Hypermutation of the inactive X chromosome is a frequent event in cancer.

Mutation is a fundamental process in tumorigenesis. However, the degree to which the rate of somatic mutation varies across the human genome and the mechanistic basis underlying this variation remain to be fully elucidated. Here, we performed a cross-cancer comparison of 402 whole genomes comprising a diverse set of childhood and adult tumors, including both solid and hematopoietic malignancies. Surprisingly, we found that the inactive X chromosome of many female cancer genomes accumulates on average twice and up to four times as many somatic mutations per megabase, as compared to the individual autosomes. Whole-genome sequencing of clonally expanded hematopoietic stem/progenitor cells (HSPCs) from healthy individuals and a premalignant myelodysplastic syndrome (MDS) sample revealed no X chromosome hypermutation. Our data suggest that hypermutation of the inactive X chromosome is an early and frequent feature of tumorigenesis resulting from DNA replication stress in aberrantly proliferating cells.

Entangling single atoms over 33 km telecom fibre.

Quantum networks promise to provide the infrastructure for many disruptive applications, such as efficient long-distance quantum communication and distributed quantum computing1,2. Central to these networks is the ability to distribute entanglement between distant nodes using photonic channels. Initially developed for quantum teleportation3,4 and loophole-free tests of Bell's inequality5,6, recently, entanglement distribution has also been achieved over telecom fibres and analysed retrospectively7,8. Yet, to fully use entanglement over long-distance quantum network links it is mandatory to know it is available at the nodes before the entangled state decays. Here we demonstrate heralded entanglement between two independently trapped single rubidium atoms generated over fibre links with a length up to 33 km. For this, we generate atom-photon entanglement in two nodes located in buildings 400 m line-of-sight apart and to overcome high-attenuation losses in the fibres convert the photons to telecom wavelength using polarization-preserving quantum frequency conversion9. The long fibres guide the photons to a Bell-state measurement setup in which a successful photonic projection measurement heralds the entanglement of the atoms10. Our results show the feasibility of entanglement distribution over telecom fibre links useful, for example, for device-independent quantum key distribution11-13 and quantum repeater protocols. The presented work represents an important step towards the realization of large-scale quantum network links.

Evidence for interictal blood-brain barrier dysfunction in people with epilepsy.

OBJECTIVE: Interictal blood-brain barrier dysfunction in chronic epilepsy has been demonstrated in animal models and pathological specimens. Ictal blood-brain barrier dysfunction has been shown in humans in vivo using an experimental quantitative magnetic resonance imaging (MRI) protocol. Here, we hypothesized that interictal blood-brain barrier dysfunction is also present in people with drug-resistant epilepsy. METHODS: Thirty-nine people (21 females, mean age at MRI ± SD = 30 ± 8 years) with drug-resistant epilepsy were prospectively recruited and underwent interictal T1-relaxometry before and after administration of a paramagnetic contrast agent. Likewise, quantitative T1 was acquired in 29 people without epilepsy (12 females, age at MRI = 48 ± 18 years). Quantitative T1 difference maps were calculated and served as a surrogate imaging marker for blood-brain barrier dysfunction. Values of quantitative T1 difference maps inside hemispheres ipsilateral to the presumed seizure onset zone were then compared, on a voxelwise level and within presumed seizure onset zones, to the contralateral side of people with epilepsy and to people without epilepsy. RESULTS: Compared to the contralateral side, ipsilateral T1 difference values were significantly higher in white matter (corrected p < .05), gray matter (uncorrected p < .05), and presumed seizure onset zones (p = .04) in people with epilepsy. Compared to people without epilepsy, significantly higher T1 difference values were found in the anatomical vicinity of presumed seizure onset zones (p = .004). A subgroup of people with hippocampal sclerosis demonstrated significantly higher T1 difference values in the ipsilateral hippocampus and in regions strongly interconnected with the hippocampus compared to people without epilepsy (corrected p < .01). Finally, z-scores reflecting the deviation of T1 difference values within the presumed seizure onset zone were associated with verbal memory performance (p = .02) in people with temporal lobe epilepsy. SIGNIFICANCE: Our results indicate a blood-brain barrier dysfunction in drug-resistant epilepsy that is detectable interictally in vivo, anatomically related to the presumed seizure onset zone, and associated with cognitive deficits.

The toxicological spectrum of the Bacillus cereus toxin cereulide points towards niche-specific specialisation.

Most microbes share their environmental niches with very different forms of life thereby engaging in specialised relationships to enable their persistence. The bacterium Bacillus cereus occurs ubiquitously in the environment with certain strain backgrounds causing foodborne and opportunistic infections in humans. The emetic lineage of B. cereus is capable of producing the toxin cereulide, which evokes emetic illnesses. Although food products favouring the accumulation of cereulide are known, the ecological role of cereulide and the environmental niche of emetic B. cereus remain elusive. To better understand the ecology of cereulide-producing B. cereus, we systematically assayed the toxicological spectrum of cereulide on a variety of organisms belonging to different kingdoms. As cereulide is a potassium ionophore, we further tested the effect of environmental potassium levels on the action of cereulide. We found that adverse effects of cereulide exposure are species-specific, which can be exacerbated with increased environmental potassium. Additionally, we demonstrate that cereulide is produced within an insect cadaver indicating its potential ecological function for a saprophytic lifestyle. Collectively, distinct cereulide susceptibilities of other organisms may reflect its role in enabling competitive niche specialization of emetic B. cereus.

A novel geometry-based analysis of hippocampal morphometry in mesial temporal lobe epilepsy.

Hippocampal volumetry is an essential tool in researching and diagnosing mesial temporal lobe epilepsy (mTLE). However, it has a limited ability to detect subtle alterations in hippocampal morphometry. Here, we establish and apply a novel geometry-based tool that enables point-wise morphometric analysis based on an intrinsic coordinate system of the hippocampus. We hypothesized that this point-wise analysis uncovers structural alterations not measurable by volumetry, but associated with histological underpinnings and the neuropsychological profile of mTLE. We conducted a retrospective study in 204 individuals with mTLE and 57 age- and gender-matched healthy subjects. FreeSurfer-based segmentations of hippocampal subfields in 3T-MRI were subjected to a geometry-based analysis that resulted in a coordinate system of the hippocampal mid-surface and allowed for point-wise measurements of hippocampal thickness and other features. Using point-wise analysis, we found significantly lower thickness and higher FLAIR signal intensity in the entire affected hippocampus of individuals with hippocampal sclerosis (HS-mTLE). In the contralateral hippocampus of HS-mTLE and the affected hippocampus of MRI-negative mTLE, we observed significantly lower thickness in the presubiculum. Impaired verbal memory was associated with lower thickness in the left presubiculum. In HS-mTLE histological subtype 3, we observed higher curvature than in subtypes 1 and 2 (all p < .05). These findings could not be observed using conventional volumetry (Bonferroni-corrected p < .05). We show that point-wise measures of hippocampal morphometry can uncover structural alterations not measurable by volumetry while also reflecting histological underpinnings and verbal memory. This substantiates the prospect of their clinical application.

Global hypomethylation in childhood asthma identified by genome-wide DNA-methylation sequencing preferentially affects enhancer regions.

BACKGROUND: Childhood asthma is a result of a complex interaction of genetic and environmental components causing epigenetic and immune dysregulation, airway inflammation and impaired lung function. Although different microarray based EWAS studies have been conducted, the impact of epigenetic regulation in asthma development is still widely unknown. We have therefore applied unbiased whole genome bisulfite sequencing (WGBS) to characterize global DNA-methylation profiles of asthmatic children compared to healthy controls. METHODS: Peripheral blood samples of 40 asthmatic and 42 control children aged 5-15 years from three birth cohorts were sequenced together with paired cord blood samples. Identified differentially methylated regions (DMRs) were categorized in genotype-associated, cell-type-dependent, or prenatally primed. Network analysis and subsequent natural language processing of DMR-associated genes was complemented by targeted analysis of functional translation of epigenetic regulation on the transcriptional and protein level. RESULTS: In total, 158 DMRs were identified in asthmatic children compared to controls of which 37% were related to the eosinophil content. A global hypomethylation was identified affecting predominantly enhancer regions and regulating key immune genes such as IL4, IL5RA, and EPX. These DMRs were confirmed in n = 267 samples and could be linked to aberrant gene expression. Out of the 158 DMRs identified in the established phenotype, 56 were perturbed already at birth and linked, at least in part, to prenatal influences such as tobacco smoke exposure or phthalate exposure. CONCLUSION: This is the first epigenetic study based on whole genome sequencing to identify marked dysregulation of enhancer regions as a hallmark of childhood asthma.

Tuning the Cross-Linking Density and Cross-Linker in Core Cross-Linked Polymeric Micelles and Its Effects on the Particle Stability in Human Blood Plasma and Mice.

Core cross-linked polymeric micelles (CCPMs) are designed to improve the therapeutic profile of hydrophobic drugs, reduce or completely avoid protein corona formation, and offer prolonged circulation times, a prerequisite for passive or active targeting. In this study, we tuned the CCPM stability by using bifunctional or trifunctional cross-linkers and varying the cross-linkable polymer block length. For CCPMs, amphiphilic thiol-reactive polypept(o)ides of polysarcosine-block-poly(S-ethylsulfonyl-l-cysteine) [pSar-b-pCys(SO2Et)] were employed. While the pCys(SO2Et) chain lengths varied from Xn = 17 to 30, bivalent (derivatives of dihydrolipoic acid) and trivalent (sarcosine/cysteine pentapeptide) cross-linkers have been applied. Asymmetrical flow field-flow fraction (AF4) displayed the absence of aggregates in human plasma, yet for non-cross-linked PM and CCPMs cross-linked with dihydrolipoic acid at [pCys(SO2Et)]17, increasing the cross-linking density or the pCys(SO2Et) chain lengths led to stable CCPMs. Interestingly, circulation time and biodistribution in mice of non-cross-linked and bivalently cross-linked CCPMs are comparable, while the trivalent peptide cross-linkers enhance the circulation half-life from 11 to 19 h.

Shape description and volumetry of hippocampus and amygdala in temporal lobe epilepsy - A beneficial combination with a clinical perspective.

Shape-based markers have entered the field of morphometric neuroimaging analysis as a second mainstay alongside conventional volumetric approaches. We aimed to assess the added value of shape description for the analysis of lesional and autoimmune temporal lobe epilepsy (TLE) focusing on hippocampus and amygdala. We retrospectively investigated MRI and clinical data from 65 patients with lesional TLE (hippocampal sclerosis (HS) and astrogliosis) and from 62 patients with limbic encephalitis (LE) with serologically proven autoantibodies. Surface reconstruction and volumetric segmentation were performed with FreeSurfer. For the shape analysis, we used BrainPrint, a tool that utilizes eigenvalues of the Laplace-Beltrami operator on triangular meshes to calculate intra-subject asymmetry. Psychometric tests of memory performance were ascertained, to evaluate clinical relevance of the shape descriptor. The potential benefit of shape in addition to volumetric information for classification was assessed by five-fold repeated cross validation and logistic regression. For the LE group, the best performing classification model consisted of a combination of volume and shape asymmetry (mean AUC = 0.728), the logistic regression model was significantly improved considering both modalities instead of just volume asymmetry. For lesional TLE, the best model only considered volumetric information (mean AUC = 0.867). Shape asymmetry of the hippocampus was largely associated with verbal memory performance only in LE patients (OR = 1.07, p = 0.02). For lesional TLE, shape description is robust, but redundant when compared to volumetric approaches. For LE, in contrast, shape asymmetry as a complementary modality significantly improves the detection of subtle morphometric changes and is further associated with memory performance, which underscores the clinical relevance of shape asymmetry as a novel imaging biomarker.

Secondary Structure-Driven Self-Assembly of Thiol-Reactive Polypept(o)ides.

Secondary structure formation differentiates polypeptides from most of the other synthetic polymers, and the transitions from random coils to rod-like α-helices or ß-sheets represent an additional parameter to direct self-assembly and the morphology of nanostructures. We investigated the influence of distinct secondary structures on the self-assembly of reactive amphiphilic polypept(o)ides. The individual morphologies can be preserved by core cross-linking via chemoselective disulfide bond formation. A series of thiol-responsive copolymers of racemic polysarcosine-block-poly(S-ethylsulfonyl-dl-cysteine) (pSar-b-p(dl)Cys), enantiopure polysarcosine-block-poly(S-ethylsulfonyl-l-cysteine) (pSar-b-p(l)Cys), and polysarcosine-block-poly(S-ethylsulfonyl-l-homocysteine) (pSar-b-p(l)Hcy) was prepared by N-carboxyanhydride polymerization. The secondary structure of the peptide segment varies from α-helices (pSar-b-p(l)Hcy) to antiparallel ß-sheets (pSar-b-p(l)Cys) and disrupted ß-sheets (pSar-b-p(dl)Cys). When subjected to nanoprecipitation, copolymers with antiparallel ß-sheets display the strongest tendency to self-assemble, whereas disrupted ß-sheets hardly induce aggregation. This translates to worm-like micelles, solely spherical micelles, or ellipsoidal structures, as analyzed by atomic force microscopy and cryogenic transmission electron microscopy, which underlines the potential of secondary structure-driven self-assembly of synthetic polypeptides.

Psychological interventions to improve sleep in college students: A meta-analysis of randomized controlled trials.

Sleep disturbances and insomnia are common in college students, and reduce their quality of life and academic performance. The aim of this meta-analysis was to evaluate the efficacy of psychological interventions aimed at improving sleep in college students. A meta-analysis was conducted with 10 randomized controlled trials with passive control conditions (N = 2,408). The overall mean effect size (Hedges' g) of all sleep-related outcomes within each trial was moderate to large (g = 0.61; 95% confidence interval: 0.41-0.81; numbers-needed-to-treat = 3). Effect sizes for global measures of sleep disturbances were g = 0.79; 95% confidence interval: 0.52-1.06; and for sleep-onset latency g = 0.65; 95% confidence interval: 0.36-0.94. The follow-up analyses revealed an effect size of g = 0.56; 95% confidence interval: 0.45-0.66 for the combined sleep-related outcomes based on three studies. No significant covariates were identified. These results should be interpreted cautiously due to an overall substantial risk of bias, and in particular with regard to blinding of participants and personnel. Nevertheless, they provide evidence that psychological interventions for improving sleep are efficacious among college students. Further research should explore long-term effects and potential moderators of treatment efficacy in college students.

Permanent loss of independence in adult febrile-infection-related epilepsy syndrome survivors: an underestimated and unsolved challenge.

BACKGROUND AND PURPOSE: Febrile-infection-related epilepsy syndrome (FIRES) is an exceedingly rare and devastating subtype of new-onset refractory status epilepticus, which causes refractory epilepsy and permanent neurocognitive impairment. METHODS: This was a long-term follow-up of adult FIRES survivors treated between 2005 and 2018 as part of the EpiCARE initiative, a European Reference Network for rare and complex epilepsies. Clinical, electroencephalography, imaging and functional outcome measures are described using the Scores of Independence for Neurologic and Geriatric Rehabilitation, the modified Rankin Scale and the Global Assessment of Severity of Epilepsy Scale. RESULTS: Six patients with refractory epilepsy following FIRES were evaluated. Despite general improvement after intensive care unit discharge, disease severity was still high at follow-up in all patients. The functional outcome, as assessed by the modified Rankin Scale, was moderately impaired in 2/6 patients. In contrast, the Scores of Independence for Neurologic and Geriatric Rehabilitation indicated a loss of independence in 5/6, serious problems in memory and planning/problem-solving in 4/6 and serious attentional problems in 3/6 patients. CONCLUSIONS: Febrile-infection-related epilepsy syndrome survivors may regain vital functions and mobility but experience a significant loss of independence and participation due to recurring seizures, structural brain damage and neurocognitive decline. Minimization of disastrous outcomes through the systematic evaluation of rescue therapies within a network of specialized centres is crucial.

Racemic S-(ethylsulfonyl)-dl-cysteine N-Carboxyanhydrides Improve Chain Lengths and Monomer Conversion for ß-Sheet-Controlled Ring-Opening Polymerization.

The secondary structure formation of polypeptides not only governs folding and solution self-assembly but also affects the nucleophilic ring-opening polymerization of α-amino acid-N-carboxyanhydrides (NCAs). Whereby helical structures are known to enhance polymerization rates, ß-sheet-like assemblies reduce the propagation rate or may even terminate chain growth by precipitation or gelation. To overcome these unfavorable properties, racemic mixtures of NCAs can be applied. In this work, racemic S-(ethylsulfonyl)-dl-cysteine NCA is investigated for the synthesis of polypeptides, diblock and triblock copolypept(o)ides. In contrast to the polymerization of stereoregular S-(ethylsulfonyl)-l-cysteine NCA, the reaction of S-(ethylsulfonyl)-dl-cysteine NCA proceeds with a rate constant of up to kp  = 1.70 × 10-3 L mol-1 s -1 and is slightly faster than the enatiopure polymerization. While the polymerization of S-(ethylsulfonyl)-l-cysteine NCA suffers from incomplete monomer conversion and degrees of polymerization (DPs) limited to 30-40, racemic mixtures yield polypeptides with DPs of up to 102 with high conversion rates and well-defined dispersities (1.2-1.3). The controlled living nature of the ring-opening polymerization of S-(ethylsulfonyl)-dl-cysteine NCA thus enables the synthesis of triblock copolymers by sequential monomer addition. This methodology allows for precise control over DPs of individual blocks and yields uniform triblock copolymers with symmetric molecular weight distributions at a reduced synthetic effort.

Zebrafish Embryos Allow Prediction of Nanoparticle Circulation Times in Mice and Facilitate Quantification of Nanoparticle-Cell Interactions.

The zebrafish embryo is a vertebrate well suited for visualizing nanoparticles at high resolution in live animals. Its optical transparency and genetic versatility allow noninvasive, real-time observations of vascular flow of nanoparticles and their interactions with cells throughout the body. As a consequence, this system enables the acquisition of quantitative data that are difficult to obtain in rodents. Until now, a few studies using the zebrafish model have only described semiquantitative results on key nanoparticle parameters. Here, a MACRO dedicated to automated quantitative methods is described for analyzing important parameters of nanoparticle behavior, such as circulation time and interactions with key target cells, macrophages, and endothelial cells. Direct comparison of four nanoparticle (NP) formulations in zebrafish embryos and mice reveals that data obtained in zebrafish can be used to predict NPs' behavior in the mouse model. NPs having long or short blood circulation in rodents behave similarly in the zebrafish embryo, with low circulation times being a consequence of NP uptake into macrophages or endothelial cells. It is proposed that the zebrafish embryo has the potential to become an important intermediate screening system for nanoparticle research to bridge the gap between cell culture studies and preclinical rodent models such as the mouse.

Long-Distance Distribution of Atom-Photon Entanglement at Telecom Wavelength.

Entanglement between stationary quantum memories and photonic channels is the essential resource for future quantum networks. Together with entanglement distillation, it will enable efficient distribution of quantum states. We report on the generation and observation of entanglement between a ^{87}Rb atom and a photon at telecom wavelength transmitted through up to 20 km of optical fiber. For this purpose, we use polarization-preserving quantum frequency conversion to transform the wavelength of a photon entangled with the atomic spin state from 780 nm to the telecom S band at 1522 nm. We achieve an unprecedented external device conversion efficiency of 57% and observe an entanglement fidelity between the atom and telecom photon of ≥78.5±0.9% after transmission through 20 km of optical fiber, mainly limited by decoherence of the atomic state. This result is an important milestone on the road to distribute quantum information on a large scale.

Structural network topology in limbic encephalitis is associated with amygdala enlargement, memory performance and serostatus.

Limbic encephalitis (LE) forms a spectrum of autoimmune diseases involving temporal lobe epilepsy and memory impairment. Imaging features of LE are known to depend on the associated antibody and to occur on the brain network level. However, first studies investigating brain networks in LE have either focused on one distinct antibody subgroup or on distinct anatomical regions. In this study, brain graphs of 17 LE patients with autoantibodies against glutamic acid decarboxylase 65 (GAD-LE), four LE patients with autoantibodies against leucine-rich glioma-inactivated 1, five LE patients with autoantibodies against contactin-associated protein-like 2, 26 age- and gender-matched healthy control subjects, and 20 epilepsy control patients with hippocampal sclerosis were constructed based on T1-weighted structural magnetic resonance imaging scans and diffusion tensor imaging. GAD-LE showed significantly altered global network topology in terms of integration and segregation as compared to healthy controls and patients with hippocampal sclerosis (P < .01, analysis of variance with Tukey-Kramer post hoc tests). Linear regression linked global network measures with amygdala volume and verbal memory performance (P < .05). Alterations of local network topology show serotype dependence in hippocampus, amygdala, insula, and various cortical regions. Our findings reveal serotype-dependent patterns of structural connectivity and prove the relevance of in silico network measures on clinical grounds.

Decoding the Papain Inhibitor from Streptomyces mobaraensis as Being Hydroxylated Chymostatin Derivatives: Purification, Structure Analysis, and Putative Biosynthetic Pathway.

Streptomyces mobaraensis produces the papain inhibitor SPI consisting of a 12 kDa protein and small active compounds (SPIac). Purification of the papain inhibitory compounds resulted in four diverse chymostatin derivatives that were characterized by NMR and MS analysis. Chymostatins are hydrophobic tetrapeptide aldehydes from streptomycetes, e.g., S. lavendulae and S. hygroscopicus, that reverse chymosin-mediated angiotensin activation and inhibit other serine and cysteine proteases. Chymotrypsin and papain were both inhibited by the SPIac compounds in the low nanomolar range. SPIac differs from the characterized chymostatins by the exchange of phenylalanine for tyrosine. The crystal structure of one of these chymostatin variants confirmed its molecular structure and revealed a S-configured hemithioacetal bond with the catalytic Cys25 thiolate as well as close interactions with hydrophobic S1 and S2 subsite amino acids. A model for chymostatin biosynthesis is provided based on the discovery of clustered genes encoding several putative nonribosomal peptide synthetases; among them, there is the unusual CstF enzyme that accommodates two canonical amino acid activation domains as well as three peptide carrier protein domains.

Impact of Branching on the Solution Behavior and Serum Stability of Starlike Block Copolymers.

The size control of nanomedicines for tumor diagnosis and therapy is of high importance, since it enables or disables deep and sufficient tumor penetration. Amphiphilic star-shaped block copolypept(o)ides offer substantial promise to precisely adjust the hydrophobic core and the hydrophilic corona, independent of each other, and therefore simultaneously control the size dimension in the interesting size range from 10 to 30 nm. To gain access to core-shell structures of such sizes, 3-arm and 6-arm PeptoStars, based on poly(γ- tert-butyloxycarbonyl-l-glutamate)- b-polysarcosine (pGlu(O tBu)- b-pSar), were prepared via controlled living ring-opening polymerization (ROP) of the corresponding N-carboxyanhydrides. Moreover, size exclusion chromatography (SEC) proves the presence of well-defined star shaped polymers with molecular weights from 38 to 88 kg/mol with low polymer dispersities of 1.16 to 1.23. By varying the α-helical peptide core and maintain a constant polysarcosine corona, hydrodynamic size analyses revealed the importance of using a sufficiently large and dense hydrophilic shielding corona to prevent aggregation of the hydrophobic core and obtain uniform-sized spherical-shaped particles with hydrodynamic diameters below 24 nm. Fluorescence correlation spectroscopy (FCS) additionally demonstrates the absence of protein adsorption in human plasma for 6-arm polypept(o)ide stars and thus confirms polysarcosine as stealthlike material.

TALEN/CRISPR-mediated engineering of a promoterless anti-viral RNAi hairpin into an endogenous miRNA locus.

Successful RNAi applications depend on strategies allowing robust and persistent expression of minimal gene silencing triggers without perturbing endogenous gene expression. Here, we propose a novel avenue which is integration of a promoterless shmiRNA, i.e. a shRNA embedded in a micro-RNA (miRNA) scaffold, into an engineered genomic miRNA locus. For proof-of-concept, we used TALE or CRISPR/Cas9 nucleases to site-specifically integrate an anti-hepatitis C virus (HCV) shmiRNA into the liver-specific miR-122/hcr locus in hepatoma cells, with the aim to obtain cellular clones that are genetically protected against HCV infection. Using reporter assays, Northern blotting and qRT-PCR, we confirmed anti-HCV shmiRNA expression as well as miR-122 integrity and functionality in selected cellular progeny. Moreover, we employed a comprehensive battery of PCR, cDNA/miRNA profiling and whole genome sequencing analyses to validate targeted integration of a single shmiRNA molecule at the expected position, and to rule out deleterious effects on the genomes or transcriptomes of the engineered cells. Importantly, a subgenomic HCV replicon and a full-length reporter virus, but not a Dengue virus control, were significantly impaired in the modified cells. Our original combination of DNA engineering and RNAi expression technologies benefits numerous applications, from miRNA, genome and transgenesis research, to human gene therapy.

Imaging the He2 quantum halo state using a free electron laser.

Quantum tunneling is a ubiquitous phenomenon in nature and crucial for many technological applications. It allows quantum particles to reach regions in space which are energetically not accessible according to classical mechanics. In this "tunneling region," the particle density is known to decay exponentially. This behavior is universal across all energy scales from nuclear physics to chemistry and solid state systems. Although typically only a small fraction of a particle wavefunction extends into the tunneling region, we present here an extreme quantum system: a gigantic molecule consisting of two helium atoms, with an 80% probability that its two nuclei will be found in this classical forbidden region. This circumstance allows us to directly image the exponentially decaying density of a tunneling particle, which we achieved for over two orders of magnitude. Imaging a tunneling particle shows one of the few features of our world that is truly universal: the probability to find one of the constituents of bound matter far away is never zero but decreases exponentially. The results were obtained by Coulomb explosion imaging using a free electron laser and furthermore yielded He2's binding energy of [Formula: see text] neV, which is in agreement with most recent calculations.

Maternal phthalate exposure promotes allergic airway inflammation over 2 generations through epigenetic modifications.

BACKGROUND: Prenatal and early postnatal exposures to environmental factors are considered responsible for the increasing prevalence of allergic diseases. Although there is some evidence for allergy-promoting effects in children because of exposure to plasticizers, such as phthalates, findings of previous studies are inconsistent and lack mechanistic information. OBJECTIVE: We investigated the effect of maternal phthalate exposure on asthma development in subsequent generations and their underlying mechanisms, including epigenetic alterations. METHODS: Phthalate metabolites were measured within the prospective mother-child cohort Lifestyle and Environmental Factors and Their Influence on Newborns Allergy Risk (LINA) and correlated with asthma development in the children. A murine transgenerational asthma model was used to identify involved pathways. RESULTS: In LINA maternal urinary concentrations of mono-n-butyl phthalate, a metabolite of butyl benzyl phthalate (BBP), were associated with an increased asthma risk in the children. Using a murine transgenerational asthma model, we demonstrate a direct effect of BBP on asthma severity in the offspring with a persistently increased airway inflammation up to the F2 generation. This disease-promoting effect was mediated by BBP-induced global DNA hypermethylation in CD4+ T cells of the offspring because treatment with a DNA-demethylating agent alleviated exacerbation of allergic airway inflammation. Thirteen transcriptionally downregulated genes linked to promoter or enhancer hypermethylation were identified. Among these, the GATA-3 repressor zinc finger protein 1 (Zfpm1) emerged as a potential mediator of the enhanced susceptibility for TH2-driven allergic asthma. CONCLUSION: These data provide strong evidence that maternal BBP exposure increases the risk for allergic airway inflammation in the offspring by modulating the expression of genes involved in TH2 differentiation through epigenetic alterations.