Targeting the microbiota-gut-brain axis: prebiotics have anxiolytic and antidepressant-like effects and reverse the impact of chronic stress in mice

Background: The realization that the microbiota-gut-brain axis plays a critical role in health and disease, including neuropsychiatric disorders, is rapidly advancing. Nurturing a beneficial gut microbiome with prebiotics, such as fructo-oligosaccharides (FOS) and galacto-oligosaccharides (GOS), is an appealing but underinvestigated microbiota manipulation. Here we tested whether chronic prebiotic treatment modifies behavior across domains relevant to anxiety, depression, cognition, stress response, and social behavior. Methods: C57BL/6J male mice were administered FOS, GOS, or a combination of FOS+GOS for 3 weeks prior to testing. Plasma corticosterone, microbiota composition, and cecal short-chain fatty acids were measured. In addition, FOS+GOS- or water-treated mice were also exposed to chronic psychosocial stress, and behavior, immune, and microbiota parameters were assessed. Results: Chronic prebiotic FOS+GOS treatment exhibited both antidepressant and anxiolytic effects. Moreover, the administration of GOS and the FOS+GOS combination reduced stress-induced corticosterone release. Prebiotics modified specific gene expression in the hippocampus and hypothalamus. Regarding short-chain fatty acid concentrations, prebiotic administration increased cecal acetate and propionate and reduced isobutyrate concentrations, changes that correlated significantly with the positive effects seen on behavior. Moreover, FOS+GOS reduced chronic stress-induced elevations in corticosterone and proinflammatory cytokine levels and depression-like and anxiety-like behavior in addition to normalizing the effects of stress on the microbiota. Conclusions: Taken together, these data strongly suggest a beneficial role of prebiotic treatment for stress-related behaviors. These findings strengthen the evidence base supporting therapeutic targeting of the gut microbiota for brain-gut axis disorders, opening new avenues in the field of nutritional neuropsychopharmacology

Terrestrial Planet Occurrence Rates for the Kepler GK Dwarf Sample

We measure planet occurrence rates using the planet candidates discovered by the Q1-Q16 Kepler pipeline search. This study examines planet occurrence rates for the Kepler GK dwarf target sample for planet radii, 0.75<Rp<2.5 Rearth, and orbital periods, 50<Porb<300 days, with an emphasis on a thorough exploration and identification of the most important sources of systematic uncertainties. Integrating over this parameter space, we measure an occurrence rate of F=0.77 planets per star, with an allowed range of 0.3<F<1.9. The allowed range takes into account both statistical and systematic uncertainties, and values of F beyond the allowed range are significantly in disagreement with our analysis. We generally find higher planet occurrence rates and a steeper increase in planet occurrence rates towards small planets than previous studies of the Kepler GK dwarf sample. Through extrapolation, we find that the one year orbital period terrestrial planet occurrence rate, zeta_1=0.1, with an allowed range of 0.01<zeta_1<2, where zeta_1 is defined as the number of planets per star within 20% of the Rp and Porb of Earth. For G dwarf hosts, the zeta_1 parameter space is a subset of the larger eta_earth parameter space, thus zeta_1 places a lower limit on eta_earth for G dwarf hosts. From our analysis, we identify the leading sources of systematics impacting Kepler occurrence rate determinations as: reliability of the planet candidate sample, planet radii, pipeline completeness, and stellar parameters.Comment: 19 Pages, 17 Figures, Submitted ApJ. Python source to support Kepler pipeline completeness estimates available at http://github.com/christopherburke/KeplerPORTs

The multiple sclerosis risk sharing scheme monitoring study - early results and lessons for the future

Background: Risk sharing schemes represent an innovative and important approach to the problems of rationing and achieving cost-effectiveness in high cost or controversial health interventions. This study aimed to assess the feasibility of risk sharing schemes, looking at long term clinical outcomes, to determine the price at which high cost treatments would be acceptable to the NHS. Methods: This case study of the first NHS risk sharing scheme, a long term prospective cohort study of beta interferon and glatiramer acetate in multiple sclerosis ( MS) patients in 71 specialist MS centres in UK NHS hospitals, recruited adults with relapsing forms of MS, meeting Association of British Neurologists (ABN) criteria for disease modifying therapy. Outcome measures were: success of recruitment and follow up over the first three years, analysis of baseline and initial follow up data and the prospect of estimating the long term cost-effectiveness of these treatments. Results: Centres consented 5560 patients. Of the 4240 patients who had been in the study for a least one year, annual review data were available for 3730 (88.0%). Of the patients who had been in the study for at least two years and three years, subsequent annual review data were available for 2055 (78.5%) and 265 (71.8%) patients respectively. Baseline characteristics and a small but statistically significant progression of disease were similar to those reported in previous pivotal studies. Conclusion: Successful recruitment, follow up and early data analysis suggest that risk sharing schemes should be able to deliver their objectives. However, important issues of analysis, and political and commercial conflicts of interest still need to be addressed

Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma.

Glioblastoma is the most common primary malignant brain tumor in adults and is associated with poor survival. The Ivy Foundation Early Phase Clinical Trials Consortium conducted a randomized, multi-institution clinical trial to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical programmed cell death protein 1 (PD-1) blockade alone. Neoadjuvant PD-1 blockade was associated with upregulation of T cell- and interferon-γ-related gene expression, but downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor

Chemical and Photometric Evolution of Extended Ultraviolet Disks: Optical Spectroscopy of M83 (NGC5236) and NGC4625

We present the results from the analysis of optical spectra of 31 Halpha-selected regions in the extended UV (XUV) disks of M83 (NGC5236) and NGC4625 recently discovered by GALEX. The spectra were obtained using IMACS at Las Campanas Observatory 6.5m Magellan I telescope and COSMIC at the Palomar 200-inch telescope, respectively for M83 and NGC4625. The line ratios measured indicate nebular oxygen abundances (derived from the R23 parameter) of the order of Zsun/5-Zsun/10. For most emission-line regions analyzed the line fluxes and ratios measured are best reproduced by models of photoionization by single stars with masses in the range 20-40 Msun and oxygen abundances comparable to those derived from the R23 parameter. We find indications for a relatively high N/O abundance ratio in the XUV disk of M83. Although the metallicities derived imply that these are not the first stars formed in the XUV disks, such a level of enrichment could be reached in young spiral disks only 1 Gyr after these first stars would have formed. The amount of gas in the XUV disks allow maintaining the current level of star formation for at least a few Gyr.Comment: 52 pages, 8 tables, 7 figures, accepted for publication in Ap

Planetary Candidates Observed by Kepler IV: Planet Sample From Q1-Q8 (22 Months)

We provide updates to the Kepler planet candidate sample based upon nearly two years of high-precision photometry (i.e., Q1-Q8). From an initial list of nearly 13,400 Threshold Crossing Events (TCEs), 480 new host stars are identified from their flux time series as consistent with hosting transiting planets. Potential transit signals are subjected to further analysis using the pixel-level data, which allows background eclipsing binaries to be identified through small image position shifts during transit. We also re-evaluate Kepler Objects of Interest (KOI) 1-1609, which were identified early in the mission, using substantially more data to test for background false positives and to find additional multiple systems. Combining the new and previous KOI samples, we provide updated parameters for 2,738 Kepler planet candidates distributed across 2,017 host stars. From the combined Kepler planet candidates, 472 are new from the Q1-Q8 data examined in this study. The new Kepler planet candidates represent ~40% of the sample with Rp~1 Rearth and represent ~40% of the low equilibrium temperature (Teq<300 K) sample. We review the known biases in the current sample of Kepler planet candidates relevant to evaluating planet population statistics with the current Kepler planet candidate sample.Comment: 12 pages, 8 figures, Accepted ApJ Supplemen

Natural Variation in Interleukin-2 Sensitivity Influences Regulatory T-Cell Frequency and Function in Individuals With Long-standing Type 1 Diabetes.

Defective immune homeostasis in the balance between FOXP3+ regulatory T cells (Tregs) and effector T cells is a likely contributing factor in the loss of self-tolerance observed in type 1 diabetes (T1D). Given the importance of interleukin-2 (IL-2) signaling in the generation and function of Tregs, observations that polymorphisms in genes in the IL-2 pathway associate with T1D and that some individuals with T1D exhibit reduced IL-2 signaling indicate that impairment of this pathway may play a role in Treg dysfunction and the pathogenesis of T1D. Here, we have examined IL-2 sensitivity in CD4+ T-cell subsets in 70 individuals with long-standing T1D, allowing us to investigate the effect of low IL-2 sensitivity on Treg frequency and function. IL-2 responsiveness, measured by STAT5a phosphorylation, was a very stable phenotype within individuals but exhibited considerable interindividual variation and was influenced by T1D-associated PTPN2 gene polymorphisms. Tregs from individuals with lower IL-2 signaling were reduced in frequency, were less able to maintain expression of FOXP3 under limiting concentrations of IL-2, and displayed reduced suppressor function. These results suggest that reduced IL-2 signaling may be used to identify patients with the highest Treg dysfunction and who may benefit most from IL-2 immunotherapy.This work was supported by the JDRF UK Centre for Diabetes Genes, Autoimmunity and Prevention (D-GAP; 4-2007-1003), the Wellcome Trust (WT061858/091157) and the NIHR Cambridge Biomedical Research Centre (CBRC). The Cambridge Institute for Medical Research (CIMR) is in receipt of a Wellcome Trust Strategic Award (100140).This is the author accepted manuscript. The final version is available from the American Diabetes Association via http://dx.doi.org/10.2337/db15-051

Muscle glycogen utilisation during Rugby match play: Effects of pre-game carbohydrate

Objectives: Although the physical demands of Rugby League (RL) match-play are well-known, the fuel sources supporting energy-production are poorly understood. We therefore assessed muscle glycogen utilisation and plasma metabolite responses to RL match-play after a relatively high (HCHO) or relatively low CHO (LCHO) diet. Design: Sixteen (mean ± SD age; 18 ± 1 years, body-mass; 88 ± 12 kg, height 180 ± 8 cm) professional players completed a RL match after 36-h consuming a non-isocaloric high carbohydrate (n = 8; 6 g kg day−1) or low carbohydrate (n = 8; 3 g kg day−1) diet. Methods: Muscle biopsies and blood samples were obtained pre- and post-match, alongside external and internal loads quantified using Global Positioning System technology and heart rate, respectively. Data were analysed using effects sizes ±90% CI and magnitude-based inferences. Results: Differences in pre-match muscle glycogen between high and low carbohydrate conditions (449 ± 51 and 444 ± 81 mmol kg−1 d.w.) were unclear. High (243 ± 43 mmol kg−1 d.w.) and low carbohydrate groups (298 ± 130 mmol kg−1 d.w.) were most and very likely reduced post-match, respectively. For both groups, differences in pre-match NEFA and glycerol were unclear, with a most likely increase in NEFA and glycerol post-match. NEFA was likely lower in the high compared with low carbohydrate group post-match (0.95 ± 0.39 mmol l−1 and 1.45 ± 0.51 mmol l−1, respectively), whereas differences between the 2 groups for glycerol were unclear (98.1 ± 33.6 mmol l−1 and 123.1 ± 39.6 mmol l−1) in the high and low carbohydrate groups, respectively. Conclusions: Professional RL players can utilise ∼40% of their muscle glycogen during a competitive match regardless of their carbohydrate consumption in the preceding 36-h

SNPs for Parentage Testing and Traceability in Globally Diverse Breeds of Sheep

DNA-based parentage determination accelerates genetic improvement in sheep by increasing pedigree accuracy. Single nucleotide polymorphism (SNP) markers can be used for determining parentage and to provide unique molecular identifiers for tracing sheep products to their source. However, the utility of a particular ‘‘parentage SNP’’ varies by breed depending on its minor allele frequency (MAF) and its sequence context. Our aims were to identify parentage SNPs with exceptional qualities for use in globally diverse breeds and to develop a subset for use in North American sheep. Starting with genotypes from 2,915 sheep and 74 breed groups provided by the International Sheep Genomics Consortium (ISGC), we analyzed 47,693 autosomal SNPs by multiple criteria and selected 163 with desirable properties for parentage testing. On average, each of the 163 SNPs was highly informative (MAF ≥ 0.3) in 48±5 breed groups. Nearby polymorphisms that could otherwise confound genetic testing were identified by whole genome and Sanger sequencing of 166 sheep from 54 breed groups. A genetic test with 109 of the 163 parentage SNPs was developed for matrix-assisted laser desorption/ionization– time-of-flight mass spectrometry. The scoring rates and accuracies for these 109 SNPs were greater than 99% in a panel of North American sheep. In a blinded set of 96 families (sire, dam, and non-identical twin lambs), each parent of every lamb was identified without using the other parent’s genotype. In 74 ISGC breed groups, the median estimates for probability of a coincidental match between two animals (PI), and the fraction of potential adults excluded from parentage (PE) were 1.1×10(−39) and 0.999987, respectively, for the 109 SNPs combined. The availability of a well-characterized set of 163 parentage SNPs facilitates the development of high-throughput genetic technologies for implementing accurate and economical parentage testing and traceability in many of the world’s sheep breeds