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"Whitaker, R"
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An exclusive metabolic niche enables strain engraftment in the gut microbiota
The dense microbial ecosystem in the gut is intimately connected to numerous facets of human biology, and manipulation of the gut microbiota has broad implications for human health. In the absence of profound perturbation, the bacterial strains that reside within an individual are mostly stable over time
1
. By contrast, the fate of exogenous commensal and probiotic strains applied to an established microbiota is variable, generally unpredictable and greatly influenced by the background microbiota
2
,
3
. Therefore, analysis of the factors that govern strain engraftment and abundance is of critical importance to the emerging field of microbiome reprogramming. Here we generate an exclusive metabolic niche in mice via administration of a marine polysaccharide, porphyran, and an exogenous
Bacteroides
strain harbouring a rare gene cluster for porphyran utilization. Privileged nutrient access enables reliable engraftment of the exogenous strain at predictable abundances in mice harbouring diverse communities of gut microbes. This targeted dietary support is sufficient to overcome priority exclusion by an isogenic strain
4
, and enables strain replacement. We demonstrate transfer of the 60-kb porphyran utilization locus into a naive strain of
Bacteroides
, and show finely tuned control of strain abundance in the mouse gut across multiple orders of magnitude by varying porphyran dosage. Finally, we show that this system enables the introduction of a new strain into the colonic crypt ecosystem. These data highlight the influence of nutrient availability in shaping microbiota membership, expand the ability to perform a broad spectrum of investigations in the context of a complex microbiota, and have implications for cell-based therapeutic strategies in the gut.
Finely tuned control of strain engraftment and abundance in the mouse gut microbiota was achieved using the marine polysaccharide porphyran, which could exclusively be used by an introduced subset of wild-type or genetically modified
Bacteroides
strains.
Journal Article
Epigenetic regulation of CD133 and tumorigenicity of CD133+ ovarian cancer cells
The cancer stem cell hypothesis posits that malignant growth arises from a rare population of progenitor cells within a tumor that provide it with unlimited regenerative capacity. Such cells also possess increased resistance to chemotherapeutic agents. Resurgence of chemoresistant disease after primary therapy typifies epithelial ovarian cancer and may be attributable to residual cancer stem cells, or cancer-initiating cells, that survive initial treatment. As the cell surface marker CD133 identifies cancer-initiating cells in a number of other malignancies, we sought to determine the potential role of CD133+ cells in epithelial ovarian cancer. We detected CD133 on ovarian cancer cell lines, in primary cancers and on purified epithelial cells from ascitic fluid of ovarian cancer patients. We found CD133+ ovarian cancer cells generate both CD133+ and CD133− daughter cells, whereas CD133− cells divide symmetrically. CD133+ cells exhibit enhanced resistance to platinum-based therapy, drugs commonly used as first-line agents for the treatment of ovarian cancer. Sorted CD133+ ovarian cancer cells also form more aggressive tumor xenografts at a lower inoculum than their CD133− progeny. Epigenetic changes may be integral to the behavior of cancer progenitor cells and their progeny. In this regard, we found that
CD133
transcription is controlled by both histone modifications and promoter methylation. Sorted CD133− ovarian cancer cells treated with DNA methyltransferase and histone deacetylase inhibitors show a synergistic increase in cell surface CD133 expression. Moreover, DNA methylation at the ovarian tissue active P2 promoter is inversely correlated with
CD133
transcription. We also found that promoter methylation increases in CD133− progeny of CD133+ cells, with CD133+ cells retaining a less methylated or unmethylated state. Taken together, our results show that CD133 expression in ovarian cancer is directly regulated by epigenetic modifications and support the idea that CD133 demarcates an ovarian cancer-initiating cell population. The activity of these cells may be epigenetically detected and such cells might serve as pertinent chemotherapeutic targets for reducing disease recurrence.
Journal Article
Psychiatry under the Influence
Psychiatry Under the Influence investigates the actions and practices of the American Psychiatric Association and academic psychiatry in the United States, and presents it as a case study of institutional corruption.
eBook
An Exploratory Study into Objective and Reported Characteristics of Neuropathic Pain in Women with Chronic Pelvic Pain
Chronic pelvic pain (CPP) affects 5.7-26.6% women worldwide. 55% have no obvious pathology and 40% have associated endometriosis. Neuropathic pain (NeP) is pain arising as a consequence of a lesion/disease affecting the somatosensory system. The prevalence of NeP in women with CPP is not known. The diagnosis of NeP is challenging because there is no gold-standard assessment. Questionnaires have been used in the clinical setting to diagnose NeP in other chronic pain conditions and quantitative sensory testing (QST) has been used in a research setting to identify abnormal sensory function. We aimed to determine if women with chronic pelvic pain (CPP) have a neuropathic pain (NeP) component to their painful symptoms and how this is best assessed. We performed an exploratory prospective cohort study of 72 pre-menopausal women with a diagnosis of CPP. They underwent a clinician completed questionnaire (DN4) and completed the S-LANSS and PainDETECT™ questionnaires. Additionally QST testing was performed by a clinician. They also completed a patient acceptability questionnaire. Clinical features of NeP were identified by both questionnaires and QST. Of the women who were NeP positive, 56%, 35% and 26% were identified by the S-LANSS, DN4 and PainDETECT™ respectively. When NeP was identified by questionnaire, the associated laparoscopy findings were similar irrespective of which questionnaire was used. No subject had entirely unchanged QST parameters. There were distinct loss and gain subgroups, as well as mixed alteration in function, but this was not necessarily clinically significant in all patients. 80% of patients were confident that questionnaires could diagnose NeP, and 90% found them easy to complete. Early identification of NeP in women with CPP with a simple questionnaire could facilitate targeted therapy with neuromodulators, which are cheap, readily available, and have good safety profiles. This approach could prevent unnecessary or fertility-compromising surgery and prolonged treatment with hormones.
Journal Article
Combining stable isotope analysis with DNA metabarcoding improves inferences of trophic ecology
Knowing what animals eat is fundamental to our ability to understand and manage biodiversity and ecosystems, but researchers often must rely on indirect methods to infer trophic position and food intake. Using an approach that combines evidence from stable isotope analysis and DNA metabarcoding, we assessed the diet and trophic position of Anthene usamba butterflies, for which there are no known direct observations of larval feeding. An earlier study that analyzed adults rather than caterpillars of A. usamba inferred that this butterfly was aphytophagous, but we found that the larval guts of A. usamba and two known herbivorous lycaenid species contain chloroplast 16S sequences. Moreover, chloroplast barcoding revealed high sequence similarity between chloroplasts found in A. usamba guts and the chloroplasts of the Vachellia drepanolobium trees on which the caterpillars live. Stable isotope analysis provided further evidence that A. usamba caterpillars feed on V. drepanolobium, and the possibilities of strict herbivory versus limited omnivory in this species are discussed. These results highlight the importance of combining multiple approaches and considering ontogeny when using stable isotopes to infer trophic ecology where direct observations are difficult or impossible.
Journal Article
A Low Affinity GCaMP3 Variant (GCaMPer) for Imaging the Endoplasmic Reticulum Calcium Store
Endoplasmic reticulum calcium homeostasis is critical for cellular functions and is disrupted in diverse pathologies including neurodegeneration and cardiovascular disease. Owing to the high concentration of calcium within the ER, studying this subcellular compartment requires tools that are optimized for these conditions. To develop a single-fluorophore genetically encoded calcium indicator for this organelle, we targeted a low affinity variant of GCaMP3 to the ER lumen (GCaMPer (10.19)). A set of viral vectors was constructed to express GCaMPer in human neuroblastoma cells, rat primary cortical neurons, and human induced pluripotent stem cell-derived cardiomyocytes. We observed dynamic changes in GCaMPer (10.19) fluorescence in response to pharmacologic manipulations of the ER calcium store. Additionally, periodic calcium efflux from the ER was observed during spontaneous beating of cardiomyocytes. GCaMPer (10.19) has utility in imaging ER calcium in living cells and providing insight into luminal calcium dynamics under physiologic and pathologic states.
Journal Article
Self-regulation and household routines at age three and obesity at age eleven: longitudinal analysis of the UK Millennium Cohort Study
Objective:
To examine, in a population-based cohort of 3-year-old children, the association between self-regulation and exposure to the household routines of regular bedtime, regular mealtime and limits on watching television/video, and to determine whether self-regulation and these routines predict the risk of obesity at age 11.
Methods:
Analyses included 10 955 children in the nationally representative UK Millennium Cohort Study. When children were age 3, parents reported whether children had a regular bedtime and mealtime, and the amount of television/video watched. Emotional and cognitive self-regulation at age 3 were assessed by parent-report with the Child Social Behaviour Questionnaire. Children’s height and weight were measured at age 11 and obesity was defined using the International Obesity Task Force (IOTF) criteria.
Results:
At age 3, 41% of children always had a regular bedtime, 47% always had a regular mealtime and 23% were limited to ⩽1 h television/video daily. At age 11, 6.2% of children were obese. All three household routines were significantly associated with better emotional self-regulation, but not better cognitive self-regulation. In a multi-variable logistic regression model, including emotional and cognitive self-regulation, all routines and controlling for sociodemographic covariates, a 1-unit difference in emotional self-regulation at age 3 was associated with an OR (95% CI) for obesity of 1.38 (1.11, 1.71) at age 11, and inconsistent bedtimes with an OR (95% CI) for obesity of 1.87 (1.39, 2.51) at age 11. There was no evidence that emotional self-regulation mediated the relationship between regular bedtimes and later obesity. Cognitive self-regulation was not associated with later obesity.
Conclusions:
Three-year-old children who had regular bedtimes, mealtimes and limits on their television/video time had better emotional self-regulation. Lack of a regular bedtime and poorer emotional self-regulation at age 3 were independent predictors of obesity at age 11.
Journal Article