularly female survivors, provides a crucial intervention opportunity to help prevent further child abuse and neglect.

Funding: Australian National Health and Medical Research Council; Channel 7 Children's Research Foundation.
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http://dx.doi.org/10.1016/S2468-2667(21)00024-4DOI Listing
July 2021

A 200-million-year delay in permanent atmospheric oxygenation.

Nature 2021 Apr 29;592(7853):232-236. Epub 2021 Mar 29.

Department of Earth and Planetary Sciences, Harvard University, Cambridge, MA, USA.

The rise of atmospheric oxygen fundamentally changed the chemistry of surficial environments and the nature of Earth's habitability. Early atmospheric oxygenation occurred over a protracted period of extreme climatic instability marked by multiple global glaciations, with the initial rise of oxygen concentration to above 10 of the present atmospheric level constrained to about 2.43 billion years ago. Subsequent fluctuations in atmospheric oxygen levels have, however, been reported to have occurred until about 2.32 billion years ago, which represents the estimated timing of irreversible oxygenation of the atmosphere. Here we report a high-resolution reconstruction of atmospheric and local oceanic redox conditions across the final two glaciations of the early Palaeoproterozoic era, as documented by marine sediments from the Transvaal Supergroup, South Africa. Using multiple sulfur isotope and iron-sulfur-carbon systematics, we demonstrate continued oscillations in atmospheric oxygen levels after about 2.32 billion years ago that are linked to major perturbations in ocean redox chemistry and climate. Oxygen levels thus fluctuated across the threshold of 10 of the present atmospheric level for about 200 million years, with permanent atmospheric oxygenation finally arriving with the Lomagundi carbon isotope excursion at about 2.22 billion years ago, some 100 million years later than currently estimated.
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http://dx.doi.org/10.1038/s41586-021-03393-7DOI Listing
April 2021

Simultaneous combustion preparation for mercury isotope analysis and detection of total mercury using a direct mercury analyzer.

Anal Chim Acta 2021 Apr 17;1154:338327. Epub 2021 Feb 17.

Harvard John A. Paulson School of Engineering & Applied Sciences, Harvard University, 29 Oxford St, Cambridge, MA, 02138, USA; Department of Earth and Planetary Sciences, Harvard University, 20 Oxford St, Cambridge, MA, 02138, USA.

Mercury (Hg) stable isotope signatures are widely used to understand Hg cycling in the environment. Sample preparation methods for determining Hg isotope ratios by CV-MC-ICP-MS vary widely among laboratory facilities and sample types. Here, we present a novel and rapid method for preparing solid samples prior to determining Hg isotope composition. We use a direct Hg analyzer (that measures total Hg) for sample combustion, amalgamation and analysis. During the thermal release of Hg from the amalgamator and following detection, the analyte gas enters a trapping solution consisting of 10% HCl/BrCl (5:1, vol/vol). We find Hg blank values are less than 1% of the Hg introduced during sample analysis, Hg detection is not altered by modifying the system, and more than 90% of the introduced Hg is recovered in the trapping solution. Hg isotope results are statistically indistinguishable from accepted values for previously published certified reference materials and uncertainty of 2σ (0.05-0.12‰) is similar to the solution standard RM8610 (2σ = 0.09‰). This new method allows for solid sample preparation for Hg isotope analysis in under 15 min. It has the additional advantage of minimizing use of sample mass during simultaneous detection and preparation.
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http://dx.doi.org/10.1016/j.aca.2021.338327DOI Listing
April 2021

Oligomeric Aβ Induces an AMD-Like Phenotype and Accumulates in Lysosomes to Impair RPE Function.

Cells 2021 Feb 17;10(2). Epub 2021 Feb 17.

Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, MP 806, Tremona Road, Southampton SO16 6YD, UK.

Alzheimer's disease-associated amyloid beta (Aβ) proteins accumulate in the outer retina with increasing age and in eyes of age-related macular degeneration (AMD) patients. To study Aβ-induced retinopathy, wild-type mice were injected with nanomolar human oligomeric Aβ, which recapitulate the Aβ burden reported in human donor eyes. In vitro studies investigated the cellular effects of Aβ in endothelial and retinal pigment epithelial (RPE) cells. Results show subretinal Aβ-induced focal AMD-like pathology within 2 weeks. Aβ exposure caused endothelial cell migration, and morphological and barrier alterations to the RPE. Aβ co-localized to late-endocytic compartments of RPE cells, which persisted despite attempts to clear it through upregulation of lysosomal cathepsin B, revealing a novel mechanism of lysosomal impairment in retinal degeneration. The rapid upregulation of cathepsin B was out of step with the prolonged accumulation of Aβ within lysosomes, and contrasted with enzymatic responses to internalized photoreceptor outer segments (POS). Furthermore, RPE cells exposed to Aβ were identified as deficient in cargo-carrying lysosomes at time points that are critical to POS degradation. These findings imply that Aβ accumulation within late-endocytic compartments, as well as lysosomal deficiency, impairs RPE function over time, contributing to visual defects seen in aging and AMD eyes.
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http://dx.doi.org/10.3390/cells10020413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922851PMC
February 2021

Comparison of Gene Editing Versus Conventional Breeding to Introgress the Allele Into the Tropically Adapted Australian Beef Cattle Population.

Front Genet 2021 11;12:593154. Epub 2021 Feb 11.

Department of Animal Science, University of California, Davis, Davis, CA, United States.

Dehorning is the process of physically removing horns to protect animals and humans from injury, but the process is costly, unpleasant, and faces increasing public scrutiny. Genetic selection for polled (hornless), which is genetically dominant to horned, is a long-term solution to eliminate the need for dehorning. However, due to the limited number of polled Australian Brahman bulls, the northern Australian beef cattle population remains predominantly horned. The potential to use gene editing to produce high-genetic-merit polled cattle was recently demonstrated. To further explore the concept, this study simulated introgression of the allele into a tropically adapted Australian beef cattle population via conventional breeding or gene editing (top 1% or 10% of seedstock bulls/year) for 3 polled mating schemes and compared results to baseline selection on genetic merit (Japan Ox selection index, $JapOx) alone, over the course of 20 years. The baseline scenario did not significantly decrease the 20-year allele frequency (80%), but resulted in one of the fastest rates of genetic gain ($8.00/year). Compared to the baseline, the conventional breeding scenarios where polled bulls were preferentially used for breeding, regardless of their genetic merit, significantly decreased the 20-year allele frequency (30%), but resulted in a significantly slower rate of genetic gain ($6.70/year, ≤ 0.05). The mating scheme that required the exclusive use of homozygous polled bulls, resulted in the lowest 20-year allele frequency (8%), but this conventional breeding scenario resulted in the slowest rate of genetic gain ($5.50/year). The addition of gene editing the top 1% or 10% of seedstock bull calves/year to each conventional breeding scenario resulted in significantly faster rates of genetic gain (up to $8.10/year, ≤ 0.05). Overall, our study demonstrates that, due to the limited number of polled Australian Brahman bulls, strong selection pressure on polled will be necessary to meaningfully increase the number of polled animals in this population. Moreover, these scenarios illustrate how gene editing could be a tool for accelerating the development of high-genetic-merit homozygous polled sires to mitigate the current trade-off of slower genetic gain associated with decreasing allele frequency in the Australian Brahman population.
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http://dx.doi.org/10.3389/fgene.2021.593154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905321PMC
February 2021

The link between health and economic preferences: Evidence from 22 OECD countries.

Health Econ 2021 Apr 27;30(4):915-920. Epub 2021 Jan 27.

Stanford University School of Medicine, Stanford University, Stanford, California, USA.

We study the link between health status and economic preferences using survey data from 22 Organisation for Economic Co-operation and Development (OECD) countries. We hypothesize that there is a relationship between poor health and the preferences that people hold, and therefore their choices and decisions. We find that individuals with a limiting health condition are more risk averse and less patient, and that this is true for physical and mental health conditions. The magnitudes of the health gap are approximately 60% and 70% of the gender gap in risk and time preferences, respectively. Importantly, the health gaps are large for males, females, young, old, school dropouts, degree holders, employed, nonemployed, rich, and poor. They also hold for countries with different levels of gross domestic product (GDP), inequality, social expenditure, and disease burden.
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http://dx.doi.org/10.1002/hec.4225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262080PMC
April 2021

Immune cell infiltrates as prognostic biomarkers in pancreatic ductal adenocarcinoma: a systematic review and meta-analysis.

J Pathol Clin Res 2021 03 22;7(2):99-112. Epub 2021 Jan 22.

The Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK.

Immune cell infiltration has been identified as a prognostic biomarker in several cancers. However, no immune based biomarker has yet been validated for use in pancreatic ductal adenocarcinoma (PDAC). We undertook a systematic review and meta-analysis of immune cell infiltration, measured by immunohistochemistry (IHC), as a prognostic biomarker in PDAC. All other IHC prognostic biomarkers in PDAC were also summarised. MEDLINE, EMBASE and Web of Science were searched between 1998 and 2018. Studies investigating IHC biomarkers and prognosis in PDAC were included. REMARK score and Newcastle-Ottawa scale were used for qualitative analysis. Random-effects meta-analyses were used to pool results, where possible. Twenty-six articles studied immune cell infiltration IHC biomarkers and PDAC prognosis. Meta-analysis found high infiltration with CD4 (hazard ratio [HR] = 0.65, 95% confidence interval [CI] = 0.51-0.83.) and CD8 (HR = 0.68, 95% CI = 0.55-0.84.) T-lymphocytes associated with better disease-free survival. Reduced overall survival was associated with high CD163 (HR = 1.62, 95% CI = 1.03-2.56). Infiltration of CD3, CD20, FoxP3 and CD68 cells, and PD-L1 expression was not prognostic. In total, 708 prognostic biomarkers were identified in 1101 studies. In summary, high CD4 and CD8 infiltration are associated with better disease-free survival in PDAC. Increased CD163 is adversely prognostic. Despite the publication of 708 IHC prognostic biomarkers in PDAC, none has been validated for clinical use. Further research should focus on reproducibility of prognostic biomarkers in PDAC in order to achieve this.
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http://dx.doi.org/10.1002/cjp2.192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869931PMC
March 2021

A novel ACE2 isoform is expressed in human respiratory epithelia and is upregulated in response to interferons and RNA respiratory virus infection.

Nat Genet 2021 02 11;53(2):205-214. Epub 2021 Jan 11.

Faculty of Medicine, School of Clinical and Experimental Sciences, University of Southampton, Southampton, UK.

Angiotensin-converting enzyme 2 (ACE2) is the main entry point in airway epithelial cells for SARS-CoV-2. ACE2 binding to the SARS-CoV-2 protein spike triggers viral fusion with the cell plasma membrane, resulting in viral RNA genome delivery into the host. Despite ACE2's critical role in SARS-CoV-2 infection, full understanding of ACE2 expression, including in response to viral infection, remains unclear. ACE2 was thought to encode five transcripts and one protein of 805 amino acids. In the present study, we identify a novel short isoform of ACE2 expressed in the airway epithelium, the main site of SARS-CoV-2 infection. Short ACE2 is substantially upregulated in response to interferon stimulation and rhinovirus infection, but not SARS-CoV-2 infection. This short isoform lacks SARS-CoV-2 spike high-affinity binding sites and, altogether, our data are consistent with a model where short ACE2 is unlikely to directly contribute to host susceptibility to SARS-CoV-2 infection.
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http://dx.doi.org/10.1038/s41588-020-00759-xDOI Listing
February 2021

Study design, rationale and methods of the Revitalising Informal Settlements and their Environments (RISE) study: a cluster randomised controlled trial to evaluate environmental and human health impacts of a water-sensitive intervention in informal settlements in Indonesia and Fiji.

BMJ Open 2021 01 8;11(1):e042850. Epub 2021 Jan 8.

School of Public Health and Primary Care, Fiji National University, College of Medicine, Nursing and Health Sciences, Tamavua Campus, Suva, Rewa, Fiji.

Introduction: Increasing urban populations have led to the growth of informal settlements, with contaminated environments linked to poor human health through a range of interlinked pathways. Here, we describe the design and methods for the Revitalising Informal Settlements and their Environments (RISE) study, a transdisciplinary randomised trial evaluating impacts of an intervention to upgrade urban informal settlements in two Asia-Pacific countries.

Methods And Analysis: RISE is a cluster randomised controlled trial among 12 settlements in Makassar, Indonesia, and 12 in Suva, Fiji. Six settlements in each country have been randomised to receive the intervention at the outset; the remainder will serve as controls and be offered intervention delivery after trial completion. The intervention involves a water-sensitive approach, delivering site-specific, modular, decentralised infrastructure primarily aimed at improving health by decreasing exposure to environmental faecal contamination. Consenting households within each informal settlement site have been enrolled, with longitudinal assessment to involve health and well-being surveys, and human and environmental sampling. Primary outcomes will be evaluated in children under 5 years of age and include prevalence and diversity of gastrointestinal pathogens, abundance and diversity of antimicrobial resistance (AMR) genes in gastrointestinal microorganisms and markers of gastrointestinal inflammation. Diverse secondary outcomes include changes in microbial contamination; abundance and diversity of pathogens and AMR genes in environmental samples; impacts on ecological biodiversity and microclimates; mosquito vector abundance; anthropometric assessments, nutrition markers and systemic inflammation in children; caregiver-reported and self-reported health symptoms and healthcare utilisation; and measures of individual and community psychological, emotional and economic well-being. The study aims to provide proof-of-concept evidence to inform policies on upgrading of informal settlements to improve environments and human health and well-being.

Ethics: Study protocols have been approved by ethics boards at Monash University, Fiji National University and Hasanuddin University.

Trial Registration Number: ACTRN12618000633280; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2020-042850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7798802PMC
January 2021

Inferring the effectiveness of government interventions against COVID-19.

Science 2021 02 15;371(6531). Epub 2020 Dec 15.

Future of Humanity Institute, University of Oxford, Oxford, UK.

Governments are attempting to control the COVID-19 pandemic with nonpharmaceutical interventions (NPIs). However, the effectiveness of different NPIs at reducing transmission is poorly understood. We gathered chronological data on the implementation of NPIs for several European and non-European countries between January and the end of May 2020. We estimated the effectiveness of these NPIs, which range from limiting gathering sizes and closing businesses or educational institutions to stay-at-home orders. To do so, we used a Bayesian hierarchical model that links NPI implementation dates to national case and death counts and supported the results with extensive empirical validation. Closing all educational institutions, limiting gatherings to 10 people or less, and closing face-to-face businesses each reduced transmission considerably. The additional effect of stay-at-home orders was comparatively small.
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http://dx.doi.org/10.1126/science.abd9338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877495PMC
February 2021

Short-range ferromagnetic order due to Ir substitutions in single-crystallineBa(CoIr)As(0 ≤ x ≤ 0.25).

J Phys Condens Matter 2020 Dec 14. Epub 2020 Dec 14.

Department of Physics and Astronomy, Ames Laboratory, 311 Iowa State University, Ames, Iowa, 50011, UNITED STATES.

The ternary-arsenide compound BaCoAswas previously proposed to be in proximity to a quantum-critical point where long-range ferromagnetic (FM) order is suppressed by quantum fluctuations. Here we report the effect of Ir substitutions for Co on the magnetic and thermal properties of Ba(CoIr)As(0 ≤ x ≤ 0.25) single crystals. These compositions all crystallize in an uncollapsed body-centered-tetragonal ThCrSistructure with space group4/. Magnetic susceptibility measurements reveal clear signatures of short-range FM ordering for x ≥ 0.11 below a nearly composition-independent characteristic temperature≈ 13 K. The small variation ofwith x, thermomagnetic irreversibility between zero-field-cooled and field-cooled magnetic susceptibility versus, the occurrence of hysteresis in magnetization versus field isotherms at low field and temperature, and very small spontaneous and remanent magnetizations < 0.01 μ/f.u. together indicate that the FM response arises from short-range FM ordering of FM spin clusters as previously inferred to occur in Ca(CoIr)As. Heat-capacity() data do not exhibit any clear feature around, consistent with the very small moments of the FM clusters. The() in the paramagnetic temperature regime 25-300 K is well described by the sum of a Sommerfeld electronic contribution and Debye and Einstein lattice contributions where the latter lattice contribution suggests the presence of low-frequency optic modes associated with the heavy Ba atoms in the crystals.
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http://dx.doi.org/10.1088/1361-648X/abd339DOI Listing
December 2020

The Role of Cholesterol on Triterpenoid Saponin-Induced Endolysosomal Escape of a Saporin-Based Immunotoxin.

Int J Mol Sci 2020 Nov 19;21(22). Epub 2020 Nov 19.

The Simon Flavell Leukaemia Research Laboratory, Southampton General Hospital, Southampton SO16 6YD, UK.

Cholesterol seems to play a central role in the augmentation of saporin-based immunotoxin (IT) cytotoxicity by triterpenoid saponins. Endolysosomal escape has been proposed as one mechanism for the saponin-mediated enhancement of targeted toxins. We investigated the effects of lipid depletion followed by repletion on (SA)-induced endolysosomal escape of Alexa Fluor labelled saporin and the saporin-based immunotoxin OKT10-SAP, directed against CD38, in Daudi lymphoma cells. Lipid deprived cells showed reduced SA-induced endolysosomal escape at two concentrations of SA, as determined by a flow cytometric method. The repletion of membrane cholesterol by low density lipoprotein (LDL) restored SA-induced endolysosomal escape at a concentration of 5 µg/mL SA but not at 1 µg/mL SA. When LDL was used to restore the cholesterol levels in lipid deprived cells, the SA augmentation of OKT10-SAP cytotoxicity was partially restored at 1 µg/mL SA and fully restored at 5 µg/mL SA. These results suggest that different mechanisms of action might be involved for the two different concentrations of SA and that endosomal escape may not be the main mechanism for the augmentation of saporin IT cytotoxicity by SA at the sub-lytic concentration of 1 µg/mL SA.
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http://dx.doi.org/10.3390/ijms21228734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699356PMC
November 2020

Pericytes on placental capillaries in terminal villi preferentially cover endothelial junctions in regions furthest away from the trophoblast.

Placenta 2021 01 7;104:1-7. Epub 2020 Nov 7.

Human Development and Health, Faculty of Medicine, University of Southampton, UK; Institute for Life Sciences, University of Southampton, UK. Electronic address:

Introduction: Pericytes are a common feature in the placental microvasculature but their roles are not well understood. Pericytes may provide physical or endocrine support for endothelium and in some tissues mediate vasoconstriction.

Methods: This study uses serial block-face scanning electron microscopy (SBFSEM) to generate three-dimensional (3D) reconstructions of placental pericytes of the terminal villi and transmission electron microscopy (TEM) to study pericyte endothelial cell interactions. The proportion of endothelial cell junctions covered by pericytes was determined.

Results: The detailed 3D models of placental pericytes show pericyte structure at a new level of detail. Placental pericytes have many fingers extending from the cell body which can span multiple capillary branches. The proportion of endothelial cell-cell junctions covered by pericytes was significantly higher than pericyte coverage of capillary endothelium as a whole (endothelium: 14%, junctions: 43%, p < 0.0001). However, the proportion of endothelial cell-cell junctions covered by pericytes in regions adjacent to trophoblast was reduced compared to regions >3 μm away from trophoblast (27% vs 62% respectively, p < 0.001). No junctional complexes were observed connecting pericytes and endothelial cells but there were regions of cell membrane with features suggestive of intercellular adhesions.

Discussion: These data suggest that the localisation of pericytes on the villous capillary is not random but organised in relation to both endothelial junctions and the location of adjacent trophoblast. This further suggests that pericyte coverage may favour capillary permeability in regions that are most important for exchange, but limit capillary permeability in other regions.
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http://dx.doi.org/10.1016/j.placenta.2020.10.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921774PMC
January 2021

When Childhood Cancer Becomes a Family Affair, It Really Hits Home.

Pediatr Clin North Am 2020 12;67(6):1021-1031

Division of Pediatric Hematology/Oncology, University of Nevada, Reno, Renown Children's Hospital, 1155 Mill Street, Reno, NV 89502, USA. Electronic address:

In this article, a father and son describe the experience of childhood leukemia treatment and its aftermath with the unique perspective of a parent who is also a pediatric oncologist. An illness that began with an apparently favorable prognosis was transformed by an early relapse, followed by unexpected complications and difficult treatment decisions. Despite unfavorable statistics, the son is a long-term survivor with an overall excellent quality of life, despite several late events and effects. His father, in the meantime, gained insights that now inform his own practice.
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http://dx.doi.org/10.1016/j.pcl.2020.07.001DOI Listing
December 2020

Isotopic Fractionation Associated With Sulfate Import and Activation by str. Hildenborough.

Front Microbiol 2020 18;11:529317. Epub 2020 Sep 18.

Department of Earth and Planetary Sciences, Washington University in St. Louis, St. Louis, MO, United States.

The use of stable isotopes to trace biogeochemical sulfur cycling relies on an understanding of how isotopic fractionation is imposed by metabolic networks. We investigated the effects of the first two enzymatic steps in the dissimilatory sulfate reduction (DSR) network - sulfate permease and sulfate adenylyl transferase (Sat) - on the sulfur and oxygen isotopic composition of residual sulfate. Mutant strains of str. Hildenborough (DvH) with perturbed expression of these enzymes were grown in batch culture, with a subset grown in continuous culture, to examine the impact of these enzymatic steps on growth rate, cell specific sulfate reduction rate and isotopic fractionations in comparison to the wild type strain. Deletion of several permease genes resulted in only small (∼1‰) changes in sulfur isotope fractionation, a difference that approaches the uncertainties of the measurement. Mutants that perturb Sat expression show higher fractionations than the wild type strain. This increase probably relates to an increased material flux between sulfate and APS, allowing an increase in the expressed fractionation of rate-limiting APS reductase. This work illustrates that flux through the initial steps of the DSR pathway can affect the fractionation imposed by the overall pathway, even though these steps are themselves likely to impose only small fractionations.
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http://dx.doi.org/10.3389/fmicb.2020.529317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7531388PMC
September 2020

Wearing one for the team: views and attitudes to face covering in New Zealand/Aotearoa during COVID-19 Alert Level 4 lockdown.

J Prim Health Care 2020 09;12(3):199-206

University of Otago, PO Box 7343, Wellington, New Zealand.

INTRODUCTION Mass masking is emerging as a key non-pharmaceutical intervention for reducing community spread of COVID-19. However, although hand washing, social distancing and bubble living have been widely adopted by the 'team of 5 million', mass masking has not been socialised to the general population. AIM To identify factors associated with face masking in New Zealand during COVID-19 Alert Level 4 lockdown to inform strategies to socialise and support mass masking. METHODS A quantitative online survey conducted in New Zealand during April 2020 invited residents aged ≥18 years to complete a questionnaire. Questions about face masking were included in the survey. The sample was drawn from a commissioned research panel survey, with boosted sampling for Māori and Pacific participants. Responses were weighted to reflect the New Zealand population for all analyses. RESULTS A total of 1015 individuals participated. Self-reported beliefs were strongly related to behaviours, with respondents viewing face masking measures as 'somewhat' or 'very' effective in preventing them from contracting COVID-19 more likely to report having worn a face mask than respondents who viewed them as 'not at all' effective. The strongest barriers to face mask use included beliefs that there was a mask shortage and that the needs of others were greater than their own. DISCUSSION Highlighting the efficacy of and dispelling myths about the relative efficacy of mask types and socialising people to the purpose of mass masking will contribute to community protective actions of mask wearing in the New Zealand response to COVID-19.
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http://dx.doi.org/10.1071/HC20089DOI Listing
September 2020

An In-Vitro Cell Model of Intracellular Protein Aggregation Provides Insights into RPE Stress Associated with Retinopathy.

Int J Mol Sci 2020 Sep 11;21(18). Epub 2020 Sep 11.

Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, MP806, Tremona Road, Southampton SO16 6YD, UK.

Impaired cargo trafficking and the aggregation of intracellular macromolecules are key features of neurodegeneration, and a hallmark of aged as well as diseased retinal pigment epithelial (RPE) cells in the eye. Here, photoreceptor outer segments (POS), which are internalized daily by RPE cells, were modified by UV-irradiation to create oxidatively modified POS (OxPOS). Oxidative modification was quantified by a protein carbonyl content assay. Human ARPE-19 cells were synchronously pulsed with POS or OxPOS to study whether oxidatively modified cargos can recapitulate features of RPE pathology associated with blinding diseases. Confocal immunofluorescence microscopy analysis showed that OxPOS was trafficked to LAMP1, LAMP2 lysosomes and to LC3b autophagy vacuoles. Whilst POS were eventually degraded, OxPOS cargos were sequestered in late compartments. Co-localization of OxPOS was also associated with swollen autolysosomes. Ultrastructural analysis revealed the presence of electron-dense OxPOS aggregates in RPE cells, which appeared to be largely resistant to degradation. Measurement of cellular autofluorescence, using parameters used to assess fundus autofluorescence (FAF) in age-related macular disease (AMD) patients, revealed that OxPOS contributed significantly to a key feature of aged and diseased RPE. This in vitro cell model therefore represents a versatile tool to study disease pathways linked with RPE damage and sight-loss.
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http://dx.doi.org/10.3390/ijms21186647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555953PMC
September 2020

Volcanic controls on seawater sulfate over the past 120 million years.

Proc Natl Acad Sci U S A 2020 09 17;117(35):21118-21124. Epub 2020 Aug 17.

Department of Earth and Planetary Sciences, Harvard University, Cambridge, MA 02139.

Changes in the geological sulfur cycle are inferred from the sulfur isotopic composition of marine barite. The structure of the S/S record from the Mesozoic to present, which includes ∼50- and 100-Ma stepwise increases, has been interpreted as the result of microbial isotope effects or abrupt changes to tectonics and associated pyrite burial. Untangling the physical processes that govern the marine sulfur cycle and associated isotopic change is critical to understanding how climate, atmospheric oxygenation, and marine ecology have coevolved over geologic time. Here we demonstrate that the sulfur outgassing associated with emplacement of large igneous provinces can produce the apparent stepwise jumps in the isotopic record when coupled to long-term changes in burial efficiency. The record of large igneous provinces map onto the required outgassing events in our model, with the two largest steps in the sulfur isotope record coinciding with the emplacement of large igneous provinces into volatile-rich sedimentary basins. This solution provides a quantitative picture of the last 120 My of change in the ocean's largest oxidant reservoir.
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http://dx.doi.org/10.1073/pnas.1921308117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474628PMC
September 2020

Peri-arterial pathways for clearance of α-Synuclein and tau from the brain: Implications for the pathogenesis of dementias and for immunotherapy.

Alzheimers Dement (Amst) 2020 28;12(1):e12070. Epub 2020 Jul 28.

Faculty of Medicine University of Southampton Southampton UK.

Introduction: Accumulation of amyloid beta (Aβ), α-synuclein (αSyn), and tau in dementias indicates their age-related failure of elimination from the brain. Aβ is eliminated along basement membranes in walls of cerebral arterioles and leptomeningeal arteries (intramural peri-arterial drainage [IPAD]); IPAD is impaired with age. We test the hypothesis that αSyn and tau are also eliminated from the normal brain along IPAD pathways.

Methods: Soluble αSyn or tau was injected into mouse hippocampus. Animals were perfused 5 minutes to 7 days post-injection. Blood vessels were identified by ROX-SE for light-sheet and immunolabeling for confocal microscopy. IPAD was quantified by measuring the proportion of arterioles with αSyn/tau.

Results: αSyn and tau are eliminated from the brain by IPAD but with different dynamics.

Discussion: Age-related failure of IPAD may play a role in the pathogenesis of synucleinopathies and tauopathies. αSyn persists within IPAD at 24 hours, which may affect immunotherapy for αSyn.
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http://dx.doi.org/10.1002/dad2.12070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409108PMC
July 2020

Preventing depression using a smartphone app: a randomized controlled trial.

Psychol Med 2020 Jul 6:1-10. Epub 2020 Jul 6.

Black Dog Institute, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.

Background: There is evidence that depression can be prevented; however, traditional approaches face significant scalability issues. Digital technologies provide a potential solution, although this has not been adequately tested. The aim of this study was to evaluate the effectiveness of a new smartphone app designed to reduce depression symptoms and subsequent incident depression amongst a large group of Australian workers.

Methods: A randomized controlled trial was conducted with follow-up assessments at 5 weeks and 3 and 12 months post-baseline. Participants were employed Australians reporting no clinically significant depression. The intervention group (N = 1128) was allocated to use HeadGear, a smartphone app which included a 30-day behavioural activation and mindfulness intervention. The attention-control group (N = 1143) used an app which included a 30-day mood monitoring component. The primary outcome was the level of depressive symptomatology (PHQ-9) at 3-month follow-up. Analyses were conducted within an intention-to-treat framework using mixed modelling.

Results: Those assigned to the HeadGear arm had fewer depressive symptoms over the course of the trial compared to those assigned to the control (F3,734.7 = 2.98, p = 0.031). Prevalence of depression over the 12-month period was 8.0% and 3.5% for controls and HeadGear recipients, respectively, with odds of depression caseness amongst the intervention group of 0.43 (p = 0.001, 95% CI 0.26-0.70).

Conclusions: This trial demonstrates that a smartphone app can reduce depression symptoms and potentially prevent incident depression caseness and such interventions may have a role in improving working population mental health. Some caution in interpretation is needed regarding the clinical significance due to small effect size and trial attrition.Trial Registration Australian and New Zealand Clinical Trials Registry (www.anzctr.org.au/) ACTRN12617000548336.
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http://dx.doi.org/10.1017/S0033291720002081DOI Listing
July 2020

ApoE4 Astrocytes Secrete Basement Membranes Rich in Fibronectin and Poor in Laminin Compared to ApoE3 Astrocytes.

Int J Mol Sci 2020 Jun 19;21(12). Epub 2020 Jun 19.

Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.

The accumulation of amyloid-β (Aβ) in the walls of capillaries and arteries as cerebral amyloid angiopathy (CAA) is part of the small vessel disease spectrum, related to a failure of elimination of Aβ from the brain. Aβ is eliminated along basement membranes in walls of cerebral capillaries and arteries (Intramural Peri-Arterial Drainage-IPAD), a pathway that fails with age and ApolipoproteinEε4 (ApoE4) genotype. IPAD is along basement membranes formed by capillary endothelial cells and surrounding astrocytes. Here, we examine (1) the composition of basement membranes synthesised by ApoE4 astrocytes; (2) structural differences between ApoE4 and ApoE3 astrocytes, and (3) how flow of Aβ affects Apo3/4 astrocytes. Using cultured astrocytes expressing ApoE3 or ApoE4, immunofluorescence, confocal, correlative light and electron microscopy (CLEM), and a millifluidic flow system, we show that ApoE4 astrocytes synthesise more fibronectin, possess smaller processes, and become rarefied when Aβ flows over them, as compared to ApoE3 astrocytes. Our results suggest that basement membranes synthesised by ApoE4 astrocytes favour the aggregation of Aβ, its reduced clearance via IPAD, thus promoting cerebral amyloid angiopathy.
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http://dx.doi.org/10.3390/ijms21124371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352194PMC
June 2020

Isotopically anomalous organic carbon in the aftermath of the Marinoan snowball Earth.

Geobiology 2020 07;18(4):476-485

Department of Earth and Planetary Sciences, Harvard University, Cambridge, MA, USA.

Throughout most of the sedimentary record, the marine carbon cycle is interpreted as being in isotopic steady state. This is most commonly inferred via isotopic reconstructions, where two export fluxes (organic carbon and carbonate) are offset by a constant isotopic fractionation of ~25 (termed ). Sedimentary deposits immediately overlying the Marinoan snowball Earth diamictites, however, stray from this prediction. In stratigraphic sections from the Ol Formation (Mongolia) and Sheepbed Formation (Canada), we observe a temporary excursion where the organic matter has anomalously heavy C and is grossly decoupled from the carbonate C. This signal may reflect the unique biogeochemical conditions that persisted in the aftermath of snowball Earth. For example, physical oceanographic modeling suggests that a strong density gradient caused the ocean to remain stratified for about 50,000 years after termination of the Marinoan snowball event, during which time the surface ocean and continental weathering consumed the large atmospheric CO reservoir. Further, we now better understand how C records of carbonate can be post-depostionally altered and thus be misleading. In an attempt to explain the observed carbon isotope record, we developed a model that tracks the fluxes and isotopic values of carbon between the surface ocean, deep ocean, and atmosphere. By comparing the model output to the sedimentary data, stratification alone cannot generate the anomalous observed isotopic signal. Reproducing the heavy C in organic matter requires the progressively diminishing contribution of an additional anomalous source of organic matter. The exact source of this organic matter is unclear.
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http://dx.doi.org/10.1111/gbi.12383DOI Listing
July 2020

Genomic sequence analysis of SH388 and proposed reassignment to fam. nov.

Microb Genom 2020 07 17;6(7). Epub 2020 Jun 17.

Department of Earth and Planetary Sciences, Harvard University, Cambridge, MA, USA.

Here, we report the draft genome sequence of SH388. Improved phylogenetic and taxonomic analysis of this organism using genome-level analyses supports assignment of this organism to a novel family within the phylum . Additionally, comparative genomic and phylogenetic analyses contextualize the convergent evolution of sulfur disproportionation and potential extracellular electron transfer in this organism relative to other members of the .
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http://dx.doi.org/10.1099/mgen.0.000390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478628PMC
July 2020

Author's Response.

Authors:
David Johnston

Am J Trop Med Hyg 2019 10;101(4):952

Hawaii Department of Health.

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http://dx.doi.org/10.4269/ajtmh.19-0546bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779198PMC
October 2019

Ediacaran reorganization of the marine phosphorus cycle.

Proc Natl Acad Sci U S A 2020 06 18;117(22):11961-11967. Epub 2020 May 18.

Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 20138

The Ediacaran Period (635 to 541 Ma) marks the global transition to a more productive biosphere, evidenced by increased availability of food and oxidants, the appearance of macroscopic animals, significant populations of eukaryotic phytoplankton, and the onset of massive phosphorite deposition. We propose this entire suite of changes results from an increase in the size of the deep-water marine phosphorus reservoir, associated with rising sulfate concentrations and increased remineralization of organic P by sulfate-reducing bacteria. Simple mass balance calculations, constrained by modern anoxic basins, suggest that deep-water phosphate concentrations may have increased by an order of magnitude without any increase in the rate of P input from the continents. Strikingly, despite a major shift in phosphorite deposition, a new compilation of the phosphorus content of Neoproterozoic and early Paleozoic shows little secular change in median values, supporting the view that changes in remineralization and not erosional P fluxes were the principal drivers of observed shifts in phosphorite accumulation. The trigger for these changes may have been transient Neoproterozoic weathering events whose biogeochemical consequences were sustained by a set of positive feedbacks, mediated by the oxygen and sulfur cycles, that led to permanent state change in biogeochemical cycling, primary production, and biological diversity by the end of the Ediacaran Period.
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http://dx.doi.org/10.1073/pnas.1916738117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275700PMC
June 2020