Human X chromosome inactivation and reactivation: implications for cell reprogramming and disease

X chromosome inactivation (XCI) is an exemplar of epigenetic regulation that is set up as pluripotent cells differentiate. Once established, XCI is stably propagated, but can be reversed in vivo or by pluripotent reprogramming in vitro. Although reprogramming provides a useful model for inactive X (Xi) reactivation in mouse, the relative instability and heterogeneity of human ESCs and iPSCs, hampers comparable progress in human. Here we review studies aimed at reactivating the human Xi using different reprogramming strategies. We outline our recent results using mouse ESCs to reprogram female human fibroblasts by cell-cell fusion. We show that pluripotent reprogramming induces widespread and rapid chromatin remodelling in which the human Xi loses XIST and H3K27m3 enrichment and selected Xi genes become reactivated, ahead of mitotic division. Using RNA sequencing to map the extent of human Xi reactivation, and chromatin modifying drugs to potentiate reactivation, we outline how this approach could be used to better design strategies to reexpress human X-linked loci. As cell fusion induces the expression of human pluripotency genes that represent both the 'primed' and 'naïve' states, this approach may also offer a fresh opportunity to segregate human pluripotent states with distinct Xi expression profiles, using single-cell-based approaches

QuickXsort: Efficient Sorting with n log n - 1.399n +o(n) Comparisons on Average

In this paper we generalize the idea of QuickHeapsort leading to the notion of QuickXsort. Given some external sorting algorithm X, QuickXsort yields an internal sorting algorithm if X satisfies certain natural conditions. With QuickWeakHeapsort and QuickMergesort we present two examples for the QuickXsort-construction. Both are efficient algorithms that incur approximately n log n - 1.26n +o(n) comparisons on the average. A worst case of n log n + O(n) comparisons can be achieved without significantly affecting the average case. Furthermore, we describe an implementation of MergeInsertion for small n. Taking MergeInsertion as a base case for QuickMergesort, we establish a worst-case efficient sorting algorithm calling for n log n - 1.3999n + o(n) comparisons on average. QuickMergesort with constant size base cases shows the best performance on practical inputs: when sorting integers it is slower by only 15% to STL-Introsort

cranial nerve abnormalities in oculo auriculo vertebral spectrum

BACKGROUND AND PURPOSE: Cranial nerve abnormalities might be observed in hemifacial microsomia and microtia (oculo-auriculo-vertebral spectrum), but the rate, features, and relationship with functional impairment or phenotype severity have not yet been defined. This study aimed at investigating absence/asymmetry, abnormal origin, morphology and course of cranial nerves, and presence/asymmetry of the foramen ovale and inferior alveolar nerve canal in a cohort of oculo-auriculo-vertebral spectrum patients. MATERIALS AND METHODS: Twenty-nine patients with oculo-auriculo-vertebral spectrum (mean age, 7 years; age range, 0.2–31 years; 12 females) underwent brain MR imaging, CT, and neurologic evaluation; 19 patients had a more severe phenotype (Goldenhar syndrome). RESULTS: Cranial nerve abnormalities were detected only in patients with Goldenhar syndrome (17/19, bilaterally in 8) and were involved the second (4/19), third (1/18), fifth (11/19), sixth (8/16), seventh (11/18), and eighth (8/18) cranial nerves. Multiple cranial nerve abnormalities were common (11/17). Eleven patients showed bone foramina abnormalities. Trigeminal and facial nerve dysfunctions were common (44% and 58%, respectively), especially in patients with Goldenhar syndrome. Trigeminal abnormalities showed a good correlation with ipsilateral dysfunction ( P = .018), which further increased when bone foramina abnormalities were included. The facial nerve showed a trend toward correlation with ipsilateral dysfunction ( P = .081). Diplopia was found only in patients with Goldenhar syndrome and was associated with third and sixth cranial nerve abnormalities ( P = .006). CONCLUSIONS: Among patients with oculo-auriculo-vertebral spectrum, cranial nerve morphologic abnormalities are common, correlate with phenotype severity, and often entail a functional impairment. The spectrum of cranial nerve abnormalities appears wider than simple hypo-/aplasia and includes an anomalous cisternal course and partial/complete fusion of diverse cranial nerves. CN : cranial nerve OAVS : oculo-auriculo-vertebral spectru

LARES/WEBER-SAT and the equivalence principle

It has often been claimed that the proposed Earth artificial satellite LARES/WEBER-SAT-whose primary goal is, in fact, the measurement of the general relativistic Lense-Thirring effect at a some percent level-would allow to greatly improve, among (many) other things, the present-day (10^-13) level of accuracy in testing the equivalence principle as well. Recent claims point towards even two orders of magnitude better, i.e. 10^-15. In this note we show that such a goal is, in fact, unattainable by many orders of magnitude being, instead, the achievable level of the order of 10^-9.Comment: LaTex, 4 pages, no figures, no tables, 26 references. Proofs corrections included. To appear in EPL (Europhysics Letters

Simultaneous learning of instantaneous and time-delayed genetic interactions using novel information theoretic scoring technique

BACKGROUND: Understanding gene interactions is a fundamental question in systems biology. Currently, modeling of gene regulations using the Bayesian Network (BN) formalism assumes that genes interact either instantaneously or with a certain amount of time delay. However in reality, biological regulations, both instantaneous and time-delayed, occur simultaneously. A framework that can detect and model both these two types of interactions simultaneously would represent gene regulatory networks more accurately. RESULTS: In this paper, we introduce a framework based on the Bayesian Network (BN) formalism that can represent both instantaneous and time-delayed interactions between genes simultaneously. A novel scoring metric having firm mathematical underpinnings is also proposed that, unlike other recent methods, can score both interactions concurrently and takes into account the reality that multiple regulators can regulate a gene jointly, rather than in an isolated pair-wise manner. Further, a gene regulatory network (GRN) inference method employing an evolutionary search that makes use of the framework and the scoring metric is also presented. CONCLUSION: By taking into consideration the biological fact that both instantaneous and time-delayed regulations can occur among genes, our approach models gene interactions with greater accuracy. The proposed framework is efficient and can be used to infer gene networks having multiple orders of instantaneous and time-delayed regulations simultaneously. Experiments are carried out using three different synthetic networks (with three different mechanisms for generating synthetic data) as well as real life networks of Saccharomyces cerevisiae, E. coli and cyanobacteria gene expression data. The results show the effectiveness of our approach

Communication with media in nuclear or radiological emergencies : General and practical recommendations for improvement

Communication with mass media during and after a nuclear emergency presents both a challenge and an opportunity for emergency management. The challenge lies with the different motivations and types of process applied by mass media and emergency management; the opportunity arises from the power of mass media to reach out to an audience with information important for compliance with protective actions. This article summarises recommendations for improved media communication by nuclear emergency management professionals. Recommendations address both the traditional and new media, and are the result of empirical and qualitative research conducted in the context of the FP7 PREPARE project, including: (i) a media content analysis of newspapers articles reporting about Fukushima (N = 1340); (ii) a content analysis of tweets about Fukushima (N = 914); and (iii) a qualitative approach - round table discussions with stakeholders (N > 100) involved in communication about nuclear emergencies. Results show that although challenging, nuclear emergency communication can be improved by using mass media and developing skills, training and resources during the preparedness phase of a nuclear emergency cycle. Some general recommendations and practical advice for communication with media is given

Efficacy and safety of honeybee and wasp tyrosine-adsorbed venom immunotherapy

It is acknowledged that any claim of efficacy of allergen immunotherapy must be done for each specific product, and this remains true also for venom immunotherapy (VIT). Thus, we evaluated the efficacy and safety of a specific tyrosine-adsorbed VIT for vespula spp. and honeybee in real-life

Application of failure mode and effects analysis (FMEA) to pretreatment phases in tomotherapy

The aim of this paper was the application of the failure mode and effects analysis (FMEA) approach to assess the risks for patients undergoing radiotherapy treatments performed by means of a helical tomotherapy unit. FMEA was applied to the preplanning imaging, volume determination, and treatment planning stages of the tomotherapy process and consisted of three steps: 1) identification of the involved subprocesses; 2) identification and ranking of the potential failure modes, together with their causes and effects, using the risk probability number (RPN) scoring system; and 3) identification of additional safety measures to be proposed for process quality and safety improvement. RPN upper threshold for little concern of risk was set at 125. A total of 74 failure modes were identified: 38 in the stage of preplanning imaging and volume determination, and 36 in the stage of planning. The threshold of 125 for RPN was exceeded in four cases: one case only in the phase of preplanning imaging and volume determination, and three cases in the stage of planning. The most critical failures appeared related to (i) the wrong or missing definition and contouring of the overlapping regions, (ii) the wrong assignment of the overlap priority to each anatomical structure, (iii) the wrong choice of the computed tomography calibration curve for dose calculation, and (iv) the wrong (or not performed) choice of the number of fractions in the planning station. On the basis of these findings, in addition to the safety strategies already adopted in the clinical practice, novel solutions have been proposed for mitigating the risk of these failures and to increase patient safety

Infrared luminescence for real time ionizing radiation detection

Radio-luminescence (RL) optical fiber sensors enable a remote, punctual, and real time detection of ionizing radiation. However, the employment of such systems for monitoring extended radiation fields with energies above the Cerenkov threshold is still challenging, since a spurious luminescence, namely, the "stem effect," is also generated in the passive fiber portion exposed to radiation. Here, we present experimental measurements on Yb-doped silica optical fibers irradiated with photon fields of different energies and sizes. The results demonstrate that the RL of Yb3+, displaying a sharp emission line at about 975 nm, is free from any spectral superposition with the spurious luminescence. This aspect, in addition with the suitable linearity, reproducibility, and sensitivity properties of the Yb-doped fibers, paves the way to their use in applications where an efficient stem effect removal is required