HESS J1826−-130: A Very Hard γ\gamma-Ray Spectrum Source in the Galactic Plane

HESS J1826$-$130 is an unidentified hard spectrum source discovered by H.E.S.S. along the Galactic plane, the spectral index being $\Gamma$ = 1.6 with an exponential cut-off at about 12 TeV. While the source does not have a clear counterpart at longer wavelengths, the very hard spectrum emission at TeV energies implies that electrons or protons accelerated up to several hundreds of TeV are responsible for the emission. In the hadronic case, the VHE emission can be produced by runaway cosmic-rays colliding with the dense molecular clouds spatially coincident with the H.E.S.S. source.Comment: 6 pages, 3 figures, Proceedings of the 6th International Symposium on High Energy Gamma-Ray Astronomy (Gamma2016), Heidelberg, German

Escherichia coli low-copy-number plasmid R1 centromere parC forms a U-shaped complex with its binding protein ParR

The Escherichia coli low-copy-number plasmid R1 contains a segregation machinery composed of parC, ParR and parM. The R1 centromere-like site parC contains two separate sets of repeats. By atomic force microscopy (AFM) we show here that ParR molecules bind to each of the 5-fold repeated iterons separately with the intervening sequence unbound by ParR. The two ParR protein complexes on parC do not complex with each other. ParR binds with a stoichiometry of about one ParR dimer per each single iteron. The measured DNA fragment lengths agreed with B-form DNA and each of the two parC 5-fold interon DNA stretches adopts a linear path in its complex with ParR. However, the overall parC/ParR complex with both iteron repeats bound by ParR forms an overall U-shaped structure: the DNA folds back on itself nearly completely, including an angle of ∼150°. Analysing linear DNA fragments, we never observed dimerized ParR complexes on one parC DNA molecule (intramolecular) nor a dimerization between ParR complexes bound to two different parC DNA molecules (intermolecular). This bacterial segrosome is compared to other bacterial segregation complexes. We speculate that partition complexes might have a similar overall structural organization and, at least in part, common functional properties

The H.E.S.S. II GRB Program

Gamma-ray bursts (GRBs) are some of the most energetic and exotic events in the Universe, however their behaviour at the highest energies (>10 GeV) is largely unknown. Although the Fermi-LAT space telescope has detected several GRBs in this energy range, it is limited by the relatively small collection area of the instrument. The H.E.S.S. experiment has now entered its second phase by adding a fifth telescope of 600 m$^{2}$ mirror area to the centre of the array. This new telescope increases the energy range of the array, allowing it to probe the sub-100 GeV range while maintaining the large collection area of ground based gamma-ray observatories, essential to probing short-term variability at these energies. We will present a description of the GRB observation scheme used by the H.E.S.S. experiment, summarising the behaviour and performance of the rapid GRB repointing system, the conditions under which potential GRB repointings are made and the data analysis scheme used for these observations.Comment: In Proceedings of the 34th International Cosmic Ray Conference (ICRC2015), The Hague, The Netherland

Core-coupled states and split proton-neutron quasi-particle multiplets in 122-126Ag

Neutron-rich silver isotopes were populated in the fragmentation of a 136Xe beam and the relativistic fission of 238U. The fragments were mass analyzed with the GSI Fragment separator and subsequently implanted into a passive stopper. Isomeric transitions were detected by 105 HPGe detectors. Eight isomeric states were observed in 122-126Ag nuclei. The level schemes of 122,123,125Ag were revised and extended with isomeric transitions being observed for the first time. The excited states in the odd-mass silver isotopes are interpreted as core-coupled states. The isomeric states in the even-mass silver isotopes are discussed in the framework of the proton-neutron split multiplets. The results of shell-model calculations, performed for the most neutron-rich silver nuclei are compared to the experimental data

Novel PI3Kγ Mutation in a 44-Year-Old Man with Chronic Infections and Chronic Pelvic Pain

A 44-year-old man is presented here with 14 years of chronic purulent sinusitis, a chronic fungal rash of the scrotum, and chronic pelvic pain. Treatment with antifungal therapy resulted in symptom improvement, however he was unable to establish an effective long-term treatment regimen, resulting in debilitating symptoms. He had undergone extensive work-up without identifying a clear underlying etiology, although Candida species were cultured from the prostatic fluid. 100 genes involved in the cellular immune response were sequenced and a missense mutation was identified in the Ras-binding domain of PI3Kγ. PI3Kγ is a crucial signaling element in leukotaxis and other leukocyte functions. We hypothesize that his mutation led to his chronic infections and pelvic pain

Trisomic dose of several chromosome 21 genes perturbs haematopoietic stem and progenitor cell differentiation in Down's syndrome

Children with Down's syndrome (DS) have 20–50-fold higher incidence of all leukaemias (lymphoid and myeloid), for reasons not understood. As incidence of many solid tumours is much lower in DS, we speculated that disturbed early haematopoietic differentiation could be the cause of increased leukaemia risk. If a common mechanism is behind the risk of both major leukaemia types, it would have to arise before the bifurcation to myeloid and lymphoid lineages. Using the transchromosomic system (mouse embryonic stem cells (ESCs)) bearing an extra human chromosome 21 (HSA21)) we analyzed the early stages of haematopoietic commitment (mesodermal colony formation) in vitro. We observed that trisomy 21 (T21) causes increased production of haemogenic endothelial cells, haematopoietic stem cell precursors and increased colony forming potential, with significantly increased immature progenitors. Transchromosomic colonies showed increased expression of Gata-2, c-Kit and Tie-2. A panel of partial T21 ESCs allowed us to assign these effects to HSA21 sub-regions, mapped by 3.5 kbp-resolution tiling arrays. The Gata-2 increase on one side, and c-Kit and Tie-2 increases on the other, could be attributed to two different, non-overlapping HSA21 regions. Using human-specific small interfering RNA silencing, we could demonstrate that an extra copy of RUNX1, but not ETS-2 or ERG, causes an increase in Tie-2/c-Kit levels. Finally, we detected significantly increased levels of RUNX1, C-KIT and PU.1 in human foetal livers with T21. We conclude that overdose of more than one HSA21 gene contributes to the disturbance of early haematopoiesis in DS, and that one of the contributors is RUNX1. As the observed T21-driven hyperproduction of multipotential immature precursors precedes the bifurcation to lymphoid and myeloid lineages, we speculate that this could create conditions of increased chance for acquisition of pre-leukaemogenic rearrangements/mutations in both lymphoid and myeloid lineages during foetal haematopoiesis, contributing to the increased risk of both leukaemia types in DS

Exome sequencing of an isolated Chilean population affected by Specific Language Impairment (SLI)

Speech and language impairments that are a primary deficit and have no obvious cause (e.g. a comorbid neurological disorder like autism) are diagnosed as Specific Language Impairment (SLI). SLI affects 5–8 % of preschool children and represents a lifelong disability associated with an increased risk of behavioural disorders, social problems and literacy deficits. SLI is highly heritable and twin studies indicate a strong genetic basis. Nonetheless, the underlying genetic mechanisms are expected to be multifactorial and, to date, only three risk variants have been identified. One way to increase the power to detect contributory genetic factors is to study isolated populations derived from relatively recent shared ancestors (founder populations). In 2008, Villanueva described a founder population with a particularly high incidence of SLI (10 times that expected). They inhabit the Robinson Crusoe Island, which lies 677 km to the west of Chile and was colonised in the late 19th century by 8 European and Amerindian families. 77 % of the current island population have a colonising surname and 14 % of marriages involve consanguineous unions. More than 80 % of language impaired individuals can be traced to a pair of founder brothers. This population thus has a short (5-generations) and well documented history and represents a unique resource which could make valuable contributions to the elucidation of genetic mechanisms underpinning SLI. We applied exome sequencing technologies to five language impaired individuals from this population and identified nine nonsynonymous coding changes or splice site mutations that were present in at least three of the five affected individuals sequenced. Sequencing of the entire cohort identified a single non-synonymous coding change that was significantly more frequent in cases than controls (genotype frequencies of 46 and 11 % respectively, p = 4.48 9 10-5). We suggest that this rare coding variant may contribute to the elevated frequency of SLI in this population

Next-generation DNA sequencing identifies novel gene variants and pathways involved in specific language impairment

A significant proportion of children have unexplained problems acquiring proficient linguistic skills despite adequate intelligence and opportunity. Developmental language disorders are highly heritable with substantial societal impact. Molecular studies have begun to identify candidate loci, but much of the underlying genetic architecture remains undetermined. We performed whole-exome sequencing of 43 unrelated probands affected by severe specific language impairment, followed by independent validations with Sanger sequencing, and analyses of segregation patterns in parents and siblings, to shed new light on aetiology. By first focusing on a pre-defined set of known candidates from the literature, we identified potentially pathogenic variants in genes already implicated in diverse language-related syndromes, including ERC1, GRIN2A, and SRPX2. Complementary analyses suggested novel putative candidates carrying validated variants which were predicted to have functional effects, such as OXR1, SCN9A and KMT2D. We also searched for potential "multiple-hit" cases; one proband carried a rare AUTS2 variant in combination with a rare inherited haplotype affecting STARD9, while another carried a novel nonsynonymous variant in SEMA6D together with a rare stop-gain in SYNPR. On broadening scope to all rare and novel variants throughout the exomes, we identified biological themes that were enriched for such variants, including 36 microtubule transport and cytoskeletal regulation

Accurate and exact CNV identification from targeted high-throughput sequence data

<p>Abstract</p> <p>Background</p> <p>Massively parallel sequencing of barcoded DNA samples significantly increases screening efficiency for clinically important genes. Short read aligners are well suited to single nucleotide and indel detection. However, methods for CNV detection from targeted enrichment are lacking. We present a method combining coverage with map information for the identification of deletions and duplications in targeted sequence data.</p> <p>Results</p> <p>Sequencing data is first scanned for gains and losses using a comparison of normalized coverage data between samples. CNV calls are confirmed by testing for a signature of sequences that span the CNV breakpoint. With our method, CNVs can be identified regardless of whether breakpoints are within regions targeted for sequencing. For CNVs where at least one breakpoint is within targeted sequence, exact CNV breakpoints can be identified. In a test data set of 96 subjects sequenced across ~1 Mb genomic sequence using multiplexing technology, our method detected mutations as small as 31 bp, predicted quantitative copy count, and had a low false-positive rate.</p> <p>Conclusions</p> <p>Application of this method allows for identification of gains and losses in targeted sequence data, providing comprehensive mutation screening when combined with a short read aligner.</p