Piezo1 channel-mediated Ca2+ signaling inhibits lipopolysaccharide-induced activation of the NF-κB inflammatory signaling pathway and generation of TNF-α and IL-6 in microglial cells.

Microglial cells are crucial in maintaining central nervous system (CNS) homeostasis and mediating CNS disease pathogenesis. Increasing evidence supports that alterations in the mechanical properties of CNS microenvironments influence glial cell phenotypes, but the mechanisms regulating microglial cell function remain elusive. Here, we examined the mechanosensitive Piezo1 channel in microglial cells, particularly, how Piezo1 channel activation regulates pro-inflammatory activation and production of pro-inflammatory cytokines, using BV2 and primary microglial cells. Piezo1 expression in microglial cells was detected both at mRNA and protein levels. Application of Piezo1 channel activator Yoda1 induced Ca2+ flux to increase intracellular Ca2+ concentration that was reduced by treatment with ruthenium red, a Piezo1 inhibitor, or Piezo1-specific siRNA, supporting that Piezo1 functions as a cell surface Ca2+ -permeable channel. Priming with lipopolysaccharide (LPS) induced microglial cell activation and production of TNF-α and IL-6, which were inhibited by treatment with Yoda1. Furthermore, LPS priming induced the activation of ERK, p38 MAPKs, and NF-κB. LPS-induced activation of NF-κB, but not ERK and p38, was inhibited by treatment with Yoda1. Yoda1-induced inhibition was blunted by siRNA-mediated depletion of Piezo1 expression and, furthermore, treatment with BAPTA-AM to prevent intracellular Ca2+ increase. Collectively, our results support that Piezo1 channel activation downregulates the pro-inflammatory function of microglial cells, especially production of TNF-α and IL-6, by initiating intracellular Ca2+ signaling to inhibit the NF-κB inflammatory signaling pathway. These findings reveal Piezo1 channel activation as a previously unrecognized mechanism regulating microglial cell function, raising an interesting perspective on targeting this molecular mechanism to alleviate neuroinflammation and associated CNS pathologies.

ORAI1 regulates sustained cytosolic free calcium fluctuations during breast cancer cell apoptosis and apoptotic resistance via a STIM1 independent pathway.

Excessive rapid increases in cytosolic free Ca2+ have a clear association with the induction of cancer cell death. Whereas, characterizing the Ca2+ signaling events that occur during the progression of the apoptotic cascade over a period of hours or days, has not yet been possible. Now using genetically encoded Ca2+ indicators complemented with automated epifluorescence microscopy we have shown that staurosporine-induced apoptosis in MDA-MB-231 breast cancer cells was associated with delayed development of cytosolic free Ca2+ fluctuations, which were then maintained for 24 h. These cytosolic free Ca2+ fluctuations were dependent on the Ca2+ channel ORAI1. Silencing of ORAI1, but not its canonical activators STIM1 and STIM2, promoted apoptosis in this model. The pathway for this regulation implicates a mechanism previously associated with the migration of cancer cells involving ORAI1, the chaperone protein SigmaR1, and Ca2+ -activated K+ channels.

Small cohort of patients with epilepsy showed increased activity on Facebook before sudden unexpected death.

Sudden Unexpected Death in Epilepsy (SUDEP) remains a leading cause of death in people with epilepsy. Despite the constant risk for patients and bereavement to family members, to date the physiological mechanisms of SUDEP remain unknown. Here we explore the potential to identify putative predictive signals of SUDEP from online digital behavioral data using text and sentiment analysis tools. Specifically, we analyze Facebook timelines of six patients with epilepsy deceased due to SUDEP, donated by surviving family members. We find preliminary evidence for behavioral changes detectable by text and sentiment analysis tools. Namely, in the months preceding their SUDEP event patient social media timelines show: i) increase in verbosity; ii) increased use of functional words; and iii) sentiment shifts as measured by different sentiment analysis tools. Combined, these results suggest that social media engagement, as well as its sentiment, may serve as possible early-warning signals for SUDEP in people with epilepsy. While the small sample of patient timelines analyzed in this study prevents generalization, our preliminary investigation demonstrates the potential of social media data as complementary data in larger studies of SUDEP and epilepsy.

Anisotropic diffusion creep in postperovskite provides a new model for deformation at the core-mantle boundary.

The lowermost portion of Earth's mantle (D″) above the core-mantle boundary shows anomalous seismic features, such as strong seismic anisotropy, related to the properties of the main mineral MgSiO3 postperovskite. But, after over a decade of investigations, the seismic observations still cannot be explained simply by flow models which assume dislocation creep in postperovskite. We have investigated the chemical diffusivity of perovskite and postperovskite phases by experiment and ab initio simulation, and derive equations for the observed anisotropic diffusion creep. There is excellent agreement between experiments and simulations for both phases in all of the chemical systems studied. Single-crystal diffusivity in postperovskite displays at least 3 orders of magnitude of anisotropy by experiment and simulation (Da = 1,000 Db; Db ≈ Dc) in zinc fluoride, and an even more extreme anisotropy is predicted (Da = 10,000 Dc; Dc = 10,000 Db) in the natural MgSiO3 system. Anisotropic chemical diffusivity results in anisotropic diffusion creep, texture generation, and a strain-weakening rheology. The results for MgSiO3 postperovskite strongly imply that regions within the D″ region of Earth dominated by postperovskite will 1) be substantially weaker than regions dominated by perovskite and 2) develop a strain-induced crystallographic-preferred orientation with strain-weakening rheology. This leads to strain localization and the possibility to bring regions with significantly varying textures into close proximity by strain on narrow shear zones. Anisotropic diffusion creep therefore provides an attractive alternative explanation for the complexity in observed seismic anisotropy and the rapid lateral changes in seismic velocities in D″.

The functions of repressor element 1-silencing transcription factor in models of epileptogenesis and post-ischemia.

Epilepsy is a debilitating neurological disorder characterised by recurrent seizures for which 30% of patients are refractory to current treatments. The genetic and molecular aetiologies behind epilepsy are under investigation with the goal of developing new epilepsy medications. The transcriptional repressor REST (Repressor Element 1-Silencing Transcription factor) is a focus of interest as it is consistently upregulated in epilepsy patients and following brain insult in animal models of epilepsy and ischemia. This review analyses data from different epilepsy models and discusses the contribution of REST to epileptogenesis. We propose that in healthy brains REST acts in a protective manner to homeostatically downregulate increases in excitability, to protect against seizure through downregulation of BDNF (Brain-Derived Neurotrophic Factor) and its receptor, TrkB (Tropomyosin receptor kinase B). However, in epilepsy patients and post-seizure, REST may increase to a larger degree, which allows downregulation of the glutamate receptor subunit GluR2. This leads to AMPA glutamate receptors lacking GluR2 subunits, which have increased permeability to Ca2+, causing excitotoxicity, cell death and seizure. This concept highlights therapeutic potential of REST modulation through gene therapy in epilepsy patients.

Carbohydrate microarrays and their use for the identification of molecular markers for plant cell wall composition.

Genetic improvement of the plant cell wall has enormous potential to increase the quality of food, fibers, and fuels. However, the identification and characterization of genes involved in plant cell wall synthesis is far from complete. Association mapping is one of the few techniques that can help identify candidate genes without relying on our currently incomplete knowledge of cell wall synthesis. However, few cell wall phenotyping methodologies have proven sufficiently precise, robust, or scalable for association mapping to be conducted for specific cell wall polymers. Here, we created high-density carbohydrate microarrays containing chemically extracted cell wall polysaccharides collected from 331 genetically diverse Brassica napus cultivars and used them to obtain detailed, quantitative information describing the relative abundance of selected noncellulosic polysaccharide linkages and primary structures. We undertook genome-wide association analysis of data collected from 57 carbohydrate microarrays and identified molecular markers reflecting a diversity of specific xylan, xyloglucan, pectin, and arabinogalactan moieties. These datasets provide a detailed insight into the natural variations in cell wall carbohydrate moieties between B. napus genotypes and identify associated markers that could be exploited by marker-assisted breeding. The identified markers also have value beyond B. napus for functional genomics, facilitated by the close genetic relatedness to the model plant Arabidopsis Together, our findings provide a unique dissection of the genetic architecture that underpins plant cell wall biosynthesis and restructuring.

Direct Feature Evaluation in Black-Box Optimization Using Problem Transformations.

Exploratory Landscape Analysis provides sample-based methods to calculate features of black-box optimization problems in a quantitative and measurable way. Many problem features have been proposed in the literature in an attempt to provide insights into the structure of problem landscapes and to use in selecting an effective algorithm for a given optimization problem. While there has been some success, evaluating the utility of problem features in practice presents some significant challenges. Machine learning models have been employed as part of the evaluation process, but they may require additional information about the problems as well as having their own hyper-parameters, biases and experimental variability. As a result, extra layers of uncertainty and complexity are added into the experimental evaluation process, making it difficult to clearly assess the effect of the problem features. In this article, we propose a novel method for the evaluation of problem features which can be applied directly to individual or groups of features and does not require additional machine learning techniques or confounding experimental factors. The method is based on the feature's ability to detect a prior ranking of similarity in a set of problems. Analysis of Variance (ANOVA) significance tests are used to determine if the feature has successfully distinguished the successive problems in the set. Based on ANOVA test results, a percentage score is assigned to each feature for different landscape characteristics. Experimental results for twelve different features on four problem transformations demonstrate the method and provide quantitative evidence about the ability of different problem features to detect specific properties of problem landscapes.

MicroRNA-21 drives the switch to a synthetic phenotype in human saphenous vein smooth muscle cells.

Cardiovascular disease is a leading cause of morbidity and mortality. Smooth muscle cells (SMC) comprising the vascular wall can switch phenotypes from contractile to synthetic, which can promote the development of aberrant remodelling and intimal hyperplasia (IH). MicroRNA-21 (miR-21) is a short, non-coding RNA that has been implicated in cardiovascular diseases including proliferative vascular disease and ischaemic heart disease. However, its involvement in the complex development of atherosclerosis has yet to be ascertained. Smooth muscle cells (SMC) were isolated from human saphenous veins (SV). miR-21 was over-expressed and the impact of this on morphology, proliferation, gene and protein expression related to synthetic SMC phenotypes monitored. Over-expression of miR-21 increased the spread cell area and proliferative capacity of SV-SMC and expression of MMP-1, whilst reducing RECK protein, indicating a switch to the synthetic phenotype. Furthermore, platelet-derived growth factor BB (PDGF-BB; a growth factor implicated in vasculoproliferative conditions) was able to induce miR-21 expression via the PI3K and ERK signalling pathways. This study has revealed a mechanism whereby PDGF-BB induces expression of miR-21 in SV-SMC, subsequently driving conversion to a synthetic SMC phenotype, propagating the development of IH. Thus, these signaling pathways may be attractive therapeutic targets to minimise progression of the disease. © 2018 IUBMB Life, 70(7):649-657, 2018.

A Model-based Framework for Black-box Problem Comparison Using Gaussian Processes.

An important challenge in black-box optimization is to be able to understand the relative performance of different algorithms on problem instances. This challenge has motivated research in exploratory landscape analysis and algorithm selection, leading to a number of frameworks for analysis. However, these procedures often involve significant assumptions, or rely on information not typically available. In this paper we propose a new, model-based framework for the characterization of black-box optimization problems using Gaussian Process regression. The framework allows problem instances to be compared to each other in a relatively simple way. The model-based approach also allows us to assess the goodness of fit and Gaussian Processes lead to an efficient means of model comparison. The implementation of the framework is described and validated on several test sets as one benchmark problem is slowly transformed into another.

Maternal Rest/Nrsf Regulates Zebrafish Behavior through snap25a/b.

UNLABELLED: During embryonic development, regulation of gene expression is key to creating the many subtypes of cells that an organism needs throughout its lifetime. Recent work has shown that maternal genetics and environmental factors have lifelong consequences on diverse processes ranging from immune function to stress responses. The RE1-silencing transcription factor (Rest) is a transcriptional repressor that interacts with chromatin-modifying complexes to repress transcription of neural-specific genes during early development. Here we show that in zebrafish, maternally supplied rest regulates expression of target genes during larval development and has lifelong impacts on behavior. Larvae deprived of maternal rest are hyperactive and show atypical spatial preferences. Adult male fish deprived of maternal rest present with atypical spatial preferences in a novel environment assay. Transcriptome sequencing revealed 158 genes that are repressed by maternal rest in blastula stage embryos. Furthermore, we found that maternal rest is required for target gene repression until at least 6 dpf. Importantly, disruption of the RE1 sites in either snap25a or snap25b resulted in behaviors that recapitulate the hyperactivity phenotype caused by absence of maternal rest Both maternal rest mutants and snap25a RE1 site mutants have altered primary motor neuron architecture that may account for the enhanced locomotor activity. These results demonstrate that maternal rest represses snap25a/b to modulate larval behavior and that early Rest activity has lifelong behavioral impacts. SIGNIFICANCE STATEMENT: Maternal factors deposited in the oocyte have well-established roles during embryonic development. We show that, in zebrafish, maternal rest (RE1-silencing transcription factor) regulates expression of target genes during larval development and has lifelong impacts on behavior. The Rest transcriptional repressor interacts with chromatin-modifying complexes to limit transcription of neural genes. We identify several synaptic genes that are repressed by maternal Rest and demonstrate that snap25a/b are key targets of maternal rest that modulate larval locomotor activity. These results reveal that zygotic rest is unable to compensate for deficits in maternally supplied rest and uncovers novel temporal requirements for Rest activity, which has implications for the broad roles of Rest-mediated repression during neural development and in disease states.

Inhibition of histone deacetylase 1 or 2 reduces induced cytokine expression in microglia through a protein synthesis independent mechanism.

Histone deacetylase (HDAC) inhibitors prevent neural cell death in in vivo models of cerebral ischaemia, brain injury and neurodegenerative disease. One mechanism by which HDAC inhibitors may do this is by suppressing the excessive inflammatory response of chronically activated microglia. However, the molecular mechanisms underlying this anti-inflammatory effect and the specific HDAC responsible are not fully understood. Recent data from in vivo rodent studies have shown that inhibition of class I HDACs suppresses neuroinflammation and is neuroprotective. In our study, we have identified that selective HDAC inhibition with inhibitors apicidin, MS-275 or MI-192, or specific knockdown of HDAC1 or 2 using siRNA, suppresses the expression of cytokines interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-α) in BV-2 murine microglia activated with lipopolysaccharide (LPS). Furthermore, we found that in the absence of HDAC1, HDAC2 is up-regulated and these increased levels are compensatory, suggesting that these two HDACs have redundancy in regulating the inflammatory response of microglia. Investigating the possible underlying anti-inflammatory mechanisms suggests an increase in protein expression is not important. Taken together, this study supports the idea that inhibitors selective towards HDAC1 or HDAC2, may be therapeutically useful for targeting neuroinflammation in brain injuries and neurodegenerative disease.

Feedstock selection for polymer and chemical production: feedstock-specific recalcitrance.

Plant cell wall materials derived from a range of waste biomass sources have great potential as a source of sustainable alternatives to petrochemicals. Perhaps the most straightforward way of realising this potential would be to hydrolyse the most efficiently fermentable polymers into their constituent sugars and use yeast to ferment these into useful chemicals. However, it also makes sense to pre-extract components which have a greater value in polymeric form. This is particularly true for non-cellulosic polymers, which are rich in poorly-fermentable pentose sugars. Liquid hot water (LHW) pretreatment can be used to extract non-cellulosic carbohydrates in a cost-effective manner, leaving a cellulose-rich substrate which is easier to hydrolyse using commercial cellulases. However, inherent differences in the plant cell wall structure and composition mean that some biomass sources may be more suitable for exploitation than others. Here, we examine eight different feedstocks (two each from hardwood, softwood, cereal straws and dicotyledonous crops), expose them to 26 different LHW pretreatment conditions and hydrolyse the entire pretreated slurry with a commercial cellulase. This enables side-by-side comparisons, in terms of saccharification yield, of the feedstocks. The results clearly demonstrate considerable differences in suitability between the feedstocks, in relation to the quantity of products released and the processes needed to obtain them.

Analysis of the genome and transcriptome of Cryptococcus neoformans var. grubii reveals complex RNA expression and microevolution leading to virulence attenuation.

Cryptococcus neoformans is a pathogenic basidiomycetous yeast responsible for more than 600,000 deaths each year. It occurs as two serotypes (A and D) representing two varieties (i.e. grubii and neoformans, respectively). Here, we sequenced the genome and performed an RNA-Seq-based analysis of the C. neoformans var. grubii transcriptome structure. We determined the chromosomal locations, analyzed the sequence/structural features of the centromeres, and identified origins of replication. The genome was annotated based on automated and manual curation. More than 40,000 introns populating more than 99% of the expressed genes were identified. Although most of these introns are located in the coding DNA sequences (CDS), over 2,000 introns in the untranslated regions (UTRs) were also identified. Poly(A)-containing reads were employed to locate the polyadenylation sites of more than 80% of the genes. Examination of the sequences around these sites revealed a new poly(A)-site-associated motif (AUGHAH). In addition, 1,197 miscRNAs were identified. These miscRNAs can be spliced and/or polyadenylated, but do not appear to have obvious coding capacities. Finally, this genome sequence enabled a comparative analysis of strain H99 variants obtained after laboratory passage. The spectrum of mutations identified provides insights into the genetics underlying the micro-evolution of a laboratory strain, and identifies mutations involved in stress responses, mating efficiency, and virulence.

A Block Successive Lower-Bound Maximization Algorithm for the Maximum Pseudo-Likelihood Estimation of Fully Visible Boltzmann Machines.

Maximum pseudo-likelihood estimation (MPLE) is an attractive method for training fully visible Boltzmann machines (FVBMs) due to its computational scalability and the desirable statistical properties of the MPLE. No published algorithms for MPLE have been proven to be convergent or monotonic. In this note, we present an algorithm for the MPLE of FVBMs based on the block successive lower-bound maximization (BSLM) principle. We show that the BSLM algorithm monotonically increases the pseudo-likelihood values and that the sequence of BSLM estimates converges to the unique global maximizer of the pseudo-likelihood function. The relationship between the BSLM algorithm and the gradient ascent (GA) algorithm for MPLE of FVBMs is also discussed, and a convergence criterion for the GA algorithm is given.

Elevated expression levels of miR-143/5 in saphenous vein smooth muscle cells from patients with Type 2 diabetes drive persistent changes in phenotype and function.

Type 2 diabetes (T2DM) promotes premature atherosclerosis and inferior prognosis after arterial reconstruction. Vascular smooth muscle cells (SMC) respond to patho/physiological stimuli, switching between quiescent contractile and activated synthetic phenotypes under the control of microRNAs (miRs) that regulate multiple genes critical to SMC plasticity. The importance of miRs to SMC function specifically in T2DM is unknown. This study was performed to evaluate phenotype and function in SMC cultured from non-diabetic and T2DM patients, to explore any aberrancies and investigate underlying mechanisms. Saphenous vein SMC cultured from T2DM patients (T2DM-SMC) exhibited increased spread cell area, disorganised cytoskeleton and impaired proliferation relative to cells from non-diabetic patients (ND-SMC), accompanied by a persistent, selective up-regulation of miR-143 and miR-145. Transfection of premiR-143/145 into ND-SMC induced morphological and functional characteristics similar to native T2DM-SMC; modulating miR-143/145 targets Kruppel-like factor 4, alpha smooth muscle actin and myosin VI. Conversely, transfection of antimiR-143/145 into T2DM-SMC conferred characteristics of the ND phenotype. Exposure of ND-SMC to transforming growth factor beta (TGFß) induced a diabetes-like phenotype; elevated miR-143/145, increased cell area and reduced proliferation. Furthermore, these effects were dependent on miR-143/145. In conclusion, aberrant expression of miR-143/145 induces a distinct saphenous vein SMC phenotype that may contribute to vascular complications in patients with T2DM, and is potentially amenable to therapeutic manipulation.

Current level of glycaemic control and its associated factors in patients with type 2 diabetes across Europe: data from the PANORAMA study.

OBJECTIVE: To provide an update on glycaemic control in European patients with type 2 diabetes based on data from the nine-country, cross-sectional PANORAMA study (NCT00916513). DESIGN: Post-hoc analysis to report the number of patients achieving/not achieving glycaemic goal (HbA(1c) <7%). PATIENTS: Patients were randomly or consecutively selected from physician practices in nine countries. Eligible patients were aged ≥40 years, diagnosed with type 2 diabetes >1 year prior to study entry, and had an available medical record of >1 year. MEASUREMENTS: All data were collected at a single visit, including HbA1c measurement using a common device (A1CNow). Bivariate and multivariate analyses were used to investigate factors associated with not reaching glycaemic goal. RESULTS: Of 5817 patients enrolled (aged 65·9 ± 10·4 years, 53·7% male), 37·4% had an HbA(1c) ≥7%; (range 25·9% in The Netherlands to 52·0% in Turkey). In adjusted multivariate analyses, higher individual glycaemic target, younger age, poor physician-reported patient adherence to lifestyle/medication, longer diabetes duration, increasing treatment regimen complexity and physician-reported patient's unwillingness to intensify treatment were associated with not achieving goal. However, bivariate analyses also found gender, socioeconomic factors, body mass index, rate of complications and hypoglycaemia to be associated with not achieving goal. CONCLUSIONS: In PANORAMA, 37·4% of patients enrolled were not at glycaemic goal. Factors relating to patient characteristics, physician selection of individualized HbA1c target and diabetes itself (longer duration, more complex treatment) were strongly associated with not achieving goal. Further studies are warranted to explore these associations and evaluate strategies for improving glycaemic control.

Hypoxia-inducible factor-1α (HIF1α) switches on transient receptor potential ankyrin repeat 1 (TRPA1) gene expression via a hypoxia response element-like motif to modulate cytokine release.

Transient receptor potential ankyrin repeat 1 (TRPA1) forms calcium (Ca(2+))- and zinc (Zn(2+))-permeable ion channels that sense noxious substances. Despite the biological and clinical importance of TRPA1, there is little knowledge of the mechanisms that lead to transcriptional regulation of TRPA1 and of the functional role of transcriptionally induced TRPA1. Here we show induction of TRPA1 by inflammatory mediators and delineate the underlying molecular mechanisms and functional relevance. In human fibroblast-like synoviocytes, key inflammatory mediators (tumor necrosis factor-α and interleukin-1α) induced TRPA1 gene expression via nuclear factor-κB signaling and downstream activation of the transcription factor hypoxia-inducible factor-1α (HIF1α). HIF1α unexpectedly acted by binding to a specific hypoxia response element-like motif and its flanking regions in the TRPA1 gene. The induced TRPA1 channels, which were intrinsically activated by endogenous hydrogen peroxide and Zn(2+), suppressed secretion of interleukin-6 and interleukin-8. The data suggest a previously unrecognized HIF1α mechanism that links inflammatory mediators to ion channel expression.

Microevolution of Cryptococcus neoformans driven by massive tandem gene amplification.

The subtelomeric regions of organisms ranging from protists to fungi undergo a much higher rate of rearrangement than is observed in the rest of the genome. While characterizing these ~40-kb regions of the human fungal pathogen Cryptococcus neoformans, we have identified a recent gene amplification event near the right telomere of chromosome 3 that involves a gene encoding an arsenite efflux transporter (ARR3). The 3,177-bp amplicon exists in a tandem array of 2-15 copies and is present exclusively in strains with the C. neoformans var. grubii subclade VNI A5 MLST profile. Strains bearing the amplification display dramatically enhanced resistance to arsenite that correlates with the copy number of the repeat; the origin of increased resistance was verified as transport-related by functional complementation of an arsenite transporter mutant of Saccharomyces cerevisiae. Subsequent experimental evolution in the presence of increasing concentrations of arsenite yielded highly resistant strains with the ARR3 amplicon further amplified to over 50 copies, accounting for up to ~1% of the whole genome and making the copy number of this repeat as high as that seen for the ribosomal DNA. The example described here therefore represents a rare evolutionary intermediate-an array that is currently in a state of dynamic flux, in dramatic contrast to relatively common, static relics of past tandem duplications that are unable to further amplify due to nucleotide divergence. Beyond identifying and engineering fungal isolates that are highly resistant to arsenite and describing the first reported instance of microevolution via massive gene amplification in C. neoformans, these results suggest that adaptation through gene amplification may be an important mechanism that C. neoformans employs in response to environmental stresses, perhaps including those encountered during infection. More importantly, the ARR3 array will serve as an ideal model for further molecular genetic analyses of how tandem gene duplications arise and expand.

Epigenetic mechanisms in development and disease.

Our advances in technology allow us to sequence DNA to uncover genetic differences not only between individuals, but also between normal and diseased cells within an individual. However, there is still a lot we have yet to understand regarding the epigenetic mechanisms that also contribute to our individuality and to disease. The 80th Biochemical Society Annual Symposium entitled Epigenetic Mechanisms in Development and Disease brought together some leading researchers in the field who discussed their latest insights into epigenetic mechanisms. Methylation of DNA has been the focus of much study from both a developmental perspective and imprinting of genes to its contribution to diseases such as cancer. Recently, the modification of methylcytosine to hydoxymethylcytosine within cells was uncovered, which opened a host of potential new mechanisms, and a flurry of new studies are underway to uncover its significance. Epigenetics is not confined to a study of DNA, and the post-translational modifications on the histone proteins have a significant role to play in regulating gene expression. There are many different modifications and, as shown at the Symposium, new variations used by cells are still being uncovered. We are some way to identifying how these modifications are added and removed and the protein complexes responsible for these changes. A focus on the function of the complexes and the interactions between individual modifications to regulate gene expression is advancing our knowledge, as discussed in the accompanying papers, although there are clearly plenty of opportunities for new breakthroughs to be made.

MgSO4·11H2O and MgCrO4·11H2O based on time-of-flight neutron single-crystal Laue data.

Hexaaquamagnesium(II) sulfate pentahydrate, [Mg(H2O)6]SO4·5H2O, and hexaaquamagnesium(II) chromate(II) pentahydrate, [Mg(H2O)6][CrO4]·5H2O, are isomorphous, being composed of hexaaquamagnesium(II) octahedra, [Mg(H2O)6](2+), and sulfate (chromate) tetrahedral oxyanions, SO4(2-) (CrO4(2-)), linked by hydrogen bonds. There are two symmetry-inequivalent centrosymmetric octahedra: M1 at (0, 0, 0) donates hydrogen bonds directly to the tetrahedral oxyanion, T1, at (0.405, 0.320, 0.201), whereas the M2 octahedron at (0, 0, ½) is linked to the oxyanion via five interstitial water molecules. Substitution of Cr(VI) for S(VI) leads to a substantial expansion of T1, since the Cr-O bond is approximately 12% longer than the S-O bond. This expansion is propagated through the hydrogen-bonded framework to produce a 3.3% increase in unit-cell volume; the greatest part of this chemically induced strain is manifested along the b* direction. The hydrogen bonds in the chromate compound mitigate ~20% of the expected strain due to the larger oxyanion, becoming shorter (i.e. stronger) and more linear than in the sulfate analogue. The bifurcated hydrogen bond donated by one of the interstitial water molecules is significantly more symmetrical in the chromate analogue.