Photomyogenic response in Niemann–Pick type C: a case report

Contains fulltext : 98214.pdf (publisher's version ) (Closed access)1 maart 201

Immune landscapes predict chemotherapy resistance and immunotherapy response in acute myeloid leukemia

Acute myeloid leukemia (AML) is a molecularly and clinically heterogeneous hematological malignancy. Although immunotherapy may be an attractive modality to exploit in patients with AML, the ability to predict the groups of patients and the types of cancer that will respond to immune targeting remains limited. This study dissected the complexity of the immune architecture of AML at high resolution and assessed its influence on therapeutic response. Using 442 primary bone marrow samples from three independent cohorts of children and adults with AML, we defined immune-infiltrated and immune-depleted disease classes and revealed critical differences in immune gene expression across age groups and molecular disease subtypes. Interferon (IFN)–γ–related mRNA profiles were predictive for both chemotherapy resistance and response of primary refractory/relapsed AML to flotetuzumab immunotherapy. Our compendium of microenvironmental gene and protein profiles provides insights into the immuno-biology of AML and could inform the delivery of personalized immunotherapies to IFN-γ–dominant AML subtypes

Text-derived concept profiles support assessment of DNA microarray data for acute myeloid leukemia and for androgen receptor stimulation

BACKGROUND: High-throughput experiments, such as with DNA microarrays, typically result in hundreds of genes potentially relevant to the process under study, rendering the interpretation of these experiments problematic. Here, we propose and evaluate an approach to find functional associations between large numbers of genes and other biomedical concepts from free-text literature. For each gene, a profile of related concepts is constructed that summarizes the context in which the gene is mentioned in literature. We assign a weight to each concept in the profile based on a likelihood ratio measure. Gene concept profiles can then be clustered to find related genes and other concepts. RESULTS: The experimental validation was done in two steps. We first applied our method on a controlled test set. After this proved to be successful the datasets from two DNA microarray experiments were analyzed in the same way and the results were evaluated by domain experts. The first dataset was a gene-expression profile that characterizes the cancer cells of a group of acute myeloid leukemia patients. For this group of patients the biological background of the cancer cells is largely unknown. Using our methodology we found an association of these cells to monocytes, which agreed with other experimental evidence. The second data set consisted of differentially expressed genes following androgen receptor stimulation in a prostate cancer cell line. Based on the analysis we put forward a hypothesis about the biological processes induced in these studied cells: secretory lysosomes are involved in the production of prostatic fluid and their development and/or secretion are androgen-regulated processes. CONCLUSION: Our method can be used to analyze DNA microarray datasets based on information explicitly and implicitly available in the literature. We provide a publicly available tool, dubbed Anni, for this purpose

Seed Mucilage Improves Seedling Emergence of a Sand Desert Shrub

The success of seedling establishment of desert plants is determined by seedling emergence response to an unpredictable precipitation regime. Sand burial is a crucial and frequent environmental stress that impacts seedling establishment on sand dunes. However, little is known about the ecological role of seed mucilage in seedling emergence in arid sandy environments. We hypothesized that seed mucilage enhances seedling emergence in a low precipitation regime and under conditions of sand burial. In a greenhouse experiment, two types of Artemisia sphaerocephala achenes (intact and demucilaged) were exposed to different combinations of burial depth (0, 5, 10, 20, 40 and 60 mm) and irrigation regimes (low, medium and high, which simulated the precipitation amount and frequency in May, June and July in the natural habitat, respectively). Seedling emergence increased with increasing irrigation. It was highest at 5 mm sand burial depth and ceased at burial depths greater than 20 mm in all irrigation regimes. Mucilage significantly enhanced seedling emergence at 0, 5 and 10 mm burial depths in low irrigation, at 0 and 5 mm burial depths in medium irrigation and at 0 and 10 mm burial depths in high irrigation. Seed mucilage also reduced seedling mortality at the shallow sand burial depths. Moreover, mucilage significantly affected seedling emergence time and quiescence and dormancy percentages. Our findings suggest that seed mucilage plays an ecologically important role in successful seedling establishment of A. sphaerocephala by improving seedling emergence and reducing seedling mortality in stressful habitats of the sandy desert environment

Effect of personal exposure to black carbon on changes in allergic asthma gene methylation measured 5 days later in urban children: importance of allergic sensitization

Background Asthma gene DNA methylation may underlie the effects of air pollution on airway inflammation. However, the temporality and individual susceptibility to environmental epigenetic regulation of asthma has not been fully elucidated. Our objective was to determine the timeline of black carbon (BC) exposure, measured by personal sampling, on DNA methylation of allergic asthma genes 5 days later to capture usual weather variations and differences related to changes in behavior and activities. We also sought to determine how methylation may vary by seroatopy and cockroach sensitization and by elevated fractional exhaled nitric oxide (FeNO). Methods Personal BC levels were measured during two 24-h periods over a 6-day sampling period in 163 New York City children (age 9–14 years), repeated 6 months later. During home visits, buccal cells were collected as noninvasive surrogates for lower airway epithelial cells and FeNO measured as an indicator of airway inflammation. CpG promoter loci of allergic asthma genes (e.g., interleukin 4 (IL4), interferon gamma (IFNγ), inducible nitric oxide synthase (NOS2A)), arginase 2 (ARG2)) were pyrosequenced at the start and end of each sampling period. Results Higher levels of BC were associated with lower methylation of IL4 promoter CpG−48 5 days later. The magnitude of association between BC exposure and demethylation of IL4 CpG−48 and NOS2A CpG+5099 measured 5 days later appeared to be greater among seroatopic children, especially those sensitized to cockroach allergens (RR [95% CI] 0.55 [0.37–0.82] and 0.67 [0.45–0.98] for IL4 CpG−48 and NOS2A CpG+5099, respectively), compared to non-sensitized children (RR [95% CI] 0.87 [0.65–1.17] and 0.95 [0.69–1.33] for IL4 CpG−48 and NOS2A CpG+5099, respectively); however, the difference was not statistically different. In multivariable linear regression models, lower DNA methylation of IL4 CpG−48 and NOS2A CpG+5099 were associated with increased FeNO. Conclusions Our results suggest that exposure to BC may exert asthma proinflammatory gene demethylation 5 days later that in turn may link to airway inflammation. Our results further suggest that seroatopic children, especially those sensitized to cockroach allergens, may be more susceptible to the effect of acute BC exposure on epigenetic changes

Spatiotemporal scaling of North American continental interior wetlands: implications for shorebird conservation

Within interior North America, erratic weather patterns and heterogeneous wetland complexes cause wide spatio-temporal variation in the resources available to migrating shorebirds. Identifying the pattern-generating components of landscape-level resources and the scales at which shorebirds respond to these patterns will better facilitate conservation efforts for these species. We constructed descriptive models that identified weather variables associated with creating the spatio-temporal patterns of shorebird habitat in ten landscapes in north-central Oklahoma. We developed a metric capable of measuring the dynamic composition and configuration of shorebird habitat in the region and used field data to empirically estimate the spatial scale at which shorebirds respond to the amount and configuration of habitat. Precipitation, temperature, solar radiation and wind speed best explained the incidence of wetland habitat, but relationships varied among wetland types. Shorebird occurrence patterns were best explained by habitat density estimates at a 1.5 km scale. This model correctly classified 86 % of shorebird observations. At this scale, when habitat density was low, shorebirds occurred in 5 % of surveyed habitat patches but occurrence reached 60 % when habitat density was high. Our results suggest scale dependence in the habitat-use patterns of migratory shorebirds. We discuss potential implications of our results and how integrating this information into conservation efforts may improve conservation strategies and management practices

Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases.

Developmental and/or epileptic encephalopathies (DEEs) are a group of devastating genetic disorders, resulting in early-onset, therapy-resistant seizures and developmental delay. Here we report on 22 individuals from 15 families presenting with a severe form of intractable epilepsy, severe developmental delay, progressive microcephaly, visual disturbance and similar minor dysmorphisms. Whole exome sequencing identified a recurrent, homozygous variant (chr2:64083454A > G) in the essential UDP-glucose pyrophosphorylase (UGP2) gene in all probands. This rare variant results in a tolerable Met12Val missense change of the longer UGP2 protein isoform but causes a disruption of the start codon of the shorter isoform, which is predominant in brain. We show that the absence of the shorter isoform leads to a reduction of functional UGP2 enzyme in neural stem cells, leading to altered glycogen metabolism, upregulated unfolded protein response and premature neuronal differentiation, as modeled during pluripotent stem cell differentiation in vitro. In contrast, the complete lack of all UGP2 isoforms leads to differentiation defects in multiple lineages in human cells. Reduced expression of Ugp2a/Ugp2b in vivo in zebrafish mimics visual disturbance and mutant animals show a behavioral phenotype. Our study identifies a recurrent start codon mutation in UGP2 as a cause of a novel autosomal recessive DEE syndrome. Importantly, it also shows that isoform-specific start-loss mutations causing expression loss of a tissue-relevant isoform of an essential protein can cause a genetic disease, even when an organism-wide protein absence is incompatible with life. We provide additional examples where a similar disease mechanism applies