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The gut microbiome plays an important role in immune function and has been implicated in several autoimmune disorders. Here we use 16S rRNA sequencing to investigate the gut microbiome in subjects with multiple sclerosis (MS, n =60) and healthy controls ( n =43). Microbiome alterations in MS include increases in Methanobrevibacter and Akkermansia and decreases in Butyricimonas , and correlate with variations in the expression of genes involved in dendritic cell maturation, interferon signalling and NF-kB signalling pathways in circulating T cells and monocytes. Patients on disease-modifying treatment show increased abundances of Prevotella and Sutterella , and decreased Sarcina , compared with untreated patients. MS patients of a second cohort show elevated breath methane compared with controls, consistent with our observation of increased gut Methanobrevibacter in MS in the first cohort. Further study is required to assess whether the observed alterations in the gut microbiome play a role in, or are a consequence of, MS pathogenesis. The gut microbiome has been implicated in several autoimmune disorders. Here, the authors study the gut microbiome of patients with multiple sclerosis, and find correlations between altered abundance of certain gut microorganisms and changes in expression of immune defence genes.

With a rapidly aging global human population, finding a cure for late onset neurodegenerative diseases has become an urgent enterprise. However, these efforts are hindered by the lack of understanding of what constitutes the phenotype of aged human microglia—the cell type that has been strongly implicated by genetic studies in the pathogenesis of age-related neurodegenerative disease. Here, we establish the set of genes that is preferentially expressed by microglia in the aged human brain. This HuMi_Aged gene set captures a unique phenotype, which we confirm at the protein level. Furthermore, we find this gene set to be enriched in susceptibility genes for Alzheimer’s disease and multiple sclerosis, to be increased with advancing age, and to be reduced by the protective APOEε2 haplotype . APOEε4 has no effect. These findings confirm the existence of an aging-related microglial phenotype in the aged human brain and its involvement in the pathological processes associated with brain aging. Aging is associated with various changes in the brain, including transcription alteration. Here, Bradshaw and colleagues describe the transcriptome of aged human cortical microglia, and show age-related gene expression as related to neurodegeneration.

We initiated the systematic profiling of the dorsolateral prefrontal cortex obtained from a subset of autopsied individuals enrolled in the Religious Orders Study (ROS) or the Rush Memory and Aging Project (MAP), which are jointly designed prospective studies of aging and dementia with detailed, longitudinal cognitive phenotyping during life and a quantitative, structured neuropathologic examination after death. They include over 3,322 subjects. Here, we outline the first generation of data including genome-wide genotypes (n=2,090), whole genome sequencing (n=1,179), DNA methylation (n=740), chromatin immunoprecipitation with sequencing using an anti-Histone 3 Lysine 9 acetylation (H3K9Ac) antibody (n=712), RNA sequencing (n=638), and miRNA profile (n=702). Generation of other omic data including ATACseq, proteomic and metabolomics profiles is ongoing. Thanks to its prospective design and recruitment of older, non-demented individuals, these data can be repurposed to investigate a large number of syndromic and quantitative neuroscience phenotypes. The many subjects that are cognitively non-impaired at death also offer insights into the biology of the human brain in older non-impaired individuals.

A new avenue in modern heat pump technology is related to the use of natural refrigerants such as carbon dioxide (CO2). The use of CO2 in direct expansion ground source heat pumps (DX-GSHP) has also gained significant interest as it offers opportunities for cost reduction of the ground loop, albeit some challenges remain in their development, design and use. To address these challenges and to characterize CO2-DX-GSHP performance for water heating applications, a detailed theoretical model and a fully-instrumented test apparatus was developed and built at CanmetENERGY Research Laboratory. The theoretical model was validated against a set of experimental results and adopted to investigate the performance of the system over a wide operating range. Validation results showed that the model predicts the experimental results within the measurement uncertainty. A detailed system performance analysis was also performed using the theoretical model to understand the system behavior and explore the actions required for performance improvement in future installations. The results of the analysis showed that improper design and control of some components, such as the gas cooler and ground heat exchanger can degrade the system performance by up to 25%, and the heat pump heating capacity by 7.5%.

Compared to conventional ground heat exchangers that require a separate pump or other mechanical devices to circulate the heat transfer fluid, ground coupled thermosiphons or naturally circulating ground heat exchangers do not require additional equipment for fluid circulation in the loop. This might lead to a better overall efficiency and much simpler operation. This paper provides a review of the current published literature on the different types of existing ground coupled thermosiphons for use in applications requiring moderate and low temperatures. Effort has been focused on their classification according to type, configurations, major designs, and chronological year of apparition. Important technological findings and characteristics are provided in summary tables. Advances are identified in terms of the latest device developments and innovative concepts of thermosiphon technology used for the heat transfer to and from the soil. Applications are presented in a novel, well-defined classification in which major ground coupled thermosiphon applications are categorized in terms of medium and low temperature technologies. Finally, performance evaluation is meticulously discussed in terms of modeling, simulations, parametric, and experimental studies.

A new borehole configuration is proposed in this study in an attempt to reduce the required length of ground heat exchangers (GHE) in cooling-dominated climates. It consists of a single U-tube borehole surrounded by a ring made of a thermally enhanced phase change material (PCM) mixed with sand. With a properly designed PCM ring around the borehole, a significant portion of the rejected heat during peak building loads is used to melt a PCM. This slows down the increase in the return temperature to the heat pump. In nonpeak periods when the heat pump is not operating, thermal energy stored in the ring is released into the ground by heat conduction. In the process, the PCM ring solidifies and is then ready for the release of heat during the next heat pump operation cycle. By taking advantage of the relatively high energy content associated with the latent heat of fusion of PCM, the PCM ring may reduce the required borehole length. This paper presents the numerical model used to obtain the temperature distribution around the borehole and in the PCM ring. Several annual simulations were undertaken to evaluate the merits of the proposed borehole configuration in a cooling-dominated climate. Preliminary results show that the proposed configuration can reduce the borehole length by up to 9%.

Background Fingolimod (FTY720), the first oral treatment for multiple sclerosis (MS), blocks immune cell trafficking and prevents disease relapses by downregulation of sphingosine-1-phosphate receptor. We determined the effect of FTY720 on human T cell activation and effector function. Methods T cells from MS patients and healthy controls were isolated to measure gene expression profiles in the presence or absence of FTY720 using nanostring and quantitative real-time polymerase chain reaction (qPCR). Cytokine protein expression was measured using luminex assay and flow cytometry analysis. Lentivirus vector carrying short hairpin RNA (shRNA) was used to knock down the expression of specific genes in CD4+ T cells. Chromatin immunoprecipitation was performed to assess T cell factor 1 (TCF-1) binding to promoter regions. Luciferase assays were performed to test the direct regulation of interferon gamma (IFN-γ) and granzyme B (GZMB) by TCF-1. Western blot analysis was used to assess the phosphorylation status of Akt and GSK3β. Results We showed that FTY720 treatment not only affects T cell trafficking but also T cell activation. Patients treated with FTY720 showed a significant reduction in circulating CD4 T cells. Activation of T cells in presence of FTY720 showed a less inflammatory phenotype with reduced production of IFN-γ and GZMB. This decreased effector phenotype of FTY720-treated T cells was dependent on the upregulation of TCF-1. FTY720-induced TCF-1 downregulated the pathogenic cytokines IFN-γ and GZMB by binding to their promoter/enhancer regions and mediating epigenetic modifications. Furthermore, we observed that TCF-1 expression was lower in T cells from multiple sclerosis patients than in those from healthy individuals, and FTY720 treatment increased TCF-1 expression in multiple sclerosis patients. Conclusions These results reveal a previously unknown mechanism of the effect of FTY720 on human CD4+ T cell modulation in multiple sclerosis and demonstrate the role of TCF-1 in human T cell activation and effector function.

A theoretical study on the alternatives to single and double U-tube boreholes is presented in this work. These nonstandard configurations consist of channels arranged in a semicircle or in quadrants. Channels are thermally insulated to reduce the thermal short circuit between the downward and the upward legs. The steady-state thermal performance of the proposed configurations is evaluated using an analytical solution for a set of coupled linear differential equations of energy balances with and without thermal interaction. The borehole thermal resistance and the circulating-fluid temperature during heat extraction are evaluated in the turbulent and laminar regimes and are used for comparison purposes. Results show that the new configurations offer up to a 20% reduction in borehole thermal resistance leading to shorter boreholes. For low mass flow rates (laminar flow), where thermal interaction between the upward and downward flowing fluid becomes more important, thermal insulation between channels can reduce the borehole thermal resistance of the proposed configurations by up to 15% over a standard double U-tube borehole con figuration.

This paper discusses a technical comparison of a direct-expansion ground-source heat pump (DX-GSHP) and an air-source heat pump (ASHP). To lower the ground heat exchanger size for cost reduction purposes, the system performance of a hybrid system is also evaluated using a supplementary air evaporator combined with the DX-GSHP. Detailed screening models previously developed for ASHPs and DX-GHSPs are first used to compare the seasonal performance of these two options for a residential building in the cold-climate city of Montreal, Canada. Then, the model is adopted for performance evaluation of the hybrid system. Additionally, different parameters including borehole total length and heat pump capacity are varied to evaluate their impact on the seasonal system performance. The results show that by adequate sizing, total and peak electricity consumption of the DX-GSHP system can be reduced by 50% and 40%, respectively, compared to an undersized DX-GSHP system. However, system energy savings from using a hybrid ground-source heat pump (HGSHP) are marginal compared to a DX-GSHP (5.5% for a low-capacity system), and these savings are happening during the shoulder months. Such results highlight the importance of further investigations in the area of DX-GSHPs to reduce the borehole installation cost and increase its performance.

Extracellular RNAs (exRNAs) have been identified in all tested biofluids and have been associated with a variety of extracellular vesicles, ribonucleoprotein complexes and lipoprotein complexes. Much of the interest in exRNAs lies in the fact that they may serve as signalling molecules between cells, their potential to serve as biomarkers for prediction and diagnosis of disease and the possibility that exRNAs or the extracellular particles that carry them might be used for therapeutic purposes. Among the most significant bottlenecks to progress in this field is the lack of robust and standardized methods for collection and processing of biofluids, separation of different types of exRNA-containing particles and isolation and analysis of exRNAs. The Sample and Assay Standards Working Group of the Extracellular RNA Communication Consortium is a group of laboratories funded by the U.S. National Institutes of Health to develop such methods. In our first joint endeavour, we held a series of conference calls and in-person meetings to survey the methods used among our members, placed them in the context of the current literature and used our findings to identify areas in which the identification of robust methodologies would promote rapid advancements in the exRNA field.