Probing the energetic particle environment near the Sun.

NASA's Parker Solar Probe mission1 recently plunged through the inner heliosphere of the Sun to its perihelia, about 24 million kilometres from the Sun. Previous studies farther from the Sun (performed mostly at a distance of 1 astronomical unit) indicate that solar energetic particles are accelerated from a few kiloelectronvolts up to near-relativistic energies via at least two processes: 'impulsive' events, which are usually associated with magnetic reconnection in solar flares and are typically enriched in electrons, helium-3 and heavier ions2, and 'gradual' events3,4, which are typically associated with large coronal-mass-ejection-driven shocks and compressions moving through the corona and inner solar wind and are the dominant source of protons with energies between 1 and 10 megaelectronvolts. However, some events show aspects of both processes and the electron-proton ratio is not bimodally distributed, as would be expected if there were only two possible processes5. These processes have been very difficult to resolve from prior observations, owing to the various transport effects that affect the energetic particle population en route to more distant spacecraft6. Here we report observations of the near-Sun energetic particle radiation environment over the first two orbits of the probe. We find a variety of energetic particle events accelerated both locally and remotely including by corotating interaction regions, impulsive events driven by acceleration near the Sun, and an event related to a coronal mass ejection. We provide direct observations of the energetic particle radiation environment in the region just above the corona of the Sun and directly explore the physics of particle acceleration and transport.

Vortical Amplification of the Magnetic Field at an Inward Shock of Supernova Remnant Cassiopeia A.

We present an interpretation of the time variability of the x-ray flux recently reported from a multiepoch campaign of 15 years of observations of the supernova remnant Cassiopeia A by Chandra. We show for the first time quantitatively that the [4.2-6] keV nonthermal flux increase up to 50% traces the growth of the magnetic field due to a vortical amplification mechanism at a reflection inward shock colliding with inner overdensities. The fast synchrotron cooling as compared with shock-acceleration time scale qualitatively supports the flux decrease.

Genetic variation in MKL2 and decreased downstream PCTAIRE1 expression in extreme, fatal primary human microcephaly.

The genetic mechanisms driving normal brain development remain largely unknown. We performed genomic and immunohistochemical characterization of a novel, fatal human phenotype including extreme microcephaly with cerebral growth arrest at 14-18 weeks gestation in three full sisters born to healthy, non-consanguineous parents. Analysis of index cases and parents included familial exome sequencing, karyotyping, and genome-wide single nucleotide polymorphism (SNP) array. From proband, control and unrelated microcephalic fetal cortical tissue, we compared gene expression of RNA and targeted immunohistochemistry. Each daughter was homozygous for a rare, non-synonymous, deleterious variant in the MKL2 gene and heterozygous for a private 185 kb deletion on the paternal allele, upstream and in cis with his MKL2 variant allele, eliminating 24 CArG transcription factor binding sites and MIR4718. MKL1 was underexpressed in probands. Dysfunction of MKL2 and its transcriptional coactivation partner, serum response factor (SRF), was supported by a decrease in gene and protein expression of PCTAIRE1, a downstream target of MKL2:SRF heterodimer transcriptional activation, previously shown to result in severe microcephaly in murine models. While disruption of the MKL2:SRF axis has been associated with severe microcephaly and disordered brain development in multiple model systems, the role of this transcription factor complex has not been previously demonstrated in human brain development.

A novel GC-rich human macrosatellite VNTR in Xq24 is differentially methylated on active and inactive X chromosomes.

A new X chromosome-specific repetitive sequence, a 3 kilobase HindIII clone with a base composition of 63% C+G, has been isolated. The sequence is organized as a hypervariable tandem repeat cluster ranging in size from 150-350 kilobases, with outlying single copies. This locus, designated DXZ4 and mapped to chromosome band Xq24, may consist of as many as 50 variable-length alleles. It represents a class of variable number of tandem repeat polymorphism which may be termed 'macrosatellite'. The cluster is highly methylated on the active X chromosome and hypomethylated on the inactive X.

Anomalous Cosmic Rays and Heliospheric Energetic Particles.

We present a review of Anomalous Cosmic Rays (ACRs), including the history of their discovery and recent insights into their acceleration and transport in the heliosphere. We focus on a few selected topics including a discussion of mechanisms of their acceleration, escape from the heliosphere, their effects on the dynamics of the heliosheath, transport in the inner heliosphere, and their solar cycle dependence. A discussion concerning their name is also presented towards the end of the review. We note that much is known about ACRs and perhaps the term Anomalous Cosmic Ray is not particularly descriptive to a non specialist. We suggest that the more-general term: "Heliospheric Energetic Particles", which is more descriptive, for which ACRs and other energetic particle species of heliospheric origin are subsets, might be more appropriate.

The Early History of Heliospheric Science and the Spacecraft That Made It Possible.

Our understanding of the interaction of the large-scale heliosphere with the local interstellar medium (LISM) has undergone a profound change since the very earliest analyses of the problem. In part, the revisions have been a consequence of ever-improving and widening observational results, especially those that identified the entrance of interstellar material and gas into the heliosphere. Accompanying these observations was the identification of the basic underlying physics of how neutral interstellar gas and interstellar charged particles of different energies, up to and including interstellar dust grains, interacted with the temporal flows and electromagnetic fields of the heliosphere. The incorporation of these various basic effects into global models of the interaction, whether focused on neutral interstellar gas and pickup ions, energetic particles such as anomalous and galactic cosmic rays, or magnetic fields and large-scale flows, has profoundly changed our view of how the heliosphere and LISM interact. This article presents a brief history of the conceptual and observation evolution of our understanding of the interaction of the heliosphere with the local interstellar medium, up until approximately 1996.

Turbulence in the Local Interstellar Medium and the IBEX Ribbon.

The effects of turbulence in the very local interstellar medium (VLISM) have been proposed by Giacalone & Jokipii (2015) to be important in determining the structure of the Interstellar Boundary Explorer (IBEX) ribbon via particle trapping by magnetic mirroring. We further explore this effect by simulating the motion of charged particles in a turbulent magnetic field superposed on a large-scale mean field, which we consider to be either spatially-uniform or a draped field derived from a 3D MHD simulation. We find that the ribbon is not double-peaked, in contrast to Giacalone & Jokipii (2015). However, the magnetic mirror force still plays an important role in trapping particles. Furthermore, the ribbon's thickness is considerably larger if the large-scale mean field is draped around the heliosphere. Voyager 1 observations in the VLISM show a turbulent field component that is stronger than previously thought, which we test in our simulation. We find that the inclusion of turbulent fluctuations at scales ≳100 au and power consistent with Voyager 1 observations produces a ribbon whose large-scale structure is inconsistent with IBEX observations. However, restricting fluctuations to <100 au produces a smoother ribbon structure similar to IBEX observations. Different turbulence realizations produce different small-scale features (≲10°) in the ribbon, but its large-scale structure is robust if the maximum fluctuation size is ≲50 au. This suggests that the magnetic field structure at scales ≲50 au is determined by the heliosphere-VLISM interaction and cannot entirely be represented by pristine interstellar turbulence.

Oncogene from human EJ bladder carcinoma is located on the short arm of chromosome 11.

The human cellular homolog of the transforming DNA sequence isolated from the bladder carcinoma cell line EJ was localized on the short arm of human chromosome 11 by Southern blot analysis of human-rodent hybrid cell DNA. This locus contains human sequences homologous to the Harvey murine sarcoma virus v-Ha-ras oncogene.

Visible spectroscopy diagnostics for tungsten source assessment in the WEST tokamak: First measurements.

The present work concerns the measurements obtained with the Tungsten (W) Environment in Steady-state Tokamak (WEST) visible spectroscopy system during the first experimental campaign. This system has been developed in the framework of the WEST project that equipped the existing Tore Supra device with a tungsten divertor in order to test actively cooled tungsten Plasma Facing Components (PFC) in view of preparing for ITER operation. The goal of this diagnostic is to measure the PFC sources and the deuterium recycling with spectral, spatial, and temporal resolution adapted to the predicted power deposition profiles on the objects observed. Three kinds of PFCs are monitored: the Ion Cyclotron Resonance Heating (ICRH) antenna and Low Hybrid Current Drive (LHCD) launcher W limiters; one of the 6 W inner bumpers; and the upper and lower W divertors. Large-aperture in-vessel actively cooled optical systems (f-number ∼ 3) were installed for each view and connected to optical fibres. A total of 240 optical fibers can be distributed on various detection systems including a fast response-time, multi-channel, filtered photodetector-based "Filterscope" system, developed by Oak Ridge National Laboratory (USA) as well as grating spectrometers optimized for multi-sightline analysis. The first WEST experimental campaign conducted in 2017 has been dedicated to plasma start-up development during which the visible spectroscopy system has provided crucial information related to the impurity content first and then impurity sources. The diagnostic setup for that first experimental campaign was limited to the inner bumper and outer limiters but was sufficient to demonstrate that the optical setup was in accordance with the specifications. The radiance calibration procedure allowed us to estimate fluxes from the main limiter of about 8 × 1018 atoms/(s m2) and to show a first W source radial profile along the outboard limiter.

Development of visible spectroscopy diagnostics for W sources assessment in WEST.

The present work concerns the development of a W sources assessment system in the framework of the tungsten-W environment in steady state tokamak project that aims at equipping the existing Tore Supra device with a tungsten divertor in order to test actively cooled tungsten Plasma Facing Components (PFCs) in view of preparing ITER operation. The goal is to assess W sources and D recycling with spectral, spatial, and temporal resolution adapted to the PFCs observed. The originality of the system is that all optical elements are installed in the vacuum vessel and compatible with steady state operation. Our system is optimized to measure radiance as low as 1016 Ph/(m2 s sr). A total of 240 optical fibers will be deployed to the detection systems such as the "Filterscope," developed by Oak Ridge National Laboratory (USA) and consisting of photomultiplier tubes and filters, or imaging spectrometers dedicated to Multiview analysis.

Excess congenital non-synonymous variation in leukemia-associated genes in MLL- infant leukemia: a Children's Oncology Group report.

Infant leukemia (IL) is a rare sporadic cancer with a grim prognosis. Although most cases are accompanied by MLL rearrangements and harbor very few somatic mutations, less is known about the genetics of the cases without MLL translocations. We performed the largest exome-sequencing study to date on matched non-cancer DNA from pairs of mothers and IL patients to characterize congenital variation that may contribute to early leukemogenesis. Using the COSMIC database to define acute leukemia-associated candidate genes, we find a significant enrichment of rare, potentially functional congenital variation in IL patients compared with randomly selected genes within the same patients and unaffected pediatric controls. IL acute myeloid leukemia (AML) patients had more overall variation than IL acute lymphocytic leukemia (ALL) patients, but less of that variation was inherited from mothers. Of our candidate genes, we found that MLL3 was a compound heterozygote in every infant who developed AML and 50% of infants who developed ALL. These data suggest a model by which known genetic mechanisms for leukemogenesis could be disrupted without an abundance of somatic mutation or chromosomal rearrangements. This model would be consistent with existing models for the establishment of leukemia clones in utero and the high rate of IL concordance in monozygotic twins.

Common sequence motifs at the rearrangement sites of a constitutional X/autosome translocation and associated deletion.

Reciprocal chromosome translocations are common de novo rearrangements that occur randomly throughout the human genome. To learn about causative mechanisms, we have cloned and sequenced the breakpoints of a cytologically balanced constitutional reciprocal translocation, t(X;4)(p21.2;q31.22), present in a girl with Duchenne muscular dystrophy (DMD). Physical mapping of the derivative chromosomes, after their separation in somatic cell hybrids, reveals that the translocation disrupts the DMD gene in Xp21 within the 18-kb intron 16. Restriction mapping and sequencing of clones that span both translocation breakpoints as well as the corresponding normal regions indicate the loss of approximately 5 kb in the formation of the derivative X chromosome, with 4-6 bp deleted from chromosome 4. RFLP and Southern analyses indicate that the de novo translocation is a paternal origin and that the father's X chromosome contains the DNA that is deleted in the derivative X. Most likely, deletion and translation arose simultaneously from a complex rearrangement event that involves three chromosomal breakpoints. Short regions of sequence homology were present at the three sites. A 5-bp sequence, GGAAT, found exactly at the translocation breakpoints on both normal chromosomes X and 4, has been preserved only on the der(4) chromosome. It is likely that the X-derived sequence GGAATCA has been lost in the formation of the der(X) chromosome, as it matches an inverted GAATCA sequence present on the opposite strand exactly at the other end of the deleted 5-kb fragment. These findings suggest a possible mechanism which may have juxtaposed the three sites and mediated sequence-specific breakage and recombination between nonhomologous chromosomes in male meiosis.

Primary care education trends in U.S. medical schools and teaching hospitals.

In 1973 Schroeder and colleagues conducted a survey of U.S. Medical schools in order to ascertain the nature of change in primary care education which had occurred by that date. In 1976 the authors of the present paper utilized the same survey instrument to document trend data over the three-year period. While conclusions from the 1973 survey pictured primary care education in a transitional state, the 1976 data suggest movement toward a general consolidation of efforts. The 1976 data indicate a continued emphasis on education in the ambulatory care area with no well-defined locus for coordinating institutionwide primary care training efforts, a leveling off of interest in health maintenance organizations (HMO) affiliations, no significant change in the number of affiliated programs for training nurse practitioners or physician's assistants, and a marked increase in the number of schools with affiliated generalist residency programs in internal medicine and pediatrics.

A health status assessment system for a rural Navajo population.

An analysis of the first year's operation of an ambulatory patient monitoring system is presented. The program was designed to accomplish the following objectives: 1) to demonstrate individual clinic effectiveness in giving each member of its service population a complete assessment of his health status, and 2) to implement patient surveillance for follow-up and periodic reevaluation. The system was adapted to the pre-existing computer-based ambulatory patient care reporting mechanism which is in use by Indian Health Service members and contracting facilities. It employs discrete health status categories whose definitions are based in specific clinical criteria. This approach permits the interpretation of categorical patient flow statistics as representative of identifiable clinic practices. Quarterly data printouts provide a basis for interpreting the degree of clinic progress toward initial health assessment of the total population served. Such data, when viewed against the backdrop of specific operational objectives allow for continuous program reassessment of community needs, and provide a technique for monitoring the effectiveness of the health care delivery system in meeting these needs. By controlling for individual variations in clinic objectives, comparisons can be made between separate facilities within the network. In addition, the technique provides a method for focusing on areas where objectives may not be realistic and provides a data base on which alternative program goals can be formulated.

High-density radiation hybrid map of human chromosome 18 and contig of 18p.

A high-resolution radiation hybrid map of human chromosome 18 has been developed by testing DNA samples of 92 radiation hybrids (RH) from a previously characterized chromosome 18-specific RH panel. Half of the 159 STS markers were tested on RH DNA amplified by primer extension preamplification. This map includes 20 genes and 95 polymorphic markers, most of which have heterozygosity frequencies greater than 65% and, therefore, allow integration with genetic maps. The framework map consists of 137 markers ordered with odds of 1000:1 or better and spaced on average 580 kb apart. A YAC contig map of 18p was generated independently by STS content mapping of YACs using the same primers as for RH mapping. The RH map and the contig map are concordant.

Large-scale purification of hepatitis B surface antigen using affinity chromatography.

Large-scale purification of hepatitis B surface antigen, applicable to the preparation of potential vaccines for prevention of hepatitis B, is described. The method involves the following steps: precipitation of serum with polyethylene glycol 6000, affinity chromatography on concanavalin A-Sepharose and on omega-aminononyl-Sepharose, and isopycnic centrifugation.

Small-scale Gradients and Large-scale Diffusion of Charged Particles in the Heliospheric Magnetic Field.

We have carried out numerical simulations of the propagation of energetic charged particles in a turbulent magnetic field similar to that observed in the solar wind. If the particles are released impulsively near the Sun, in a region small compared with the field coherence scale (a solar flare, for example), they exhibit characteristic fluctuations in intensity at 1 AU (dropouts) associated with very steep localized gradients. These numerical simulations are quantitatively very similar to recent observations by the Advanced Composition Explorer spacecraft and are the result of the convection of alternatively filled and empty flux tubes past the spacecraft. These fluctuations occur naturally as part of the particle transport in the same field, which results in large-scale cross field diffusion and which has previously been used to study the propagation of corotating interaction region-associated particles to high heliographic latitudes.

Generation of a human chromosome 18-specific YAC clone collection and mapping of 55 unique YACs by FISH and fingerprinting.

A yeast artificial chromosome (YAC) library was constructed from a somatic cell hybrid line in which the human chromosome content had been reduced by repeated subcloning to one or two copies of chromosome 18. Screening of 4700 primary yeast transformants generated 74 clones containing a YAC with a human DNA insert averaging 190 kb in size. The human YACs were localized to subregions of chromosome 18 by in situ hybridization of biotin-labeled Alu-PCR products obtained using total yeast DNA as a template. Comparisons of interspersed repetitive sequence-PCR and restriction fragment fingerprint patterns identified five sets of identical and three sets of overlapping YACs. Dual-label fluorescence in situ hybridization interphase mapping was used to determine the order of some nonoverlapping YACs. STS (sequence-tagged site) content mapping was carried out with PCR primers for 56 chromosome 18-specific markers. The identification of YACs containing four known genes--encoding the pituitary adenylate cyclase activating polypeptide (PA-CAP), the myelin basic protein (MBP), ferrochelatase (FECH), and SSAV1, an endogenous retroviral element related to the SSAV virus--provides a precise cytological map position for the respective loci. Our final collection of 55 randomly isolated, unique, and regionally localized YACs (D18S107-D18S161) is distributed over the entire chromosome and collectively covers approximately 12 Mb, i.e., 16% of the estimated 77 Mb of DNA in euchromatin of chromosome 18. These YACs provide reagents for the isolation of genes in these regions and represent nucleation points for the generation of STS to increase coverage of the chromosome by YAC contigs.

Regional localization of 56 new human chromosome 18-specific yeast artificial chromosomes.

Fifty-six chromosome 18-specific yeast artificial chromosomes (YAC) were isolated from a human monochromosomal somatic cell hybrid DNA library. Fluorescence in situ hybridization revealed that the clones were evenly distributed throughout the chromosome. The clones, with an average insert size of 250 kb, cover about 18% of the euchromatic part of chromosome 18. Of 90 STS markers tested, 17 were represented in this YAC collection. Together with our previously reported set of unique chromosome 18-specific YACs, we now have available 111 regionally mapped, essentially nonchimeric, clones that provide more than 30% coverage and form a framework for the complete physical map.

A radiation hybrid map of human chromosome 18.

A human x Chinese hamster (CH) somatic cell hybrid subclone deficient in HPRT and containing only human chromosome 18 was irradiated with 7000 rad and fused to a thymidine kinase deficient CH cell line. Radiation-rescued hybrid cell lines, selected in HAT medium, were analyzed for human DNA with human interspersed-repeat sequence primers. Size and number of human chromosome fragments retained in a subset of hybrids were determined by FISH. A panel of 98 radiation hybrids (RH) was selected and analyzed for 90 chromosome 18-specific STSs by PCR, and for the D18Z1 centromeric marker by Southern blotting. STSs were developed from previously mapped RFLP loci and from published sequences. In addition, 32 novel STSs were generated from an 18-specific lambda library and from 18-specific YACs previously localized to chromosome bands by FISH. Marker retention frequency varied from 8-65% with an average of 24%. In selected RH the STS typing data were correlated with the chromosome 18 regions retained using 'reverse FISH' of IRS-PCR products from the RH to normal metaphase chromosomes. The order and intermarker distances of loci were determined using two-point and multipoint maximum likelihood methods. The resulting RH map covers most of chromosome 18 with four groups of tightly linked markers and three regions of loosely linked markers, one around the centromere and two on the long arm. More than a third of the markers are polymorphic and allow integration with the linkage map. This RH map provides a framework for establishing a clone contig of the entire chromosome 18.