The genomics of neonatal abstinence syndrome

Significant variability has been observed in the development and severity of neonatal abstinence syndrome (NAS) among neonates exposed to prenatal opioids. Since maternal opioid dose does not appear to correlate directly with neonatal outcome, maternal, placental, and fetal genomic variants may play important roles in NAS. Previous studies in small cohorts have demonstrated associations of variants in maternal and infant genes that encode the μ-opioid receptor (OPRM1), catechol-O-methyltransferase (COMT), and prepronociceptin (PNOC) with a shorter length of hospital stay and less need for treatment in neonates exposed to opioids in utero. Consistently falling genomic sequencing costs and computational approaches to predict variant function will permit unbiased discovery of genomic variants and gene pathways associated with differences in maternal and fetal opioid pharmacokinetics and pharmacodynamics and with placental opioid transport and metabolism. Discovery of pathogenic variants should permit better delineation of the risk of developing more severe forms of NAS. This review provides a summary of the current role of genomic factors in the development of NAS and suggests strategies for further genomic discovery

An orbitally derived single-atom magnetic memory

A single magnetic atom on a surface epitomizes the scaling limit for magnetic information storage. Indeed, recent work has shown that individual atomic spins can exhibit magnetic remanence and be read out with spin-based methods, demonstrating the fundamental requirements for magnetic memory. However, atomic spin memory has been only realized on thin insulating surfaces to date, removing potential tunability via electronic gating or distance-dependent exchange-driven magnetic coupling. Here, we show a novel mechanism for single-atom magnetic information storage based on bistability in the orbital population, or so-called valency, of an individual Co atom on semiconducting black phosphorus (BP). Distance-dependent screening from the BP surface stabilizes the two distinct valencies and enables us to electronically manipulate the relative orbital population, total magnetic moment and spatial charge density of an individual magnetic atom without a spin-dependent readout mechanism. Furthermore, we show that the strongly anisotropic wavefunction can be used to locally tailor the switching dynamics between the two valencies. This orbital memory derives stability from the energetic barrier to atomic relaxation and demonstrates the potential for high-temperature single-atom information storage

Sequencing of idiopathic pulmonary fibrosis-related genes reveals independent single gene associations

BACKGROUND: Previous studies investigating a genetic basis for idiopathic pulmonary fibrosis (IPF) have focused on resequencing single genes in IPF kindreds or cohorts to determine the genetic contributions to IPF. None has investigated interactions among the candidate genes. OBJECTIVE: To compare the frequencies and interactions of mutations in six IPF-associated genes in a cohort of 132 individuals with IPF with those of a disease-control cohort of 192 individuals with chronic obstructive pulmonary disease (COPD) and the population represented in the Exome Variant Server. METHODS: We resequenced the genes encoding surfactant proteins A2 (SFTPA2), and C (SFTPC), the ATP binding cassette member A3 (ABCA3), telomerase (TERT), thyroid transcription factor (NKX2-1) and mucin 5B (MUC5B) and compared the collapsed frequencies of rare (minor allele frequency <1%), computationally predicted deleterious variants in each cohort. We also genotyped a common MUC5B promoter variant that is over-represented in individuals with IPF. RESULTS: We found 15 mutations in 14 individuals (11%) in the IPF cohort: (SFTPA2 (n=1), SFTPC (n=5), ABCA3 (n=4) and TERT (n=5)). No individual with IPF had two different mutations, but one individual with IPF was homozygous for p.E292V, the most common ABCA3 disease-causing variant. We did not detect an interaction between any of the mutations and the MUC5B promoter variant. CONCLUSIONS: Rare mutations in SFTPA2, SFTPC and TERT are collectively over-represented in individuals with IPF. Genetic analysis and counselling should be considered as part of the IPF evaluation

Commonalities across computational workflows for uncovering explanatory variants in undiagnosed cases

PURPOSE: Genomic sequencing has become an increasingly powerful and relevant tool to be leveraged for the discovery of genetic aberrations underlying rare, Mendelian conditions. Although the computational tools incorporated into diagnostic workflows for this task are continually evolving and improving, we nevertheless sought to investigate commonalities across sequencing processing workflows to reveal consensus and standard practice tools and highlight exploratory analyses where technical and theoretical method improvements would be most impactful. METHODS: We collected details regarding the computational approaches used by a genetic testing laboratory and 11 clinical research sites in the United States participating in the Undiagnosed Diseases Network via meetings with bioinformaticians, online survey forms, and analyses of internal protocols. RESULTS: We found that tools for processing genomic sequencing data can be grouped into four distinct categories. Whereas well-established practices exist for initial variant calling and quality control steps, there is substantial divergence across sites in later stages for variant prioritization and multimodal data integration, demonstrating a diversity of approaches for solving the most mysterious undiagnosed cases. CONCLUSION: The largest differences across diagnostic workflows suggest that advances in structural variant detection, noncoding variant interpretation, and integration of additional biomedical data may be especially promising for solving chronically undiagnosed cases

Robustness Generalizations of the Shortest Feasible Path Problem for Electric Vehicles

Electric Vehicle routing is often modeled as a Shortest Feasible Path Problem (SFPP), which minimizes total travel time while maintaining a non-zero State of Charge (SoC) along the route. However, the problem assumes perfect information about energy consumption and charging stations, which are difficult to even estimate in practice. Further, drivers might have varying risk tolerances for different trips. To overcome these limitations, we propose two generalizations to the SFPP; they compute the shortest feasible path for any initial SoC and, respectively, for every possible minimum SoC threshold. We present algorithmic solutions for each problem, and provide two constructs: Starting Charge Maps and Buffer Maps, which represent the tradeoffs between robustness of feasible routes and their travel times. The two constructs are useful in many ways, including presenting alternate routes or providing charging prompts to users. We evaluate the performance of our algorithms on realistic input instances

Redshifts for 2410 Galaxies in the Century Survey Region

The `Century Survey' strip covers 102 square degrees within the limits 8.5h \leq \alpha_{1950} \leq 16.5h, 29.0 degrees \leq \delta_{1950} \leq 30.0 degrees. The strip passes through the Corona Borealis supercluster and the outer region of the Coma cluster. Within the Century Survey region, we have measured 2410 redshifts which constitute four overlapping complete redshift surveys: (1) 1728 galaxies with Kron-Cousins R_{phot} \leq 16.13 covering the entire strip, (2) 507 galaxies with R_{phot} \leq 16.4 in the right ascension range 8h 32m \leq \alpha_{1950} \leq 10h 45m, (3) 1251 galaxies with absorption- and K-corrected R_{CCD, corr} \leq 16.2 covering the right ascension range 8.5h \leq \alpha_{1950} \leq 13.5h and (4) 1255 galaxies with absorption- and K-corrected V_{CCD, corr} \leq 16.7 also covering the right ascension range 8.5h \leq \alpha_{1950} \leq 13.5h. All of these redshift samples are more than 98 % complete to the specified magnitude limit.Comment: 18 pages, 9 figures, 3 tables, 2 abbreviated tables. In press, to appear in Astronomical Journal, Dec. 2001 issu

An Optical and X-Ray Study of Abell 576, a Galaxy Cluster with a Cold Core

We analyze the galaxy population and dynamics of the galaxy cluster A576; the observational constraints include 281 redshifts (230 new), R- band CCD galaxy photometry over a 2 h^-1^ Mpc x 2 h^-1^ Mpc region centered on the cluster, an Einstein IPC X-ray image, and an Einstein MPC X-ray spectrum. We focus on an 86% complete magnitude-limited sample (R_23.5_ \u3c 17) of 169 cluster galaxies. The cluster galaxies with emission lines in their spectra have a larger velocity dispersion and are significantly less clustered on this 2 h^-1^ Mpc scale than galaxies without emission lines. We show that excluding the emission-line galaxies from the cluster sample decreases the velocity dispersion by 18% and the virial mass estimate by a factor of 2. The central cluster region contains a nonemission galaxy population and an intracluster medium which is significantly cooler (σ_core_ = 387_-105_^+250^ km s^-1^ and T_x_ = 1.6_-0.3_^+0.4^ keV at 90% confidence) than the global populations (σ = 977_-96_^+124^ km s^- 1^ for the nonemission population and T_X_ \u3e 4 keV at 90% confidence). Because (1) the low-dispersion galaxy population is no more luminous than the global population and (2) the evidence for a cooling flow is weak, we suggest that the core of A576 may contain the remnants of a lower mass subcluster. We examine the cluster mass, baryon fraction, and luminosity function. The cluster virial mass varies significantly depending on the galaxy sample used. Consistency between the hydrostatic and virial estimators can be achieved if (1) the gas temperature at r~1 h^-1^ Mpc is T_X_ ~ 8 keV (the best-fit value) and (2) several velocity outliers are excluded from the virial calculation. Although the best-fit Schechter function parameters and the ratio of galaxy to gas mass in A576 are typical of other clusters, the baryon fraction is relatively low. Using the consistent cluster binding mass, we show that the gas mass fraction is ~3 h^-3/2^% and the baryon fraction is ~6%

Rare recessive loss-of-function methionyl-tRNA synthetase mutations presenting as a multi-organ phenotype

BACKGROUND: Methionyl-tRNA synthetase (MARS) catalyzes the ligation of methionine to its cognate transfer RNA and therefore plays an essential role in protein biosynthesis. METHODS: We used exome sequencing, aminoacylation assays, homology modeling, and immuno-isolation of transfected MARS to identify and characterize mutations in the methionyl-tRNA synthetase gene (MARS) in an infant with an unexplained multi-organ phenotype. RESULTS: We identified compound heterozygous mutations (F370L and I523T) in highly conserved regions of MARS. The parents were each heterozygous for one of the mutations. Aminoacylation assays documented that the F370L and I523T MARS mutants had 18 ± 6% and 16 ± 6%, respectively, of wild-type activity. Homology modeling of the human MARS sequence with the structure of E. coli MARS showed that the F370L and I523T mutations are in close proximity to each other, with residue I523 located in the methionine binding pocket. We found that the F370L and I523T mutations did not affect the association of MARS with the multisynthetase complex. CONCLUSION: This infant expands the catalogue of inherited human diseases caused by mutations in aminoacyl-tRNA synthetase genes

Coherent terabit communications with microresonator Kerr frequency combs

Optical frequency combs enable coherent data transmission on hundreds of wavelength channels and have the potential to revolutionize terabit communications. Generation of Kerr combs in nonlinear integrated microcavities represents a particularly promising option enabling line spacings of tens of GHz, compliant with wavelength-division multiplexing (WDM) grids. However, Kerr combs may exhibit strong phase noise and multiplet spectral lines, and this has made high-speed data transmission impossible up to now. Recent work has shown that systematic adjustment of pump conditions enables low phase-noise Kerr combs with singlet spectral lines. Here we demonstrate that Kerr combs are suited for coherent data transmission with advanced modulation formats that pose stringent requirements on the spectral purity of the optical source. In a first experiment, we encode a data stream of 392 Gbit/s on subsequent lines of a Kerr comb using quadrature phase shift keying (QPSK) and 16-state quadrature amplitude modulation (16QAM). A second experiment shows feedback-stabilization of a Kerr comb and transmission of a 1.44 Tbit/s data stream over a distance of up to 300 km. The results demonstrate that Kerr combs can meet the highly demanding requirements of multi-terabit/s coherent communications and thus offer a solution towards chip-scale terabit/s transceivers