Implications of very rapid TeV variability in blazars

We discuss the implications of rapid (few-minute) variability in the TeV flux of blazars, which has been observed recently with the HESS and MAGIC telescopes. The variability timescales seen in PKS 2155-304 and Mrk 501 are much shorter than inferred light-crossing times at the black hole horizon, suggesting that the variability involves enhanced emission in a small region within an outflowing jet. The enhancement could be triggered by dissipation in part of the black hole's magnetosphere at the base of the outflow, or else by instabilities in the jet itself. By considering the energetics of the observed flares, along with the requirement that TeV photons escape without producing pairs, we deduce that the bulk Lorentz factors in the jets must be >50. The distance of the emission region from the central black hole is less well-constrained. We discuss possible consequences for multi-wavelength observations.Comment: 5 pages, no figures, accepted for publication in Monthly Notices of the Royal Astronomical Society Letter

k-d Darts: Sampling by k-Dimensional Flat Searches

We formalize the notion of sampling a function using k-d darts. A k-d dart is a set of independent, mutually orthogonal, k-dimensional subspaces called k-d flats. Each dart has d choose k flats, aligned with the coordinate axes for efficiency. We show that k-d darts are useful for exploring a function's properties, such as estimating its integral, or finding an exemplar above a threshold. We describe a recipe for converting an algorithm from point sampling to k-d dart sampling, assuming the function can be evaluated along a k-d flat. We demonstrate that k-d darts are more efficient than point-wise samples in high dimensions, depending on the characteristics of the sampling domain: e.g. the subregion of interest has small volume and evaluating the function along a flat is not too expensive. We present three concrete applications using line darts (1-d darts): relaxed maximal Poisson-disk sampling, high-quality rasterization of depth-of-field blur, and estimation of the probability of failure from a response surface for uncertainty quantification. In these applications, line darts achieve the same fidelity output as point darts in less time. We also demonstrate the accuracy of higher dimensional darts for a volume estimation problem. For Poisson-disk sampling, we use significantly less memory, enabling the generation of larger point clouds in higher dimensions.Comment: 19 pages 16 figure

Corrigendum: A Pipeline for Volume Electron Microscopy of the Caenorhabditis elegans Nervous System.

[This corrects the article DOI: 10.3389/fncir.2018.00094.]

A Pipeline for Volume Electron Microscopy of the Caenorhabditis elegans Nervous System.

The "connectome," a comprehensive wiring diagram of synaptic connectivity, is achieved through volume electron microscopy (vEM) analysis of an entire nervous system and all associated non-neuronal tissues. White et al. (1986) pioneered the fully manual reconstruction of a connectome using Caenorhabditis elegans. Recent advances in vEM allow mapping new C. elegans connectomes with increased throughput, and reduced subjectivity. Current vEM studies aim to not only fill the remaining gaps in the original connectome, but also address fundamental questions including how the connectome changes during development, the nature of individuality, sexual dimorphism, and how genetic and environmental factors regulate connectivity. Here we describe our current vEM pipeline and projected improvements for the study of the C. elegans nervous system and beyond

Impact of \u3cem\u3eMYH6\u3c/em\u3e Variants in Hypoplastic Left Heart Syndrome

Hypoplastic left heart syndrome (HLHS) is a clinically and anatomically severe form of congenital heart disease (CHD). Although prior studies suggest that HLHS has a complex genetic inheritance, its etiology remains largely unknown. The goal of this study was to characterize a risk gene in HLHS and its effect on HLHS etiology and outcome. We performed next-generation sequencing on a multigenerational family with a high prevalence of CHD/HLHS, identifying a rare variant in the α-myosin heavy chain (MYH6) gene. A case-control study of 190 unrelated HLHS subjects was then performed and compared with the 1000 Genomes Project. Damaging MYH6 variants, including novel, missense, in-frame deletion, premature stop, de novo, and compound heterozygous variants, were significantly enriched in HLHS cases (P \u3c 1 × 10−5). Clinical outcomes analysis showed reduced transplant-free survival in HLHS subjects with damaging MYH6 variants (P \u3c 1 × 10−2). Transcriptome and protein expression analyses with cardiac tissue revealed differential expression of cardiac contractility genes, notably upregulation of the β-myosin heavy chain (MYH7) gene in subjects with MYH6 variants (P \u3c 1 × 10−3). We subsequently used patient-specific induced pluripotent stem cells (iPSCs) to model HLHS in vitro. Early stages of in vitro cardiomyogenesis in iPSCs derived from two unrelated HLHS families mimicked the increased expression of MYH7 observed in vivo (P \u3c 1 × 10−2), while revealing defective cardiomyogenic differentiation. Rare, damaging variants in MYH6 are enriched in HLHS, affect molecular expression of contractility genes, and are predictive of poor outcome. These findings indicate that the etiology of MYH6-associated HLHS can be informed using iPSCs and suggest utility in future clinical applications

Proteolysis Controls Endogenous Substance P Levels

Substance P (SP) is a prototypical neuropeptide with roles in pain and inflammation. Numerous mechanisms regulate endogenous SP levels, including the differential expression of SP mRNA and the controlled secretion of SP from neurons. Proteolysis has long been suspected to regulate extracellular SP concentrations but data in support of this hypothesis is scarce. Here, we provide evidence that proteolysis controls SP levels in the spinal cord. Using peptidomics to detect and quantify endogenous SP fragments, we identify the primary SP cleavage site as the C-terminal side of the ninth residue of SP. If blocking this pathway increases SP levels, then proteolysis controls SP concentration. We performed a targeted chemical screen using spinal cord lysates as a proxy for the endogenous metabolic environment and identified GM6001 (galardin, ilomastat) as a potent inhibitor of the SP 1–9-producing activity present in the tissue. Administration of GM6001 to mice results in a greater-than-three-fold increase in the spinal cord levels of SP, which validates the hypothesis that proteolysis controls physiological SP levels

Temperature-composition Phase Diagrams for Ba1-xSrxFe2As2 and Ba0.5Sr0.5(Fe1-yCoy)2As2

Single crystals of mixed alkaline earth metal iron arsenide materials of Ba1-xSrxFe2As2 and Ba0.5Sr0.5(Fe1-yCoy)2As2 are synthesized via the self-flux method. Ba1-xSrxFe2As2 display spin-density wave features (TN) at temperatures intermediate to the parent materials, x = 0 and 1, with TN(x) following an approximately linear trend. Cobalt doping of the 1 to 1 Ba:Sr mixture, Ba0.5Sr0.5(Fe1-yCoy)2As2, results in a superconducting dome with maximum transition temperature of TC = 19 K at y = 0.092, close to the maximum transition temperatures observed in unmixed A(Fe1-yCoy)2As2; however, an annealed crystal with y = 0.141 showed a TC increase from 11 to 16 K with a decrease in Sommerfeld coefficient from 2.58(2) to 0.63(2) mJ/(K2 mol atom). For the underdoped y = 0.053, neutron diffraction results give evidence that TN and structural transition (To) are linked at 78 K, with anomalies observed in magnetization, resistivity and heat capacity data, while a superconducting transition at TC ~ 6 K is seen in resistivity and heat capacity data. Scanning tunneling microscopy measurements for y = 0.073 give Dynes broadening factor of 1.15 and a superconducting gap of 2.37 meV with evidence of surface inhomogeneity.Comment: Submitted to PR

Local Magnetization in the Boundary Ising Chain at Finite Temperature

We study the local magnetization in the 2-D Ising model at its critical temperature on a semi-infinite cylinder geometry, and with a nonzero magnetic field $h$ applied at the circular boundary of circumference $\beta$. This model is equivalent to the semi-infinite quantum critical 1-D transverse field Ising model at temperature $T \propto \beta^{-1}$, with a symmetry-breaking field $\propto h$ applied at the point boundary. Using conformal field theory methods we obtain the full scaling function for the local magnetization analytically in the continuum limit, thereby refining the previous results of Leclair, Lesage and Saleur in Ref. \onlinecite{Leclair}. The validity of our result as the continuum limit of the 1-D lattice model is confirmed numerically, exploiting a modified Jordan-Wigner representation. Applications of the result are discussed.Comment: 9 pages, 3 figure

Human gene copy number spectra analysis in congenital heart malformations

The clinical significance of copy number variants (CNVs) in congenital heart disease (CHD) continues to be a challenge. Although CNVs including genes can confer disease risk, relationships between gene dosage and phenotype are still being defined. Our goal was to perform a quantitative analysis of CNVs involving 100 well-defined CHD risk genes identified through previously published human association studies in subjects with anatomically defined cardiac malformations. A novel analytical approach permitting CNV gene frequency “spectra” to be computed over prespecified regions to determine phenotype-gene dosage relationships was employed. CNVs in subjects with CHD (n = 945), subphenotyped into 40 groups and verified in accordance with the European Paediatric Cardiac Code, were compared with two control groups, a disease-free cohort (n = 2,026) and a population with coronary artery disease (n = 880). Gains (≥200 kb) and losses (≥100 kb) were determined over 100 CHD risk genes and compared using a Barnard exact test. Six subphenotypes showed significant enrichment (P ≤ 0.05), including aortic stenosis (valvar), atrioventricular canal (partial), atrioventricular septal defect with tetralogy of Fallot, subaortic stenosis, tetralogy of Fallot, and truncus arteriosus. Furthermore, CNV gene frequency spectra were enriched (P ≤ 0.05) for losses at: FKBP6, ELN, GTF2IRD1, GATA4, CRKL, TBX1, ATRX, GPC3, BCOR, ZIC3, FLNA and MID1; and gains at: PRKAB2, FMO5, CHD1L, BCL9, ACP6, GJA5, HRAS, GATA6 and RUNX1. Of CHD subjects, 14% had causal chromosomal abnormalities, and 4.3% had likely causal (significantly enriched), large, rare CNVs. CNV frequency spectra combined with precision phenotyping may lead to increased molecular understanding of etiologic pathways

A Gibbs approach to Chargaff's second parity rule

Chargaff's second parity rule (CSPR) asserts that the frequencies of short polynucleotide chains are the same as those of the complementary reversed chains. Up to now, this hypothesis has only been observed empirically and there is currently no explanation for its presence in DNA strands. Here we argue that CSPR is a probabilistic consequence of the reverse complementarity between paired strands, because the Gibbs distribution associated with the chemical energy between the bonds satisfies CSPR. We develop a statistical test to study the validity of CSPR under the Gibbsian assumption and we apply it to a large set of bacterial genomes taken from the GenBank repository.Comment: 16 page