Autism spectrum disorders (ASD) are increasingly common neurodevelopmental disorders defined clinically by a triad of features including impairment in social interaction, impairment in communication ...in social situations and restricted and repetitive patterns of behavior and interests, with considerable phenotypic heterogeneity among individuals. Although heritability estimates for ASD are high, conventional genetic-based efforts to identify genes involved in ASD have yielded only few reproducible candidate genes that account for only a small proportion of ASDs. There is mounting evidence to suggest environmental and epigenetic factors play a stronger role in the etiology of ASD than previously thought. To begin to understand the contribution of epigenetics to ASD, we have examined DNA methylation (DNAm) in a pilot study of postmortem brain tissue from 19 autism cases and 21 unrelated controls, among three brain regions including dorsolateral prefrontal cortex, temporal cortex and cerebellum. We measured over 485,000 CpG loci across a diverse set of functionally relevant genomic regions using the Infinium HumanMethylation450 BeadChip and identified four genome-wide significant differentially methylated regions (DMRs) using a bump hunting approach and a permutation-based multiple testing correction method. We replicated 3/4 DMRs identified in our genome-wide screen in a different set of samples and across different brain regions. The DMRs identified in this study represent suggestive evidence for commonly altered methylation sites in ASD and provide several promising new candidate genes.
Aims/hypothesis
Increasing evidence suggests that environmental factors changing the normal colonisation pattern in the gut strongly influence the risk of developing autoimmune diabetes. The aim of ...this study was to investigate, both during infancy and adulthood, whether treatment with vancomycin, a glycopeptide antibiotic specifically directed against Gram-positive bacteria, could influence immune homeostasis and the development of diabetic symptoms in the NOD mouse model for diabetes.
Methods
Accordingly, one group of mice received vancomycin from birth until weaning (day 28), while another group received vancomycin from 8 weeks of age until onset of diabetes. Pyrosequencing of the gut microbiota and flow cytometry of intestinal immune cells was used to investigate the effect of vancomycin treatment.
Results
At the end of the study, the cumulative diabetes incidence was found to be significantly lower for the neonatally treated group compared with the untreated group, whereas the insulitis score and blood glucose levels were significantly lower for the mice treated as adults compared with the other groups. Mucosal inflammation was investigated by intracellular cytokine staining of the small intestinal lymphocytes, which displayed an increase in cluster of differentiation (CD)4
+
T cells producing pro-inflammatory cytokines in the neonatally treated mice. Furthermore, bacteriological examination of the gut microbiota composition by pyrosequencing revealed that vancomycin depleted many major genera of Gram-positive and Gram-negative microbes while, interestingly, one single species,
Akkermansia muciniphila
, became dominant.
Conclusions/interpretation
The early postnatal period is a critical time for microbial protection from type 1 diabetes and it is suggested that the mucolytic bacterium
A. muciniphila
plays a protective role in autoimmune diabetes development, particularly during infancy.
Planting tested forest reproductive material is crucial to ensure the increased resilience of intensively managed productive stands for timber and wood product markets under climate change scenarios. ...Single-step Genomic Best Linear Unbiased Prediction (ssGBLUP) analysis is a cost-effective option for using genomic tools to enhance the accuracy of predicted breeding values and genetic parameter estimation in forest tree species. Here, we tested the efficiency of ssGBLUP in a tropical multipurpose tree species, Cordia africana, by partial population genotyping. A total of 8070 trees from three breeding seedling orchards (BSOs) were phenotyped for height. We genotyped 6.1% of the phenotyped individuals with 4373 single nucleotide polymorphisms. The results of ssGBLUP were compared with pedigree-based best linear unbiased prediction (ABLUP) and genomic best linear unbiased prediction (GBLUP), based on genetic parameters, theoretical accuracy of breeding values, selection candidate ranking, genetic gain, and predictive accuracy and prediction bias.
Genotyping a subset of the study population provided insights into the level of relatedness in BSOs, allowing better genetic management. Due to the inbreeding detected within the genotyped provenances, we estimated genetic parameters both with and without accounting for inbreeding. The ssGBLUP model showed improved performance in terms of additive genetic variance and theoretical breeding value accuracy. Similarly, ssGBLUP showed improved predictive accuracy and lower bias than the pedigree-based relationship matrix (ABLUP).
This study of C. africana, a species in decline due to deforestation and selective logging, revealed inbreeding depression. The provenance exhibiting the highest level of inbreeding had the poorest overall performance. The use of different relationship matrices and accounting for inbreeding did not substantially affect the ranking of candidate individuals. This is the first study of this approach in a tropical multipurpose tree species, and the analysed BSOs represent the primary effort to breed C. africana.
Herbivory, defined as feeding on live plant tissues, is characteristic of highly successful and diverse groups of insects and represents an evolutionarily derived mode of feeding. Plants present ...various nutritional and defensive barriers against herbivory; nevertheless, insects have evolved a diverse array of mechanisms that enable them to feed and develop on live plant tissues. For decades, it has been suggested that insect‐associated microbes may facilitate host plant use, and new molecular methodologies offer the possibility to elucidate such roles. Based on genomic data, specialized feeding on phloem and xylem sap is highly dependent on nutrient provisioning by intracellular symbionts, as exemplified by Buchnera in aphids, although it is unclear whether such symbionts play a substantive role in host plant specificity of their hosts. Microorganisms present in the gut or outside the insect body could provide more functions including digestion of plant polymers and detoxification of plant‐produced toxins. However, the extent of such contributions to insect herbivory remains unclear. We propose that the potential functions of microbial symbionts in facilitating or restricting the use of host plants are constrained by their location (intracellular, gut or environmental), and by the fidelity of their associations with insect host lineages. Studies in the next decade, using molecular methods from environmental microbiology and genomics, will provide a more comprehensive picture of the role of microbial symbionts in insect herbivory.
Glucagon-like peptide-1 (GLP-1) receptor agonists are effective therapies for the treatment of type 2 diabetes and are all currently available as an injection.
To compare the effects of oral ...semaglutide with placebo (primary) and open-label subcutaneous semaglutide (secondary) on glycemic control in patients with type 2 diabetes.
Phase 2, randomized, parallel-group, dosage-finding, 26-week trial with 5-week follow-up at 100 sites (hospital clinics, general practices, and clinical research centers) in 14 countries conducted between December 2013 and December 2014. Of 1106 participants assessed, 632 with type 2 diabetes and insufficient glycemic control using diet and exercise alone or a stable dose of metformin were randomized. Randomization was stratified by metformin use.
Once-daily oral semaglutide of 2.5 mg (n = 70), 5 mg (n = 70), 10 mg (n = 70), 20 mg (n = 70), 40-mg 4-week dose escalation (standard escalation; n = 71), 40-mg 8-week dose escalation (slow escalation; n = 70), 40-mg 2-week dose escalation (fast escalation, n = 70), oral placebo (n = 71; double-blind) or once-weekly subcutaneous semaglutide of 1.0 mg (n = 70) for 26 weeks.
The primary end point was change in hemoglobin A1c (HbA1c) from baseline to week 26. Secondary end points included change from baseline in body weight and adverse events.
Baseline characteristics were comparable across treatment groups. Of the 632 randomized patients (mean age, 57.1 years SD, 10.6; men, 395 (62.7%); diabetes duration, 6.3 years SD, 5.2; body weight, 92.3 kg SD, 16.8; BMI, 31.7 SD, 4.3), 583 (92%) completed the trial. Mean change in HbA1c level from baseline to week 26 decreased with oral semaglutide (dosage-dependent range, -0.7% to -1.9%) and subcutaneous semaglutide (-1.9%) and placebo (-0.3%); oral semaglutide reductions were significant vs placebo (dosage-dependent estimated treatment difference ETD range for oral semaglutide vs placebo, -0.4% to -1.6%; P = .01 for 2.5 mg, <.001 for all other dosages). Reductions in body weight were greater with oral semaglutide (dosage-dependent range, -2.1 kg to -6.9 kg) and subcutaneous semaglutide (-6.4 kg) vs placebo (-1.2 kg), and significant for oral semaglutide dosages of 10 mg or more vs placebo (dosage-dependent ETD range, -0.9 to -5.7 kg; P < .001). Adverse events were reported by 63% to 86% (371 of 490 patients) in the oral semaglutide groups, 81% (56 of 69 patients) in the subcutaneous semaglutide group, and 68% (48 of 71 patients) in the placebo group; mild to moderate gastrointestinal events were most common.
Among patients with type 2 diabetes, oral semaglutide resulted in better glycemic control than placebo over 26 weeks. These findings support phase 3 studies to assess longer-term and clinical outcomes, as well as safety.
clinicaltrials.gov Identifier: NCT01923181.
Surveys of 16S rDNA sequences from the honey bee, Apis mellifera, have revealed the presence of eight distinctive bacterial phylotypes in intestinal tracts of adult worker bees. Because previous ...studies have been limited to relatively few sequences from samples pooled from multiple hosts, the extent of variation in this microbiota among individuals within and between colonies and locations has been unclear. We surveyed the gut microbiota of 40 individual workers from two sites, Arizona and Maryland USA, sampling four colonies per site. Universal primers were used to amplify regions of 16S ribosomal RNA genes, and amplicons were sequenced using 454 pyrotag methods, enabling analysis of about 330,000 bacterial reads. Over 99% of these sequences belonged to clusters for which the first blastn hits in GenBank were members of the known bee phylotypes. Four phylotypes, one within Gammaproteobacteria (corresponding to "Candidatus Gilliamella apicola") one within Betaproteobacteria ("Candidatus Snodgrassella alvi"), and two within Lactobacillus, were present in every bee, though their frequencies varied. The same typical bacterial phylotypes were present in all colonies and at both sites. Community profiles differed significantly among colonies and between sites, mostly due to the presence in some Arizona colonies of two species of Enterobacteriaceae not retrieved previously from bees. Analysis of Sanger sequences of rRNA of the Snodgrassella and Gilliamella phylotypes revealed that single bees contain numerous distinct strains of each phylotype. Strains showed some differentiation between localities, especially for the Snodgrassella phylotype.
HEALPix--the Hierarchical Equal Area isoLatitude Pixelization--is a versatile structure for the pixelization of data on the sphere. An associated library of computational algorithms and visualization ...software supports fast scientific applications executable directly on discretized spherical maps generated from very large volumes of astronomical data. Originally developed to address the data processing and analysis needs of the present generation of cosmic microwave background experiments (e.g., BOOMERANG, WMAP), HEALPix can be expanded to meet many of the profound challenges that will arise in confrontation with the observational output of future missions and experiments, including, e.g., Planck, Herschel, SAFIR, and the Beyond Einstein inflation probe. In this paper we consider the requirements and implementation constraints on a framework that simultaneously enables an efficient discretization with associated hierarchical indexation and fast analysis/synthesis of functions defined on the sphere. We demonstrate how these are explicitly satisfied by HEALPix.
Aims/hypothesis
The sodium–glucose cotransporter 2 (SGLT2) inhibitor canagliflozin slows progression of kidney function decline in type 2 diabetes. The aim of this study was to assess the effect of ...the SGLT2 inhibitor canagliflozin on biomarkers for progression of diabetic kidney disease (DKD).
Methods
A canagliflozin mechanism of action (MoA) network model was constructed based on an in vitro transcriptomics experiment in human proximal tubular cells and molecular features linked to SGLT2 inhibitors from scientific literature. This model was mapped onto an established DKD network model that describes molecular processes associated with DKD. Overlapping areas in both networks were subsequently used to select candidate biomarkers that change with canagliflozin therapy. These biomarkers were measured in 296 stored plasma samples from a previously reported 2 year clinical trial comparing canagliflozin with glimepiride.
Results
Forty-four proteins present in the canagliflozin MoA molecular model overlapped with proteins in the DKD network model. These proteins were considered candidates for monitoring impact of canagliflozin on DKD pathophysiology. For ten of these proteins, scientific evidence was available suggesting that they are involved in DKD progression. Of these, compared with glimepiride, canagliflozin 300 mg/day decreased plasma levels of TNF receptor 1 (TNFR1; 9.2%;
p
< 0.001), IL-6 (26.6%;
p
= 0.010), matrix metalloproteinase 7 (MMP7; 24.9%;
p
= 0.011) and fibronectin 1 (FN1; 14.9%;
p
= 0.055) during 2 years of follow-up.
Conclusions/interpretation
The observed reduction in TNFR1, IL-6, MMP7 and FN1 suggests that canagliflozin contributes to reversing molecular processes related to inflammation, extracellular matrix turnover and fibrosis.
Trial registration ClinicalTrials.gov NCT00968812
The aim of this longitudinal study was to assess with positron emission tomography (PET) the relationship between levels of inflammation and the loads of aggregated β-amyloid and tau at baseline and ...again after 2 years in prodromal Alzheimer's disease.
Forty-three subjects with mild cognitive impairment (MCI) had serial
C-PK11195 PET over 2 years to measure inflammation changes, and
C-PiB PET to determine β-amyloid fibril load; 22 also had serial
F-Flortaucipir PET to determine tau tangle load. Cortical surface statistical mapping was used to localise areas showing significant changes in tracer binding over time and to interrogate correlations between tracer binding of the tracers at baseline and after 2 years.
Those MCI subjects with high
C-PiB uptake at baseline (classified as prodromal Alzheimer's disease) had raised inflammation levels which significantly declined across cortical regions over 2 years although their β-amyloid levels continued to rise. Those MCI cases who had low/normal
C-PiB uptake at baseline but their levels then rose over 2 years were classified as prodromal AD with low Thal phase 1-2 amyloid deposition at baseline. They showed levels of cortical inflammation which correlated with their rising β-amyloid load. Those MCI cases with baseline low
C-PiB uptake that remained stable were classified as non-AD, and they showed no correlated inflammation levels. Finally, MCI cases which showed both high
C-PiB and
F-Flortaucipir uptake at baseline (MCI due to AD) showed a further rise in their tau tangle load over 2 years with a correlated rise in levels of inflammation.
Our baseline and 2-year imaging findings are compatible with a biphasic trajectory of inflammation in Alzheimer's disease: MCI cases with low baseline but subsequently rising β-amyloid load show correlated levels of microglial activation which then later decline when the β-amyloid load approaches AD levels. Later, as tau tangles form in β-amyloid positive MCI cases with prodromal AD, the rising tau load is associated with higher levels of inflammation.
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