Guidelines for reporting on animal fecal transplantation (GRAFT) studies: recommendations from a systematic review of murine transplantation protocols

Fecal microbiota transplant (FMT) is a powerful tool used to connect changes in gut microbial composition with a variety of disease states and pathologies. While FMT enables potential causal relationships to be identified, the experimental details reported in preclinical FMT protocols are highly inconsistent and/or incomplete. This limitation reflects a current lack of authoritative guidance on reporting standards that would facilitate replication efforts and ultimately reproducible science. We therefore systematically reviewed all FMT protocols used in mouse models with the goal of formulating recommendations on the reporting of preclinical FMT protocols. Search strategies were applied across three databases (PubMed, EMBASE, and Ovid Medline) until June 30, 2020. Data related to donor attributes, stool collection, processing/storage, recipient preparation, administration, and quality control were extracted. A total of 1753 papers were identified, with 241 identified for data extraction and analysis. Of the papers included, 92.5% reported a positive outcome with FMT intervention. However, the vast majority of studies failed to address core methodological aspects including the use of anaerobic conditions (91.7% of papers lacked information), storage (49.4%), homogenization (33.6%), concentration (31.5%), volume (19.9%) and administration route (5.3%). To address these reporting limitations, we developed theGuidelines for Reporting Animal Fecal Transplant (GRAFT) that guide reporting standards for preclinical FMT. The GRAFT recommendations will enable robust reporting of preclinical FMT design, and facilitate high-quality peer review, improving the rigor and translation of knowledge gained through preclinical FMT studies.Kate R. Secombe, Ghanyah H. Al-Qadami, Courtney B. Subramaniam, Joanne M. Bowen, Jacqui Scott, Ysabella Z.A. Van Sebille ... et a

Cognitive endpoints for therapy development for neuronopathic mucopolysaccharidoses: Results of a consensus procedure

The design and conduct of clinical studies to evaluate the effects of novel therapies on central nervous system manifestations in children with neuronopathic mucopolysaccharidoses is challenging. Owing to the rarity of these disorders, multinational studies are often needed to recruit enough patients to provide meaningful data and statistical power. This can make the consistent collection of reliable data across study sites difficult. To address these challenges, an International MPS Consensus Conference for Cognitive Endpoints was convened to discuss approaches for evaluating cognitive and adaptive function in patients with mucopolysaccharidoses. The goal was to develop a consensus on best practice for the design and conduct of clinical studies investigating novel therapies for these conditions, with particular focus on the most appropriate outcome measures for cognitive function and adaptive behavior. The outcomes from the consensus panel discussion are reported here

A Galaxy-scale Fountain of Cold Molecular Gas Pumped by a Black Hole

We present Atacama Large Millimeter/submillimeter Array and Multi-Unit Spectroscopic Explorer observations of the brightest cluster galaxy in Abell 2597, a nearby (z = 0.0821) cool core cluster of galaxies. The data map the kinematics of a three billion solar mass filamentary nebula that spans the innermost 30 kpc of the galaxy's core. Its warm ionized and cold molecular components are both cospatial and comoving, consistent with the hypothesis that the optical nebula traces the warm envelopes of many cold molecular clouds that drift in the velocity field of the hot X-ray atmosphere. The clouds are not in dynamical equilibrium, and instead show evidence for inflow toward the central supermassive black hole, outflow along the jets it launches, and uplift by the buoyant hot bubbles those jets inflate. The entire scenario is therefore consistent with a galaxy-spanning "fountain," wherein cold gas clouds drain into the black hole accretion reservoir, powering jets and bubbles that uplift a cooling plume of low-entropy multiphase gas, which may stimulate additional cooling and accretion as part of a self-regulating feedback loop. All velocities are below the escape speed from the galaxy, and so these clouds should rain back toward the galaxy center from which they came, keeping the fountain long lived. The data are consistent with major predictions of chaotic cold accretion, precipitation, and stimulated feedback models, and may trace processes fundamental to galaxy evolution at effectively all mass scales

An Analysis of Two Genome-wide Association Meta-analyses Identifies a New Locus for Broad Depression Phenotype

AbstractBackgroundThe genetics of depression has been explored in genome-wide association studies that focused on either major depressive disorder or depressive symptoms with mostly negative findings. A broad depression phenotype including both phenotypes has not been tested previously using a genome-wide association approach. We aimed to identify genetic polymorphisms significantly associated with a broad phenotype from depressive symptoms to major depressive disorder.MethodsWe analyzed two prior studies of 70,017 participants of European ancestry from general and clinical populations in the discovery stage. We performed a replication meta-analysis of 28,328 participants. Single nucleotide polymorphism (SNP)-based heritability and genetic correlations were calculated using linkage disequilibrium score regression. Discovery and replication analyses were performed using a p-value-based meta-analysis. Lifetime major depressive disorder and depressive symptom scores were used as the outcome measures.ResultsThe SNP-based heritability of major depressive disorder was 0.21 (SE = 0.02), the SNP-based heritability of depressive symptoms was 0.04 (SE = 0.01), and their genetic correlation was 1.001 (SE = 0.2). We found one genome-wide significant locus related to the broad depression phenotype (rs9825823, chromosome 3: 61,082,153, p = 8.2 × 10–9) located in an intron of the FHIT gene. We replicated this SNP in independent samples (p = .02) and the overall meta-analysis of the discovery and replication cohorts (1.0 × 10–9).ConclusionsThis large study identified a new locus for depression. Our results support a continuum between depressive symptoms and major depressive disorder. A phenotypically more inclusive approach may help to achieve the large sample sizes needed to detect susceptibility loci for depression

Genome-wide interaction study of a proxy for stress-sensitivity and its prediction of major depressive disorder

Individual response to stress is correlated with neuroticism and is an important predictor of both neuroticism and the onset of major depressive disorder (MDD). Identification of the genetics underpinning individual differences in response to negative events (stress-sensitivity) may improve our understanding of the molecular pathways involved, and its association with stress-related illnesses. We sought to generate a proxy for stress-sensitivity through modelling the interaction between SNP allele and MDD status on neuroticism score in order to identify genetic variants that contribute to the higher neuroticism seen in individuals with a lifetime diagnosis of depression compared to unaffected individuals. Meta-analysis of genome-wide interaction studies (GWIS) in UK Biobank (N = 23,092) and Generation Scotland: Scottish Family Health Study (N = 7,155) identified no genome-wide significance SNP interactions. However, gene-based tests identified a genome-wide significant gene, ZNF366, a negative regulator of glucocorticoid receptor function implicated in alcohol dependence (p = 1.48x10-7; Bonferroni-corrected significance threshold p < 2.79x10-6). Using summary statistics from the stress-sensitivity term of the GWIS, SNP heritability for stress-sensitivity was estimated at 5.0%. In models fitting polygenic risk scores of both MDD and neuroticism derived from independent GWAS, we show that polygenic risk scores derived from the UK Biobank stress-sensitivity GWIS significantly improved the prediction of MDD in Generation Scotland. This study may improve interpretation of larger genome-wide association studies of MDD and other stress-related illnesses, and the understanding of the etiological mechanisms underpinning stress-sensitivity

Velocity-space sensitivity of the time-of-flight neutron spectrometer at JET

The velocity-space sensitivities of fast-ion diagnostics are often described by so-called weight functions. Recently, we formulated weight functions showing the velocity-space sensitivity of the often dominant beam-target part of neutron energy spectra. These weight functions for neutron emission spectrometry (NES) are independent of the particular NES diagnostic. Here we apply these NES weight functions to the time-of-flight spectrometer TOFOR at JET. By taking the instrumental response function of TOFOR into account, we calculate time-of-flight NES weight functions that enable us to directly determine the velocity-space sensitivity of a given part of a measured time-of-flight spectrum from TOFOR