Epistatic interactions have an important role in phenotypic variability, yet the genetic dissection of such phenomena remains challenging. Here we report the identification of a novel locus, MGC1203, ...that contributes epistatic alleles to Bardet-Biedl syndrome (BBS), a pleiotropic, oligogenic disorder. MGC1203 encodes a pericentriolar protein that interacts and colocalizes with the BBS proteins. Sequencing of two independent BBS cohorts revealed a significant enrichment of a heterozygous C430T mutation in patients, and a transmission disequilibrium test (TDT) showed strong over-transmission of this variant. Further analyses showed that the 430T allele enhances the use of a cryptic splice acceptor site, causing the introduction of a premature termination codon (PTC) and the reduction of steady-state MGC1203 messenger RNA levels. Finally, recapitulation of the human genotypes in zebrafish shows that modest suppression of mgc1203 exerts an epistatic effect on the developmental phenotype of BBS morphants. Our data demonstrate how the combined use of biochemical, genetic and in vivo tools can facilitate the dissection of epistatic phenomena, and enhance our appreciation of the genetic basis of phenotypic variability.
The heterocyclic bisdithiazolyl radical 1b (R1 = Me, R2 = F) crystallizes in two phases. The α-phase, space group P21/n, contains two radicals in the asymmetric unit, both of which adopt slipped ...π-stack structures. The β-phase, space group P21/c, consists of cross-braced π-stacked arrays of dimers in which the radicals are linked laterally by hypervalent 4-center 6-electron S···S–S···S σ-bonds. Variable-temperature magnetic susceptibility measurements on α-1b indicate Curie–Weiss behavior (with Θ = −14.9 K), while the dimer phase β-1b is diamagnetic, showing no indication of thermal dissociation below 400 K. High-pressure crystallographic measurements indicate that the cross-braced π-stacked arrays of dimers undergo a wine-rack compression, but the dimer remains intact up to 8 GPa (at ambient temperature). The resistance of β-1b to dissociate under pressure, also observed in its conductivity versus pressure profile, is in marked contrast to the behavior of the related dimer β-1a (R1 = Et, R2 = F), which readily dissociates into a pair of radicals at 0.8 GPa. The different response of the two dimers to pressure has been rationalized in terms of differences in their linear compressibilities occasioned by changes in the degree of cross-bracing of the π-stacks. Dissociation of both dimers can be effected by irradiation with visible (λ = 650 nm) light; the transformation has been monitored by optical spectroscopy, magnetic susceptibility measurements, and single crystal X-ray diffraction. The photoinduced radical pairs persist up to temperatures of 150 K (β-1b) and 242 K (β-1a) before reverting to the dimer state. Variable-temperature optical measurements on β-1b and β-1a have afforded Arrhenius activation energies of 8.3 and 19.6 kcal mol–1, respectively, for the radical-to-dimer reconversion. DFT and CAS-SCF calculations have been used to probe the ground and excited electronic state structures of the dimer and radical pair. The results support the interpretation that the ground-state interconversion of the dimer and radical forms of β-1a and β-1b is symmetry forbidden, while the photochemical transformation is symmetry allowed.
BBS4 is one of several proteins that cause Bardet-Biedl syndrome (BBS), a multisystemic disorder of genetic and clinical complexity. Here we show that BBS4 localizes to the centriolar satellites of ...centrosomes and basal bodies of primary cilia, where it functions as an adaptor of the p150(glued) subunit of the dynein transport machinery to recruit PCM1 (pericentriolar material 1 protein) and its associated cargo to the satellites. Silencing of BBS4 induces PCM1 mislocalization and concomitant deanchoring of centrosomal microtubules, arrest in cell division and apoptotic cell death. Expression of two truncated forms of BBS4 that are similar to those found in some individuals with BBS had a similar effect on PCM1 and microtubules. Our findings indicate that defective targeting or anchoring of pericentriolar proteins and microtubule disorganization contribute to the BBS phenotype and provide new insights into possible causes of familial obesity, diabetes and retinal degeneration.
Here, we constrain anisotropic cosmic birefringence using four-point correlations of even-parity E-mode and odd-parity B-mode polarization in the cosmic microwave background measurements made by the ...POLARization of the Background Radiation (POLARBEAR) experiment in its first season of observations. We find that the anisotropic cosmic birefringence signal from any parity-violating processes is consistent with zero. The Faraday rotation from anisotropic cosmic birefringence can be compared with the equivalent quantity generated by primordial magnetic fields if they existed. The POLARBEAR nondetection translates into a 95% confidence level (C.L.) upper limit of 93 nanogauss (nG) on the amplitude of an equivalent primordial magnetic field inclusive of systematic uncertainties. This four-point correlation constraint on Faraday rotation is about 15 times tighter than the upper limit of 1380 nG inferred from constraining the contribution of Faraday rotation to two-point correlations of B-modes measured by Planck in 2015. Metric perturbations sourced by primordial magnetic fields would also contribute to the B-mode power spectrum. Using the POLARBEAR measurements of the B-mode power spectrum (two-point correlation), we set a 95% C.L. upper limit of 3.9 nG on primordial magnetic fields assuming a flat prior on the field amplitude. This limit is comparable to what was found in the Planck 2015 two-point correlation analysis with both temperature and polarization. Finally, we perform a set of systematic error tests and find no evidence for contamination. This work marks the first time that anisotropic cosmic birefringence or primordial magnetic fields have been constrained from the ground at subdegree scales.
Outbursts from active galactic nuclei (AGN) can inflate cavities in the intracluster medium (ICM) of galaxy clusters and are believed to play the primary role in offsetting radiative cooling in the ...ICM. However, the details of how the energy from AGN feedback thermalizes to heat the ICM is not well understood, partly due to the unknown composition and energetics of the cavities. The Sunyaev-Zel'dovich (SZ) effect, a measure of the integrated pressure along the line of sight, provides a means of measuring the thermal contents of the cavities, to discriminate between thermal, nonthermal, and other sources of pressure support. Here we report measurements of the SZ effect at 30 GHz toward the galaxy cluster MS 0735.6+7421 (MS0735), using the Combined Array for Research in Millimeter-wave Astronomy (CARMA). MS0735 hosts the most energetic AGN outburst known and lobes of radio synchrotron emission coincident with a pair of giant X-ray cavities ∼200 kpc across. Our CARMA maps show a clear deficit in the SZ signal coincident with the X-ray identified cavities, when compared to a smooth X-ray derived pressure model. We find that the cavities have very little SZ-contributing material, suggesting that they are either supported by very diffuse thermal plasma with temperature in excess of hundreds of keV, or are not supported thermally. Our results represent the first detection (with 4.4 significance) of this phenomenon with the SZ effect.
We present the first weak-lensing-based scaling relation between galaxy cluster mass, M sub(WL), and integrated Compton parameter Y sub(sph). Observations of 18 galaxy clusters at z Asymptotically = ...to 0.2 were obtained with the Subaru 8.2 m telescope and the Sunyaev-Zel'dovich Array. The M sub(WL)-Y sub(sph) scaling relations, measured at Delta = 500, 1000, and 2500 rho sub(c), are consistent in slope and normalization with previous results derived under the assumption of hydrostatic equilibrium (HSE). We find an intrinsic scatter in M sub(WL) at fixed Y sub(sph) of 20%, larger than both previous measurements of M sub(HSE)-Y sub(sph) scatter as well as the scatter in true mass at fixed Y sub(sph) found in simulations. Moreover, the scatter in our lensing-based scaling relations is morphology dependent, with 30%-40% larger M sub(WL) for undisturbed compared to disturbed clusters at the same Y sub(sph) at r sub(500). Further examination suggests that the segregation may be explained by the inability of our spherical lens models to faithfully describe the three-dimensional structure of the clusters, in particular, the structure along the line of sight. We find that the ellipticity of the brightest cluster galaxy, a proxy for halo orientation, correlates well with the offset in mass from the mean scaling relation, which supports this picture. This provides empirical evidence that line-of-sight projection effects are an important systematic uncertainty in lensing-based scaling relations.
The synthesis and solid-state characterization of the resonance-stabilized heterocyclic thia/selenazyl radicals 1a−4a is described. While all the radicals crystallize in undimerized slipped π-stacked ...arrays, the four crystal structures do not constitute an isomorphous set; crystals of 1a and 3a belong to the orthorhombic space group P212121, while those of 2a and 4a belong to the monoclinic space group P21/n. The origin of the structural dichotomy can be traced back to the packing of the radicals in the P21/n structure, which maximizes intermolecular Se−Se′ contacts. There are marked differences in the transport properties of the two groups. Variable temperature conductivity measurements reveal high, but activated, conductivity for the monoclinic pair (2a/4a), with σ(298 K) > 10−3 S cm−1. The application of physical pressure increases the conductivity of both compounds, with σ(298 K) at 5 GPa reaching 0.5 S cm−1 for 2a and 2 S cm−1 for 4a. Variable-temperature magnetic susceptibility measurements indicate strong antiferromagnetic (AFM) coupling for the monoclinic pair 2a and 4a, the behavior of which has been modeled in terms of a molecular-field modified 1D Heisenberg chain of AFM coupled S = 1/2 centers. Extended Hückel theory band structure calculations and density functional theory first principles methods have been used to develop a qualitative understanding of the conductive and magnetic properties of radicals of the type 1−4 as a function of the degree and direction of slippage of the radical π-stacks.
Castleman disease (CD) describes a group of heterogeneous hematologic disorders with characteristic histopathological features. CD can present with unicentric or multicentric (MCD) regions of lymph ...node enlargement. Some cases of MCD are caused by human herpesvirus-8 (HHV-8), whereas others are HHV-8–negative/idiopathic (iMCD). Treatment of iMCD is challenging, and outcomes can be poor because no uniform treatment guidelines exist, few systematic studies have been conducted, and no agreed upon response criteria have been described. The purpose of this paper is to establish consensus, evidence-based treatment guidelines based on the severity of iMCD to improve outcomes. An international Working Group of 42 experts from 10 countries was convened by the Castleman Disease Collaborative Network to establish consensus guidelines for the management of iMCD based on published literature, review of treatment effectiveness for 344 cases, and expert opinion. The anti–interleukin-6 monoclonal antibody siltuximab (or tocilizumab, if siltuximab is not available) with or without corticosteroids is the preferred first-line therapy for iMCD. In the most severe cases, adjuvant combination chemotherapy is recommended. Additional agents are recommended, tailored by disease severity, as second- and third-line therapies for treatment failures. Response criteria were formulated to facilitate the evaluation of treatment failure or success. These guidelines should help treating physicians to stratify patients based on disease severity in order to select the best available therapeutic option. An international registry for patients with CD (ACCELERATE, #NCT02817997) was established in October 2016 to collect patient outcomes to increase the evidence base for selection of therapies in the future.
We present high-resolution CARMA 230 GHz continuum imaging of nine deeply embedded protostars in the Serpens Molecular Cloud, including six of the nine known Class 0 protostars in Serpens. This work ...is part of a program to characterize disk and envelope properties for a complete sample of Class 0 protostars in nearby low-mass star-forming regions. Here, we present CARMA maps and visibility amplitudes as a function of uv-distance for the Serpens sample. Observations are made in the B, C, D, and E antenna configurations, with B configuration observations utilizing the CARMA Paired Antenna Calibration System. Combining data from multiple configurations provides excellent uv-coverage (4-500 k Delta *l), allowing us to trace spatial scales from 102 to 104 AU. We find evidence for compact disk components in all of the observed Class 0 protostars, suggesting that disks form at very early times (t < 0.2 Myr) in Serpens. We make a first estimate of disk masses using the flux at 50 k Delta *l, where the contribution from the envelope should be negligible, assuming an unresolved disk. The resulting disk masses range from 0.04 M to 1.7 M , with a mean of approximately 0.2 M . Our high-resolution maps are also sensitive to binary or multiple sources with separations 250 AU, but significant evidence of multiplicity on scales <2000 AU is seen in only one source.
Two clones of Miscanthus, grown under the names M. xgiganteus and M. sacchariflorus, have been used in biomass trials in Europe, but neither the identity of these clones nor their origin has been ...established. DNA sequencing, amplified fragment length polymorphism (AFLP), and chromosome studies confirm that M. xgiganteus is an allotriploid (2n = 3x = 57) combining genomes from M. sinensis {2n = 2x = 38) and M. sacchariflorus (2n = 38 or 76). Two alleles of the internal transcribed spacer of 18S-25S nuclear ribosomal DNA (ITS) were discovered in polymerase chain reaction products of M. xgiganteus. Cloning of these revealed that one matched M. sinensis and the other M. sacchariflorus. Plastid trnL intron and trnL-F spacer sequences showed that the maternal lineage of M. xgiganteus was M. sacchariflorus. Fluorescent in situ hybridization. FISH, was used to investigate genome organization in Miscanthus but was unable to differentiate between the different parental genomes present in M. xgiganteus, indicating that two parental genomes are still extremely similar at the repetitive DNA level. This study is an example in which rDNA sequences and AFLP fingerprints permit identification of the parental genomes in a hybrid, but FISH methods, at the repetitive DNA level (including genomic in situ hybridization, GISH), were unable to do so because their sequences remain too similar.
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