Catalogue Search | MBRL
Are you sure you want to remove the book from the shelf?
{{itemTitle}}
2,339
result(s) for
"Smith, Samantha"
Sort by:
Autism genes converge on asynchronous development of shared neuron classes
Genetic risk for autism spectrum disorder (ASD) is associated with hundreds of genes spanning a wide range of biological functions
1
–
6
. The alterations in the human brain resulting from mutations in these genes remain unclear. Furthermore, their phenotypic manifestation varies across individuals
7
,
8
. Here we used organoid models of the human cerebral cortex to identify cell-type-specific developmental abnormalities that result from haploinsufficiency in three ASD risk genes—
SUV420H1
(also known as
KMT5B
),
ARID1B
and
CHD8
—in multiple cell lines from different donors, using single-cell RNA-sequencing (scRNA-seq) analysis of more than 745,000 cells and proteomic analysis of individual organoids, to identify phenotypic convergence. Each of the three mutations confers asynchronous development of two main cortical neuronal lineages—γ-aminobutyric-acid-releasing (GABAergic) neurons and deep-layer excitatory projection neurons—but acts through largely distinct molecular pathways. Although these phenotypes are consistent across cell lines, their expressivity is influenced by the individual genomic context, in a manner that is dependent on both the risk gene and the developmental defect. Calcium imaging in intact organoids shows that these early-stage developmental changes are followed by abnormal circuit activity. This research uncovers cell-type-specific neurodevelopmental abnormalities that are shared across ASD risk genes and are finely modulated by human genomic context, finding convergence in the neurobiological basis of how different risk genes contribute to ASD pathology.
Haploinsufficiency in three genes associated with risk of autism spectrum disorder—
KMT5B
,
ARID1B
and
CHD8
—in cell lines from multiple donors results in cell-type-specific asynchronous development of GABAergic neurons and cortical deep-layer excitatory projection neurons.
Journal Article
Meteorites : the story of our solar system
\"A fascinating and authoritative introduction to the science of meteorites, written by leading experts in the field. Meteorites are rocks from space that have fallen to the Earth's surface. Once considered bad omens, they are now recognized for giving us a unique insight into the nature of the material that was present when our solar system formed. In Meteorites, experts from the Natural History Museum in London, England, provide a compelling and up-to-date introduction to these otherworldly objects. This fully illustrated guide reveals: What meteorites are; where meteorites come from; what type of celestial bodie s they come from; and information on key meteorite falls. In clear, jargon-free language, the authors explain how meteorites provide us with invaluable information about planets beyond Earth-- both within our solar system and around other stars. With its combination of color photographs, diagrams and maps, Meteorites is the ultimate reference to these mysterious objects from space\"-- Provided by publisher.
Book
Evidence on the cost and cost-effectiveness of palliative care: A literature review
Background:
In the context of limited resources, evidence on costs and cost-effectiveness of alternative methods of delivering health-care services is increasingly important to facilitate appropriate resource allocation. Palliative care services have been expanding worldwide with the aim of improving the experience of patients with terminal illness at the end of life through better symptom control, coordination of care and improved communication between professionals and the patient and family.
Aim:
To present results from a comprehensive literature review of available international evidence on the costs and cost-effectiveness of palliative care interventions in any setting (e.g. hospital-based, home-based and hospice care) over the period 2002–2011.
Design:
Key bibliographic and review databases were searched. Quality of retrieved papers was assessed against a set of 31 indicators developed for this review.
Data Sources:
PubMed, EURONHEED, the Applied Social Sciences Index and the Cochrane library of databases.
Results:
A total of 46 papers met the criteria for inclusion in the review, examining the cost and/or utilisation implications of a palliative care intervention with some form of comparator. The main focus of these studies was on direct costs with little focus on informal care or out-of-pocket costs. The overall quality of the studies is mixed, although a number of cohort studies do undertake multivariate regression analysis.
Conclusion:
Despite wide variation in study type, characteristic and study quality, there are consistent patterns in the results. Palliative care is most frequently found to be less costly relative to comparator groups, and in most cases, the difference in cost is statistically significant.
Journal Article
Clinician’s perspectives on gene therapy for Alzheimer’s disease: A qualitative study
We aimed to understand clinician views regarding gene therapy as a future treatment for Alzheimer's disease (AD) and potential barriers and facilitators to its use.
We interviewed ten clinicians who treat patients with AD. Clinicians helped design a semi-structured interview including the following domains: establishing understanding, cost/access, quality of life, and religion/spirituality. Transcripts were analyzed by a coding team using descriptive content analysis with inductive approach.
Clinicians identified three main areas of concern: 1) potential clinician and patient understanding of gene therapy and Alzheimer's disease 2) consideration of inequity (i.e., care access, disease awareness along with education level, family support, trust in care systems); and 3) considerations in decision-making (i.e., religious/spiritual beliefs and method of treatment delivery as a decision-making tools).
Findings highlight areas for knowledge-building for patients and clinicians alike. Clinicians must be aware of patient/family educational needs and gaps in their own clinical knowledge before engaging patients/families with new technology. Allowing time for questions is crucial to building rapport and trust.
Journal Article
Characterisation of CD4+ T-cell subtypes using single cell RNA sequencing and the impact of cell number and sequencing depth
CD4+ T-cells represent a heterogeneous collection of specialised sub-types and are a key cell type in the pathogenesis of many diseases due to their role in the adaptive immune system. By investigating CD4+ T-cells at the single cell level, using RNA sequencing (scRNA-seq), there is the potential to identify specific cell states driving disease or treatment response. However, the impact of sequencing depth and cell numbers, two important factors in scRNA-seq, has not been determined for a complex cell population such as CD4+ T-cells. We therefore generated a high depth, high cell number dataset to determine the effect of reduced sequencing depth and cell number on the ability to accurately identify CD4+ T-cell subtypes. Furthermore, we investigated T-cell signatures under resting and stimulated conditions to assess cluster specific effects of stimulation. We found that firstly, cell number has a much more profound effect than sequencing depth on the ability to classify cells; secondly, this effect is greater when cells are unstimulated and finally, resting and stimulated samples can be combined to leverage additional power whilst still allowing differences between samples to be observed. While based on one individual, these results could inform future scRNA-seq studies to ensure the most efficient experimental design.
Journal Article
Opposing functions of the plant TOPLESS gene family during SNC1-mediated autoimmunity
Regulation of the plant immune system is important for controlling the specificity and amplitude of responses to pathogens and in preventing growth-inhibiting autoimmunity that leads to reductions in plant fitness. In previous work, we reported that SRFR1, a negative regulator of effector-triggered immunity, interacts with SNC1 and EDS1. When SRFR1 is non-functional in the Arabidopsis accession Col-0, SNC1 levels increase, causing a cascade of events that lead to autoimmunity phenotypes. Previous work showed that some members of the transcriptional co-repressor family TOPLESS interact with SNC1 to repress negative regulators of immunity. Therefore, to explore potential connections between SRFR1 and TOPLESS family members, we took a genetic approach that examined the effect of each TOPLESS member in the srfr1 mutant background. The data indicated that an additive genetic interaction exists between SRFR1 and two members of the TOPLESS family, TPR2 and TPR3 , as demonstrated by increased stunting and elevated PR2 expression in srfr1 tpr2 and srfr1 tpr2 tpr3 mutants. Furthermore, the tpr2 mutation intensifies autoimmunity in the auto-active snc1-1 mutant, indicating a novel role of these TOPLESS family members in negatively regulating SNC1 -dependent phenotypes. This negative regulation can also be reversed by overexpressing TPR2 in the srfr1 tpr2 background. Similar to TPR1 that positively regulates snc1-1 phenotypes by interacting with SNC1, we show here that TPR2 directly binds the N-terminal domain of SNC1. In addition, TPR2 interacts with TPR1 in vivo , suggesting that the opposite functions of TPR2 and TPR1 are based on titration of SNC1-TPR1 complexes by TPR2 or altered functions of a SNC1-TPR1-TPR2 complex. Thus, this work uncovers diverse functions of individual members of the TOPLESS family in Arabidopsis and provides evidence for the additive effect of transcriptional and post-transcriptional regulation of SNC1 .
Journal Article
Trainee growth vs. fixed mindset in clinical learning environments: enhancing, hindering and goldilocks factors
Background
Doctors in training (trainees) have higher rates of burnout, anxiety and depression than other professionals. An important psychological tool to combat this crisis is promotion of a growth mindset, which increases resilience and improves mental health outcomes. How growth mindset might be promoted within the clinical learning environment is underexplored. This study aimed to explore the factors promoting a growth mindset versus fixed mindset in trainees from the perspective of the trainees.
Methods
This constructivist study employed a novel method of encouraging trainees’ reflections on mindset adoption in the clinical learning environment. Trainees played Mindset, a tabletop simulation board game that included challenges encountered within training. This was followed by a facilitated debriefing, focusing on factors that promoted growth or fixed mindset adoption in the clinical learning environment. Debriefing transcripts were analysed using template analysis.
Results
Three groups of oncology trainees and one group of medical education fellows participated (16 participants in total). Factors promoting growth mindset adoption included passion, collaboration, diverse career and role modelling. Factors promoting fixed mindset adoption included burnout and competition. Some factors, such as grit, previous success experience and singular training location promoted a fixed mindset when too much or too little were present, and promoted a growth mindset when they were in balance (the Goldilocks principle).
Conclusions
The importance of balance versus excess of certain factors, and the ubiquitous competitive culture in medicine promoting a fixed mindset, were compelling reflections. This study may aid invested parties to reflect on what factors they can upregulate and down regulate to optimise trainees’ adoption of a growth mindset.
Journal Article
CD163+ macrophages promote angiogenesis and vascular permeability accompanied by inflammation in atherosclerosis
Intake of hemoglobin by the hemoglobin-haptoglobin receptor CD163 leads to a distinct alternative non-foam cell antiinflammatory macrophage phenotype that was previously considered atheroprotective. Here, we reveal an unexpected but important pathogenic role for these macrophages in atherosclerosis. Using human atherosclerotic samples, cultured cells, and a mouse model of advanced atherosclerosis, we investigated the role of intraplaque hemorrhage on macrophage function with respect to angiogenesis, vascular permeability, inflammation, and plaque progression. In human atherosclerotic lesions, CD163+ macrophages were associated with plaque progression, microvascularity, and a high level of HIF1α and VEGF-A expression. We observed irregular vascular endothelial cadherin in intraplaque microvessels surrounded by CD163+ macrophages. Within these cells, activation of HIF1α via inhibition of prolyl hydroxylases promoted VEGF-mediated increases in intraplaque angiogenesis, vascular permeability, and inflammatory cell recruitment. CD163+ macrophages increased intraplaque endothelial VCAM expression and plaque inflammation. Subjects with homozygous minor alleles of the SNP rs7136716 had elevated microvessel density, increased expression of CD163 in ruptured coronary plaques, and a higher risk of myocardial infarction and coronary heart disease in population cohorts. Thus, our findings highlight a nonlipid-driven mechanism by which alternative macrophages promote plaque angiogenesis, leakiness, inflammation, and progression via the CD163/HIF1α/VEGF-A pathway.
Journal Article
Combined genetic analysis of juvenile idiopathic arthritis clinical subtypes identifies novel risk loci, target genes and key regulatory mechanisms
ObjectivesJuvenile idiopathic arthritis (JIA) is the most prevalent form of juvenile rheumatic disease. Our understanding of the genetic risk factors for this disease is limited due to low disease prevalence and extensive clinical heterogeneity. The objective of this research is to identify novel JIA susceptibility variants and link these variants to target genes, which is essential to facilitate the translation of genetic discoveries to clinical benefit.MethodsWe performed a genome-wide association study (GWAS) in 3305 patients and 9196 healthy controls, and used a Bayesian model selection approach to systematically investigate specificity and sharing of associated loci across JIA clinical subtypes. Suggestive signals were followed-up for meta-analysis with a previous GWAS (2751 cases/15 886 controls). We tested for enrichment of association signals in a broad range of functional annotations, and integrated statistical fine-mapping and experimental data to identify target genes.ResultsOur analysis provides evidence to support joint analysis of all JIA subtypes with the identification of five novel significant loci. Fine-mapping nominated causal single nucleotide polymorphisms with posterior inclusion probabilities ≥50% in five JIA loci. Enrichment analysis identified RELA and EBF1 as key transcription factors contributing to disease risk. Our integrative approach provided compelling evidence to prioritise target genes at six loci, highlighting mechanistic insights for the disease biology and IL6ST as a potential drug target.ConclusionsIn a large JIA GWAS, we identify five novel risk loci and describe potential function of JIA association signals that will be informative for future experimental works and therapeutic strategies.
Journal Article