Four ultra-short period eclipsing M-dwarf binaries in the WFCAM Transit Survey

We report on the discovery of four ultra-short period (P<0.18 days) eclipsing M-dwarf binaries in the WFCAM Transit Survey. Their orbital periods are significantly shorter than of any other known main-sequence binary system, and are all significantly below the sharp period cut-off at P~0.22 days as seen in binaries of earlier type stars. The shortest-period binary consists of two M4 type stars in a P=0.112 day orbit. The binaries are discovered as part of an extensive search for short-period eclipsing systems in over 260,000 stellar lightcurves, including over 10,000 M-dwarfs down to J=18 mag, yielding 25 binaries with P<0.23 days. In a popular paradigm, the evolution of short period binaries of cool main-sequence stars is driven by loss of angular momentum through magnetised winds. In this scheme, the observed P~0.22 day period cut-off is explained as being due to timescales that are too long for lower-mass binaries to decay into tighter orbits. Our discovery of low-mass binaries with significantly shorter orbits implies that either these timescales have been overestimated for M-dwarfs, e.g. due to a higher effective magnetic activity, or that the mechanism for forming these tight M-dwarf binaries is different from that of earlier type main-sequence stars.Comment: 22 pages, 17 figures, 3 tables Accepted for publication in MNRA

Radio Observations of a Large Sample of Late-M, L, and T Dwarfs: The Distribution of Magentic Field Strengths

We present radio observations of a comprehensive sample of 90 dwarf stars and brown dwarfs ranging from spectral type M5 to T8. We detect three radio active sources in addition to the six objects previously detected in quiescence and outburst, leading to an overall detection rate of about 10% for objects later than M7. From the properties of the radio emission we infer magnetic field strengths of ~100 G in quiescence and nearly 1 kG during flares, while the majority of the non-detected objects have B<50 G. Depending on the configuration and size of the magnetic loops, the surface magnetic fields may approach 1 kG even in quiescence, at most a factor of few smaller than in early-M dwarfs. With the larger sample of sources we find continued evidence for (i) a sharp transition around spectral type M7 from a ratio of radio to X-ray luminosity of log(L_R/L_X) ~ -15.5 to >-12, (ii) increased radio activity with later spectral type, in contrast to H-alpha and X-ray observations, and (iii) an overall drop in the fraction of active sources from about 30% for M dwarfs to about 5% for L dwarfs, fully consistent with H-alpha and X-ray observations. Taken together, these trends suggest that some late-M and L dwarfs are capable of generating 0.1-1 kG magnetic fields, but the overall drop in the fraction of such objects is likely accompanied by a change in the structure of the chromospheres and coronae, possibly due to the increasingly neutral atmospheres and/or a transition to a turbulent dynamo. A more extended radio survey currently holds the best promise for measuring the magnetic field properties of a large number of dwarf stars. [abridged]Comment: Submitted to ApJ; 14 pages, 4 figures, 2 table

Whole genome and exome sequencing of monozygotic twins discordant for Crohn's disease

Background Crohn's disease (CD) is an inflammatory bowel disease caused by genetic and environmental factors. More than 160 susceptibility loci have been identified for IBD, yet a large part of the genetic variance remains unexplained. Recent studies have demonstrated genetic differences between monozygotic twins, who were long thought to be genetically completely identical. Results We aimed to test if somatic mutations play a role in CD etiology by sequencing the genomes and exomes of directly affected tissue from the bowel and blood samples of one and the blood-derived exomes of two further monozygotic discordant twin pairs. Our goal was the identification of mutations present only in the affected twins, pointing to novel candidates for CD susceptibility loci. We present a thorough genetic characterization of the sequenced individuals but detected no consistent differences within the twin pairs. An estimate of the CD susceptibility based on known CD loci however hinted at a higher mutational load in all three twin pairs compared to 1,920 healthy individuals. Conclusion Somatic mosaicism does not seem to play a role in the discordance of monozygotic CD twins. Our study constitutes the first to perform whole genome sequencing for CD twins and therefore provides a valuable reference dataset for future studies. We present an example framework for mosaicism detection and point to the challenges in these types of analyses

Endosome dysfunction leads to gain-of-function TLR7 and human lupus

Hyperactive Toll-like receptor (TLR) 7 signaling has long been appreciated as a driver of autoimmune disease by breaking tolerance to self-nucleic acids in mouse models1–5. Recently, mutations in TLR7 or its associated regulator UNC93B16, 7, were identified as monogenic causes of human lupus; the unifying feature of these mutations being TLR7 gain-of-function. TLR7 is an intracellular transmembrane receptor, sensing RNA breakdown products within late endosomes8, 9. Hence, its function depends on intricate transport mechanisms and membrane interactions within the endomembrane network. Whether perturbations of any of these endosome-related processes can give rise to TLR7 gain-of-function and facilitate self-reactivity has not been investigated. Here, we show that a dysregulated endosomal compartment leads to unrestricted TLR7 signaling and human lupus. The late endosomal BLOC-1-related protein complex (BORC) together with the small Arf1-like GTPase Arl8b controls TLR7 protein levels, and a direct interaction between Arl8b and Unc93b1 is required to regulate TLR7 turnover. We identified an amino acid insertion in UNC93B1 in a patient with childhood-onset lupus, which reduces the interaction with the BORC-Arl8b complex and leads to endosomal TLR7 accumulation. Therefore, a failure to control the proper progression of TLR7 through its endocytic life cycle is sufficient to break immunological tolerance to nucleic acids in humans. Our results highlight the importance of an intact endomembrane system to prevent autoimmune disease. As the cellular mechanisms restricting TLR7 signaling can be manifold, identifying and stratifying lupus patients based on a TLR7-driven pathogenesis could be a viable strategy towards a targeted therapy

Disrupted degradative sorting of TLR7 is associated with human lupus

Hyperactive TLR7 signaling has long been appreciated as driver of autoimmune disease in mouse models. Recently, gain-of-function mutations in TLR7 were identified as a monogenic cause of human lupus. TLR7 is an intracellular transmembrane receptor, sensing RNA breakdown products within late endosomes. Here, we show that endosome dysfunction leads to unrestricted TLR7 signaling and is associated with human lupus. The late endosomal BORC complex together with the small GTPase Arl8b controls intracellular TLR7 levels by regulating receptor turnover. This requires a direct interaction between the TLR7-associated trafficking factor Unc93b1 and Arl8b. We identified an UNC93B1 mutation in a patient with childhood-onset lupus, which results in reduced BORC interaction and endosomal TLR7 accumulation. Therefore, a failure to control TLR7 turnover is sufficient to break immunological tolerance to nucleic acids. Our results highlight the importance of an intact endomembrane system in preventing pathological TLR7 signaling and autoimmune disease

Combining SAXS analysis and MD simulation to determine structure and hydration of ionizable lipid hexagonal phases

Cationic ionizable lipids (CILs) are fundamental components of inverse hexagonal (HII) lipid assemblies, which mediate the encapsulation and release of negatively charged mRNA through a pH-dependent mechanism. Since variations in the structure and composition of the HII phases can significantly impact the biological efficacy of the mRNA-carrying lipid nanoparticles (LNP), a comprehensive understanding of the ionizable lipid HII phases is necessary. We present an integrated approach combining small-angle X-ray scattering (SAXS) experiments, molecular dynamics (MD) simulations and a continuum model to elucidate lipid distribution and water content within HII phases. Our results indicate strong agreement between structures derived from MD simulations and SAXS data. To this end, we introduce a method to correct for periodic boundary artifacts when computing scattering profiles from MD simulations. This enables direct, model-free comparisons between experimental and simulated data, enhancing the reliability of structural interpretations, specifically the water content of the HII phases. Next, we developed a continuum model to extend structural analysis to CIL HII phases for which MD data is unavailable. This integrative framework not only provides molecular-level insights into the ionizable lipid HII mesophase but also enables the prediction of hydration properties across different CIL compositions. The different approaches consistently yield water contents that seem to correlate with the lipids’ transfection efficiencies. By bridging experimental and simulation data, our approach offers a powerful tool for the rational design and optimization of lipid nanoparticles, potentially linking a lower water content with an increased therapeutic performance

Wideband dynamic radio spectra of two ultra-cool dwarfs

A number of radio-loud ultra-cool dwarf (UCD ) stars exhibit both continuous broadband and highly polarized pulsed radio emission. In order to determine the nature of the emission and the physical characteristics in the source region, we have made multi-epoch, wideband spectral observations of TVLM 0513-46 and 2M 0746+20. We combine these observations with archival radio data to fully characterize both the temporal and spectral properties of the radio emission. The continuum spectral energy distribution can be well modeled using gyrosynchrotron emission from mildly relativistic electrons in a dipolar field. The pulsed emission exhibits a variety of time-variable characteristics, including frequency drifts, frequency cutoffs, and multiple pulses per period. For 2M 0746+20 we determine a pulse period consistent with previously determined values. We modeled locations of pulsed emission using an oblique rotating magnetospheric model with beamed electron-cyclotron maser ( ECM) sources. The bestfit models have narrow ECM beaming angles aligned with the local source magnetic field direction, except for one isolated burst from 2M 0746+20. For TVLM 0513-46, the best-fit rotation axis inclination is nearly orthogonal to the line of sight. For 2M0746+20 we found a good fit using a fixed inclination i = 36°, determined from optical observations. For both stars the ECM sources are located near feet of magnetic loops with radial extents 1.2Rs-2.7Rsand surface fields 2.2-2.5 kG. These results support recent suggestions that radio over-luminous UCDs have a global "weak field" non-axisymmetric magnetic topologies

向精神薬服用患者の突然死症例におけるカリウムイオンチャネルに関する分子生物学的解析：QT延長症候群関連遺伝子の多型が危険因子となり得るか？

Psychotropic drugs can pose the risk of acquired long QT syndrome (LQTS). Unexpected autopsy-negative sudden death in patients taking psychotropic drugs may be associated with prolonged QT intervals and life-threatening arrhythmias. We analyzed genes that encode for cardiac ion channels and potentially associated with LQTS, examining specifically the potassium channel genes KCNQ1 and KCNH2 in 10 cases of sudden death involving patients administered psychotropic medication in which autopsy findings identified no clear cause of death. We amplified and sequenced all exons of KCNQ1 and KCNH2, identifying G643S, missense polymorphism in KCNQ1, in 6 of the 10 cases. A study analysis indicated that only 11% of 381 healthy Japanese individuals carry this polymorphism. Reports of previous functional analyses indicate that the G643S polymorphism in the KCNQ1 potassium channel protein causes mild IKs channel dysfunction. Our present study suggests that administering psychotropic drug therapy to individuals carrying the G643S polymorphism may heighten the risk of prolonged QT intervals and life-threatening arrhythmias. Thus, screening for the G643S polymorphism before prescribing psychotropic drugs may help reduce the risk of unexpected sudden death2013博士（歯学）松本歯科大