Damaging variants in FOXI3 cause microtia and craniofacial microsomia

Q1Q1Pacientes con Microtia y Microsomía craneofacialPurpose: Craniofacial microsomia (CFM) represents a spectrum of craniofacial malformations, ranging from isolated microtia with or without aural atresia to underdevelopment of the mandible, maxilla, orbit, facial soft tissue, and/or facial nerve. The genetic causes of CFM remain largely unknown. Methods: We performed genome sequencing and linkage analysis in patients and families with microtia and CFM of unknown genetic etiology. The functional consequences of damaging missense variants were evaluated through expression of wild-type and mutant proteins in vitro. Results: We studied a 5-generation kindred with microtia, identifying a missense variant in FOXI3 (p.Arg236Trp) as the cause of disease (logarithm of the odds = 3.33). We subsequently identified 6 individuals from 3 additional kindreds with microtia-CFM spectrum phenotypes harboring damaging variants in FOXI3, a regulator of ectodermal and neural crest development. Missense variants in the nuclear localization sequence were identified in cases with isolated microtia with aural atresia and found to affect subcellular localization of FOXI3. Loss of function variants were found in patients with microtia and mandibular hypoplasia (CFM), suggesting dosage sensitivity of FOXI3. Conclusion: Damaging variants in FOXI3 are the second most frequent genetic cause of CFM, causing 1% of all cases, including 13% of familial cases in our cohort.https://orcid.org/0000-0003-3822-7780https://orcid.org/0000-0002-0729-6866Revista Internacional - IndexadaA1N

Upper limits on the strength of periodic gravitational waves from PSR J1939+2134

The first science run of the LIGO and GEO gravitational wave detectors presented the opportunity to test methods of searching for gravitational waves from known pulsars. Here we present new direct upper limits on the strength of waves from the pulsar PSR J1939+2134 using two independent analysis methods, one in the frequency domain using frequentist statistics and one in the time domain using Bayesian inference. Both methods show that the strain amplitude at Earth from this pulsar is less than a few times $10^{-22}$.Comment: 7 pages, 1 figure, to appear in the Proceedings of the 5th Edoardo Amaldi Conference on Gravitational Waves, Tirrenia, Pisa, Italy, 6-11 July 200

Improving the sensitivity to gravitational-wave sources by modifying the input-output optics of advanced interferometers

We study frequency dependent (FD) input-output schemes for signal-recycling interferometers, the baseline design of Advanced LIGO and the current configuration of GEO 600. Complementary to a recent proposal by Harms et al. to use FD input squeezing and ordinary homodyne detection, we explore a scheme which uses ordinary squeezed vacuum, but FD readout. Both schemes, which are sub-optimal among all possible input-output schemes, provide a global noise suppression by the power squeeze factor, while being realizable by using detuned Fabry-Perot cavities as input/output filters. At high frequencies, the two schemes are shown to be equivalent, while at low frequencies our scheme gives better performance than that of Harms et al., and is nearly fully optimal. We then study the sensitivity improvement achievable by these schemes in Advanced LIGO era (with 30-m filter cavities and current estimates of filter-mirror losses and thermal noise), for neutron star binary inspirals, and for narrowband GW sources such as low-mass X-ray binaries and known radio pulsars. Optical losses are shown to be a major obstacle for the actual implementation of these techniques in Advanced LIGO. On time scales of third-generation interferometers, like EURO/LIGO-III (~2012), with kilometer-scale filter cavities, a signal-recycling interferometer with the FD readout scheme explored in this paper can have performances comparable to existing proposals. [abridged]Comment: Figs. 9 and 12 corrected; Appendix added for narrowband data analysi

Quantum state preparation and macroscopic entanglement in gravitational-wave detectors

Long-baseline laser-interferometer gravitational-wave detectors are operating at a factor of 10 (in amplitude) above the standard quantum limit (SQL) within a broad frequency band. Such a low classical noise budget has already allowed the creation of a controlled 2.7 kg macroscopic oscillator with an effective eigenfrequency of 150 Hz and an occupation number of 200. This result, along with the prospect for further improvements, heralds the new possibility of experimentally probing macroscopic quantum mechanics (MQM) - quantum mechanical behavior of objects in the realm of everyday experience - using gravitational-wave detectors. In this paper, we provide the mathematical foundation for the first step of a MQM experiment: the preparation of a macroscopic test mass into a nearly minimum-Heisenberg-limited Gaussian quantum state, which is possible if the interferometer's classical noise beats the SQL in a broad frequency band. Our formalism, based on Wiener filtering, allows a straightforward conversion from the classical noise budget of a laser interferometer, in terms of noise spectra, into the strategy for quantum state preparation, and the quality of the prepared state. Using this formalism, we consider how Gaussian entanglement can be built among two macroscopic test masses, and the performance of the planned Advanced LIGO interferometers in quantum-state preparation

Search for gravitational wave bursts in LIGO's third science run

We report on a search for gravitational wave bursts in data from the three LIGO interferometric detectors during their third science run. The search targets subsecond bursts in the frequency range 100-1100 Hz for which no waveform model is assumed, and has a sensitivity in terms of the root-sum-square (rss) strain amplitude of hrss ~ 10^{-20} / sqrt(Hz). No gravitational wave signals were detected in the 8 days of analyzed data.Comment: 12 pages, 6 figures. Amaldi-6 conference proceedings to be published in Classical and Quantum Gravit

Searching for a Stochastic Background of Gravitational Waves with LIGO

The Laser Interferometer Gravitational-wave Observatory (LIGO) has performed the fourth science run, S4, with significantly improved interferometer sensitivities with respect to previous runs. Using data acquired during this science run, we place a limit on the amplitude of a stochastic background of gravitational waves. For a frequency independent spectrum, the new limit is $\Omega_{\rm GW} < 6.5 \times 10^{-5}$. This is currently the most sensitive result in the frequency range 51-150 Hz, with a factor of 13 improvement over the previous LIGO result. We discuss complementarity of the new result with other constraints on a stochastic background of gravitational waves, and we investigate implications of the new result for different models of this background.Comment: 37 pages, 16 figure

Energy security and shifting modes of governance

The concept of energy security fits uneasily into contemporary security debates. It is neither a clearly traditional nor a fully ‘non-traditional’ security issue. There are also limits to the social constructedness of the concept. This article argues that, while it is important to identify the differing securitizations of energy, these must be contextualized within the material realities and the differing historical modes of governance of the political economy of resources. This is essential for understanding the differing meanings accorded to energy security, the shifting modes through which energy is governed, and the extent to which energy security concerns drive international politics. In this context, contemporary concerns over energy security have both material and ideological dimensions: anxiety over the dual shift of power from West to East and from resource-importing to resource-exporting countries; and concern over the normative weakening of the neo-liberal mode of energy governance

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

A web-based self-management programme for people with type 2 diabetes : the HeLP-Diabetes research programme including RCT

Background: In the UK, 6% of the UK population have diabetes mellitus, 90% of whom have type 2 diabetes mellitus (T2DM). Diabetes mellitus accounts for 10% of NHS expenditure (£14B annually). Good self-management may improve health outcomes. NHS policy is to refer all people with T2DM to structured education, on diagnosis, to improve their self-management skills, with annual reinforcement thereafter. However, uptake remains low (5.6% in 2014–15). Almost all structured education is group based, which may not suit people who work, who have family or other caring commitments or who simply do not like group-based formats. Moreover, patient needs vary with time and a single education session at diagnosis is unlikely to meet these evolving needs. A web-based programme may increase uptake. / Objectives: Our aim was to develop, evaluate and implement a web-based self-management programme for people with T2DM at any stage of their illness journey, with the goal of improving access to, and uptake of, self-management support, thereby improving health outcomes in a cost-effective manner. Specific objectives were to (1) develop an evidence-based theoretically informed programme that was acceptable to patients and health-care professionals (HCPs) and that could be readily implemented within routine NHS care, (2) determine the clinical effectiveness and cost-effectiveness of the programme compared with usual care and (3) determine how best to integrate the programme into routine care. / Design: There were five linked work packages (WPs). WP A determined patient requirements and WP B determined HCP requirements for the self-management programme. WP C developed and user-tested the Healthy Living for People with type 2 Diabetes (HeLP-Diabetes) programme. WP D was an individually randomised controlled trial in primary care with a health economic analysis. WP E used a mixed-methods and case-study design to study the potential for implementing the HeLP-Diabetes programme within routine NHS practice. / Setting: English primary care. / Participants: People with T2DM (WPs A, D and E) or HCPs caring for people with T2DM (WPs B, C and E). / Intervention: The HeLP-Diabetes programme; an evidence-based theoretically informed web-based self-management programme for people with T2DM at all stages of their illness journey, developed using participatory design principles. / Main outcome measures: WPs A and B provided data on user ‘wants and needs’, including factors that would improve the uptake and accessibility of the HeLP-Diabetes programme. The outcome for WP C was the HeLP-Diabetes programme itself. The trial (WP D) had two outcomes measures: glycated haemoglobin (HbA1c) level and diabetes mellitus-related distress, as measured with the Problem Areas in Diabetes (PAID) scale. The implementation outcomes (WP E) were the adoption and uptake at clinical commissioning group, general practice and patient levels and the identification of key barriers and facilitators. / Results: Data from WPs A and B supported our holistic approach and addressed all areas of self-management (medical, emotional and role management). HCPs voiced concerns about linkage with the electronic medical records (EMRs) and supporting patients to use the programme. The HeLP-Diabetes programme was developed and user-tested in WP C. The trial (WP D) recruited to target (n = 374), achieved follow-up rates of over 80% and the intention-to-treat analysis showed that there was an additional improvement in HbA1c levels at 12 months in the intervention group [mean difference –0.24%, 95% confidence interval (CI) –0.44% to –0.049%]. There was no difference in overall PAID score levels (mean difference –1.5 points, 95% CI –3.9 to 0.9 points). The within-trial health economic analysis found that incremental costs were lower in the intervention group than in the control group (mean difference –£111, 95% CI –£384 to £136) and the quality-adjusted life-years (QALYs) were higher (mean difference 0.02 QALYs, 95% CI 0.000 to 0.044 QALYs), meaning that the HeLP-Diabetes programme group dominated the control group. In WP E, we found that the HeLP-Diabetes programme could be successfully implemented in primary care. General practices that supported people in registering for the HeLP-Diabetes programme had better uptake and registered patients from a wider demographic than those relying on patient self-registration. Some HCPs were reluctant to do this, as they did not see it as part of their professional role. / Limitations: We were unable to link the HeLP-Diabetes programme with the EMRs or to determine the effects of the HeLP-Diabetes programme on users in the implementation study. / Conclusions: The HeLP-Diabetes programme is an effective self-management support programme that is implementable in primary care. / Future work: The HeLP-Diabetes research team will explore the following in future work: research to determine how to improve patient uptake of self-management support; develop and evaluate a structured digital educational pathway for newly diagnosed people; develop and evaluate a digital T2DM prevention programme; and the national implementation of the HeLP-Diabetes programme. / Trial registration: Research Ethics Committee reference number 10/H0722/86 for WPs A–C; Research Ethics Committee reference number 12/LO/1571 and UK Clinical Research Network/National Institute for Health Research (NIHR) Portfolio 13563 for WP D; and Research Ethics Committee 13/EM/0033 for WP E. In addition, for WP D, the study was registered with the International Standard Randomised Controlled Trial Register as reference number ISRCTN02123133. / Funding details: This project was funded by the NIHR Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 6, No. 5. See the NIHR Journals Library website for further project information