The gut microbiota, the collection of all bacterial members in the intestinal tract, plays a key role in health. Disruption of the indigenous microbiota by a variety of stressors, including ...antibiotic therapy and intestinal infections, is associated with multiple health problems. We sought to determine if infection with Norovirus disrupts the gut microbiota. Barcoded pyrosequencing of the 16S rRNA-encoding gene was used to characterize the stool microbiota in Norovirus-infected human patients (n = 38). While the microbiota in most infected patients (n = 31) resembled that seen in uninfected healthy controls, a minority of patients (n = 7) possessed a significantly altered microbiota characterized by reduced relative numbers of Bacteriodetes and a corresponding increase in Proteobacteria. In these patients, the increase in Proteobacteria was due to a single operational taxonomic unit (OTU) of Escherichia coli. We cultured E. coli from Norovirus-infected patients and characterized them using PCR-ribotyping and virulence factor analysis. Multiple ribotypes were encountered, but none possessed typical virulence factors commonly carried by enteropathogenic E. coli strains. Microbiota disruption and elevated Proteobacteria were not significantly correlated to patient age, gender, sampling time following illness onset, or overall gut inflammation. These results demonstrate that some patients have a disrupted microbiota following Norovirus infection, and therefore may be at elevated risk for long-term health complications.
Antibiotics can have significant and long-lasting effects on the gastrointestinal tract microbiota, reducing colonization resistance against pathogens including Clostridium difficile. Here we show ...that antibiotic treatment induces substantial changes in the gut microbial community and in the metabolome of mice susceptible to C. difficile infection. Levels of secondary bile acids, glucose, free fatty acids and dipeptides decrease, whereas those of primary bile acids and sugar alcohols increase, reflecting the modified metabolic activity of the altered gut microbiome. In vitro and ex vivo analyses demonstrate that C. difficile can exploit specific metabolites that become more abundant in the mouse gut after antibiotics, including the primary bile acid taurocholate for germination, and carbon sources such as mannitol, fructose, sorbitol, raffinose and stachyose for growth. Our results indicate that antibiotic-mediated alteration of the gut microbiome converts the global metabolic profile to one that favours C. difficile germination and growth.
TLX (NR2E1), an orphan member of the nuclear receptor superfamily, is a transcription factor that has been described to be generally repressive in nature. It has been implicated in several aspects of ...physiology and disease. TLX is best known for its ability to regulate the proliferation of neural stem cells and retinal progenitor cells. Dysregulation, overexpression, or loss of TLX expression has been characterized in numerous studies focused on a diverse range of pathological conditions, including abnormal brain development, psychiatric disorders, retinopathies, metabolic disease, and malignant neoplasm. Despite the lack of an identified endogenous ligand, several studies have described putative synthetic and natural TLX ligands, suggesting that this receptor may serve as a therapeutic target. Therefore, this article aims to briefly review what is known about TLX structure and function in normal physiology, and provide an overview of TLX in regard to pathological conditions. Particular emphasis is placed on TLX and cancer, and the potential utility of this receptor as a therapeutic target.
•OpenMC is an open source Monte Carlo particle transport code.•Solid geometry and continuous-energy physics allow high-fidelity simulations.•Development has focused on high performance and modern I/O ...techniques.•OpenMC is capable of scaling up to hundreds of thousands of processors.•Other features include plotting, CMFD acceleration, and variance reduction.
This paper gives an overview of OpenMC, an open source Monte Carlo particle transport code recently developed at the Massachusetts Institute of Technology. OpenMC uses continuous-energy cross sections and a constructive solid geometry representation, enabling high-fidelity modeling of nuclear reactors and other systems. Modern, portable input/output file formats are used in OpenMC: XML for input, and HDF5 for output. High performance parallel algorithms in OpenMC have demonstrated near-linear scaling to over 100,000 processors on modern supercomputers. Other topics discussed in this paper include plotting, CMFD acceleration, variance reduction, eigenvalue calculations, and software development processes.
Shwachman-Diamond syndrome (SDS) is an inherited bone marrow failure syndrome classically associated with exocrine pancreatic dysfunction and neutropenia, with a predisposition toward progressive ...marrow failure, risk of myelodysplastic syndrome, and leukemia. Most patients carry biallelic mutations in the Shwachman-Bodian-Diamond Syndrome gene, which is an integral component of ribosome maturation and biogenesis. This article reviews the diagnosis, clinical characteristics, and treatment modalities of SDS, and reports advances in the understanding of the molecular pathophysiology of SDS.
HDL and cardiovascular disease Nicholls, Stephen J.; Nelson, Adam J.
Pathology,
02/2019, Letnik:
51, Številka:
2
Journal Article
Recenzirano
High-density lipoprotein (HDL) has received increasing interest due to observations of an inverse relationship between its systemic levels and cardiovascular risk and targeted interventions in animal ...models that have had favourable effects on atherosclerotic plaque. In addition to its pivotal role in reverse cholesterol transport, HDL has been reported to possess a range of functional properties, which may exert a protective influence on inflammation, oxidation, angiogenesis and glucose homeostasis. This has led to the development of a range of HDL targeted therapeutics, which have undergone evaluation in clinical trials. The current state of HDL in cardiovascular prevention will be reviewed.
Managing hypercholesterolaemia Nelson, Adam J; Nicholls, Stephen J
Australian prescriber,
02/2024, Letnik:
47, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Hypercholesterolaemia is one of the most common conditions treated by clinicians in Australia. Low-density lipoprotein cholesterol (LDL-C) plays a causal role in the development and progression of ...atherosclerosis and cardiovascular disease. Every 1 mmol/L reduction in LDL-C concentration is associated with a 21 to 25% reduction in the relative risk of prospective atherosclerotic cardiovascular events, and emerging evidence suggests this benefit increases over time. Absolute cardiovascular risk assessment identifies patients likely to derive the most benefit from lowering LDL-C concentration, and helps determine the intensity of their treatment regimens and targets. Optimal management of LDL-C may require combination treatment with multiple classes of drugs.
NKT cells are a specialized subset of lipid-reactive T lymphocytes that play direct and indirect roles in immunosurveillance and anti-tumor immunity. Preclinical studies have shown that NKT cell ...activation via delivery of exogenous glycolipids elicits a significant anti-tumor immune response. Furthermore, infiltration of NKT cells is associated with a good prognosis in several cancers. In this review, we aim to summarize the role of NKT cells in cancer as well as the current strategies and status of NKT cell immunotherapy. This review also examines challenges and future directions for improving the therapy.
Breast cancer remains one of the leading causes of cancer mortality in the US. Elevated cholesterol is a major risk factor for breast cancer onset and recurrence, while cholesterol-lowering drugs, ...such as statins, are associated with a good prognosis. Previous work in murine models showed that cholesterol increases breast cancer metastasis, and the pro-metastatic effects of cholesterol were due to its primary metabolite, 27-hydroxycholesterol (27HC). In our prior work, myeloid cells were found to be required for the pro-metastatic effects of 27HC, but their precise contribution remains unclear. Here we report that 27HC impairs T cell expansion and cytotoxic function through its actions on myeloid cells, including macrophages, in a Liver X receptor (LXR) dependent manner. Many oxysterols and LXR ligands had similar effects on T cell expansion. Moreover, their ability to induce the LXR target gene ABCA1 was associated with their effectiveness in impairing T cell expansion. Induction of T cell apoptosis was likely one mediator of this impairment. Interestingly, the enzyme responsible for the synthesis of 27HC, CYP27A1, is highly expressed in myeloid cells, suggesting that 27HC may have important autocrine or paracrine functions in these cells, a hypothesis supported by our finding that breast cancer metastasis was reduced in mice with a myeloid specific knockout of CYP27A1. Importantly, pharmacologic inhibition of CYP27A1 reduced metastatic growth and improved the efficacy of checkpoint inhibitor, anti-PD-L1. Taken together, our work suggests that targeting the CYP27A1 axis in myeloid cells may present therapeutic benefits and improve the response rate to immune therapies in breast cancer.
•The cholesterol metabolite, 27-Hydroxycholesterol (27HC), works on myeloid cells to suppress T cell activity.•27HC-LXR activity mediates myeloid cell-driven immune suppression.•Myeloid cell-driven T cell inhibition likely results from accelerated T cell apoptosis.•Pharmacologic inhibition of 27HC synthesis enhances immune check-point inhibition.•The immune suppression is likely a dominant mechanism by which 27HC promotes breast cancer progression.
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