Genome-wide signatures of differential DNA methylation in pediatric acute lymphoblastic leukemia

Background

Although aberrant DNA methylation has been observed previously in acute lymphoblastic leukemia (ALL), the patterns of differential methylation have not been comprehensively determined in all subtypes of ALL on a genome-wide scale. The relationship between DNA methylation, cytogenetic background, drug resistance and relapse in ALL is poorly understood.

Results

We surveyed the DNA methylation levels of 435,941 CpG sites in samples from 764 children at diagnosis of ALL and from 27 children at relapse. This survey uncovered four characteristic methylation signatures. First, compared with control blood cells, the methylomes of ALL cells shared 9,406 predominantly hypermethylated CpG sites, independent of cytogenetic background. Second, each cytogenetic subtype of ALL displayed a unique set of hyper- and hypomethylated CpG sites. The CpG sites that constituted these two signatures differed in their functional genomic enrichment to regions with marks of active or repressed chromatin. Third, we identified subtype-specific differential methylation in promoter and enhancer regions that were strongly correlated with gene expression. Fourth, a set of 6,612 CpG sites was predominantly hypermethylated in ALL cells at relapse, compared with matched samples at diagnosis. Analysis of relapse-free survival identified CpG sites with subtype-specific differential methylation that divided the patients into different risk groups, depending on their methylation status.

Conclusions

Our results suggest an important biological role for DNA methylation in the differences between ALL subtypes and in their clinical outcome after treatment.     

Dynamics of Baltic Sea phages driven by environmental changes

Phage predation constitutes a major mortality factor for bacteria in aquatic ecosystems, and thus, directly impacts nutrient cycling and microbial community dynamics. Yet, the population dynamics of specific phages across time scales from days to months remain largely unexplored, which limits our understanding of their influence on microbial succession. To investigate temporal changes in diversity and abundance of phages infecting particular host strains, we isolated 121 phage strains that infected three bacterial hosts during a Baltic Sea mesocosm experiment. Genome analysis revealed a novel Flavobacterium phage genus harboring gene sets putatively coding for synthesis of modified nucleotides and glycosylation of bacterial cell surface components. Another novel phage genus revealed a microdiversity of phage species that was largely maintained during the experiment and across mesocosms amended with different nutrients. In contrast to the newly described Flavobacterium phages, phages isolated from a Rheinheimera strain were highly similar to previously isolated genotypes, pointing to genomic consistency in this population. In the mesocosm experiment, the investigated phages were mainly detected after a phytoplankton bloom peak. This concurred with recurrent detection of the phages in the Baltic Proper during summer months, suggesting an influence on the succession of heterotrophic bacteria associated with phytoplankton blooms.     

Uterine clearance and resistance to persistent endometritis in the mare

The objective of this article is to review the role of uterine defense mechanisms in natural resistance to chronic or persistent endometritis. A breakdown of uterine physical clearance mechanisms is currently believed to play a major role in susceptibility to persistent endometritis. Mares with increased susceptibility to persistent endometritis have impaired myometrial contractility in response to an acute inflammation, resulting in an accumulation of fluid and inflammatory products within the uterine lumen. The origin of this defect remains unknown. Recent studies have demonstrated that spermatozoa trigger PMN chemotaxis into the uterine lumen. This observation suggests that a transient endometritis is a normal physiological response to breeding. However, in mares with impaired uterine defense mechanisms, the condition may develop into a persistent endometritis and subsequent subfertility. In contrast to spermatozoa, seminal plasma has a suppressive effect on complement activation and PMN chemotaxis (65). The exact role of seminal components in breeding-induced inflammation needs further investigation.     

Streptococcus pyogenes in human plasma: adaptive mechanisms analyzed by mass spectrometry-based proteomics

Streptococcus pyogenes is a major bacterial pathogen and a potent inducer of inflammation causing plasma leakage at the site of infection. A combination of label-free quantitative mass spectrometry-based proteomics strategies were used to measure how the intracellular proteome homeostasis of S. pyogenes is influenced by the presence of human plasma, identifying and quantifying 842 proteins. In plasma the bacterium modifies its production of 213 proteins, and the most pronounced change was the complete down-regulation of proteins required for fatty acid biosynthesis. Fatty acids are transported by albumin (HSA) in plasma. S. pyogenes expresses HSA-binding surface proteins, and HSA carrying fatty acids reduced the amount of fatty acid biosynthesis proteins to the same extent as plasma. The results clarify the function of HSA-binding proteins in S. pyogenes and underline the power of the quantitative mass spectrometry strategy used here to investigate bacterial adaptation to a given environment.     

Transient small molecule interactions kinetically modulate amyloid β peptide self-assembly

Small organic molecules, like Congo red and lacmoid, have been shown to modulate the self-assembly of the amyloid β peptide (Aβ). Here, we show that Aβ forms NMR invisible non-toxic co-aggregates together with lacmoid as well as Congo red. We find that the interaction involves two distinct kinetic processes and at every given time point only a small fraction of Aβ is in the co-aggregate. These weak transient interactions kinetically redirect the aggregation prone Aβ from self-assembling into amyloid fibrils. These findings suggest that even such weak binders might be effective as therapeutics against pathogenic protein aggregation.     

Interval-counting neurons in the anuran auditory midbrain: factors underlying diversity of interval tuning

In anurans, the temporal patterning of sound pulses is the primary information used for differentiating between spectrally similar calls. One class of midbrain neurons, referred to as ‘interval-counting’ cells, appears to be particularly important for discriminating among calls that differ in pulse repetition rate (PRR). These cells only respond after several pulses are presented with appropriate interpulse intervals. Here we show that the range of selectivity and sharpness of interval tuning vary considerably across neurons. Whole-cell recordings revealed that neurons showing temporally summating excitatory postsynaptic potentials (EPSPs) with little or no inhibition or activity-dependent enhancement of excitation exhibited low-pass or band-pass tuning to slow PRRs. Neurons that showed inhibition and rate-dependent enhancement of excitation, however, were band-pass or high-pass to intermediate or fast PRRs. Surprisingly, across cells, interval tuning based on membrane depolarization and spike rate measures were not significantly correlated. Neurons that lacked inhibition showed the greatest disparities between these two measures of interval tuning. Cells that showed broad membrane potential-based tuning, for example, varied considerably in their spike rate-based tuning; narrow spike rate-based tuning resulted from ‘thresholding’ processes, whereby only the largest depolarizations triggered spikes. The potential constraints associated with generating interval tuning in this manner are discussed.     

The diagnosis and treatment of endometritis in the mare: yesterday and today

Diagnosis and treatment of endometritis in the mare has been controversial and mostly empirical. The lack or inability of researchers to establish or develop a model that can serve as a standard or control makes this area of equine reproduction difficult to address scientifically. However, major advances have been made, particularly with the demonstration of the importance of uterine contractility in the elimination of bacteria, fluid, and inflammatory products from the uterus after breeding. This review provides a historical perspective of what has been done, and where we are now, in the approach to the diagnosis and therapy of endometritis in the mare.     

Reduced Wind Speed Improves Plant Growth in a Desert City

Background

The often dramatic effects of urbanization on community and ecosystem properties, such as primary productivity, abundances, and diversity are now well-established. In most cities local primary productivity increases and this extra energy flows upwards to alter diversity and relative abundances in higher trophic levels. The abiotic mechanisms thought to be responsible for increases in urban productivity are altered temperatures and light regimes, and increased nutrient and water inputs. However, another abiotic factor, wind speed, is also influenced by urbanization and well known for altering primary productivity in agricultural systems. Wind effects on primary productivity have heretofore not been studied in the context of urbanization.

Methodology/Principal Findings

We designed a field experiment to test if increased plant growth often observed in cities is explained by the sheltering effects of built structures. Wind speed was reduced by protecting Encelia farinosa (brittlebush) plants in urban, desert remnant and outlying desert localities via windbreaks while controlling for water availability and nutrient content. In all three habitats, we compared E. farinosa growth when protected by experimental windbreaks and in the open. E. farinosa plants protected against ambient wind in the desert and remnant areas grew faster in terms of biomass and height than exposed plants. As predicted, sheltered plants did not differ from unprotected plants in urban areas where wind speed is already reduced.

Conclusion/Significance

Our results indicate that reductions in wind speed due to built structures in cities contribute to increased plant productivity and thus also to changes in abundances and diversity of higher trophic levels. Our study emphasizes the need to incorporate wind speed in future urban ecological studies, as well as in planning for green space and sustainable cities.     

3D J-resolved NMR spectroscopy for unstructured polypeptides: fast measurement of <Superscript>3</Superscript>J<Subscript>HNHα</Subscript> coupling constants with outstanding spectral resolution

A powerful experiment for the investigation of conformational properties of unstructured states of proteins is presented. The method combines a phase sensitive J-resolved experiment with a ¹H-¹⁵N SOFAST-HMQC to provide a 3D spectrum with an E.COSY pattern originating from splittings due to ³J_HNHα and ²J_NHα couplings. Thereby an effectively homodecoupled ¹H-¹⁵N correlation spectrum is obtained with significantly improved resolution and greatly reduced spectral overlap compared to standard HSQC and HMQC experiments. The ³J_HNHα is revealed in three independent ways directly from the peak positions, allowing for internal consistency testing. In addition, the natural H^N linewidths can easily be extracted from the lineshapes. Thanks to the SOFAST principle, the limited sweep width needed in the J-dimension and the short phase cycle, data accumulation is rapid with excellent sensitivity per time unit. The experiment is demonstrated for the intrinsically unstructured 14 kDa protein α-synuclein. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.