Transit Timing and Duration Variations for the Discovery and Characterization of Exoplanets

Transiting exoplanets in multi-planet systems have non-Keplerian orbits which can cause the times and durations of transits to vary. The theory and observations of transit timing variations (TTV) and transit duration variations (TDV) are reviewed. Since the last review, the Kepler spacecraft has detected several hundred perturbed planets. In a few cases, these data have been used to discover additional planets, similar to the historical discovery of Neptune in our own Solar System. However, the more impactful aspect of TTV and TDV studies has been characterization of planetary systems in which multiple planets transit. After addressing the equations of motion and parameter scalings, the main dynamical mechanisms for TTV and TDV are described, with citations to the observational literature for real examples. We describe parameter constraints, particularly the origin of the mass/eccentricity degeneracy and how it is overcome by the high-frequency component of the signal. On the observational side, derivation of timing precision and introduction to the timing diagram are given. Science results are reviewed, with an emphasis on mass measurements of transiting sub-Neptunes and super-Earths, from which bulk compositions may be inferred.Comment: Revised version. Invited review submitted to 'Handbook of Exoplanets,' Exoplanet Discovery Methods section, Springer Reference Works, Juan Antonio Belmonte and Hans Deeg, Eds. TeX and figures may be found at https://github.com/ericagol/TTV_revie

Population genomics of sub-Saharan Drosophila melanogaster: African diversity and non-African admixture

(ABRIDGED) We report the genome sequencing of 139 wild-derived strains of D. melanogaster, representing 22 population samples from the sub-Saharan ancestral range of this species, along with one European population. Most genomes were sequenced above 25X depth from haploid embryos. Results indicated a pervasive influence of non-African admixture in many African populations, motivating the development and application of a novel admixture detection method. Admixture proportions varied among populations, with greater admixture in urban locations. Admixture levels also varied across the genome, with localized peaks and valleys suggestive of a non-neutral introgression process. Genomes from the same location differed starkly in ancestry, suggesting that isolation mechanisms may exist within African populations. After removing putatively admixed genomic segments, the greatest genetic diversity was observed in southern Africa (e.g. Zambia), while diversity in other populations was largely consistent with a geographic expansion from this potentially ancestral region. The European population showed different levels of diversity reduction on each chromosome arm, and some African populations displayed chromosome arm-specific diversity reductions. Inversions in the European sample were associated with strong elevations in diversity across chromosome arms. Genomic scans were conducted to identify loci that may represent targets of positive selection. A disproportionate number of candidate selective sweep regions were located near genes with varied roles in gene regulation. Outliers for Europe-Africa FST were found to be enriched in genomic regions of locally elevated cosmopolitan admixture, possibly reflecting a role for some of these loci in driving the introgression of non-African alleles into African populations

Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas

Summary Sarcomas are a broad family of mesenchymal malignancies exhibiting remarkable histologic diversity. We describe the multi-platform molecular landscape of 206 adult soft tissue sarcomas representing 6 major types. Along with novel insights into the biology of individual sarcoma types, we report three overarching findings: (1) unlike most epithelial malignancies, these sarcomas (excepting synovial sarcoma) are characterized predominantly by copy-number changes, with low mutational loads and only a few genes (TP53, ATRX, RB1) highly recurrently mutated across sarcoma types; (2) within sarcoma types, genomic and regulomic diversity of driver pathways defines molecular subtypes associated with patient outcome; and (3) the immune microenvironment, inferred from DNA methylation and mRNA profiles, associates with outcome and may inform clinical trials of immune checkpoint inhibitors. Overall, this large-scale analysis reveals previously unappreciated sarcoma-type-specific changes in copy number, methylation, RNA, and protein, providing insights into refining sarcoma therapy and relationships to other cancer types

Alignment of the ALICE Inner Tracking System with cosmic-ray tracks

37 pages, 15 figures, revised version, accepted by JINSTALICE (A Large Ion Collider Experiment) is the LHC (Large Hadron Collider) experiment devoted to investigating the strongly interacting matter created in nucleus-nucleus collisions at the LHC energies. The ALICE ITS, Inner Tracking System, consists of six cylindrical layers of silicon detectors with three different technologies; in the outward direction: two layers of pixel detectors, two layers each of drift, and strip detectors. The number of parameters to be determined in the spatial alignment of the 2198 sensor modules of the ITS is about 13,000. The target alignment precision is well below 10 micron in some cases (pixels). The sources of alignment information include survey measurements, and the reconstructed tracks from cosmic rays and from proton-proton collisions. The main track-based alignment method uses the Millepede global approach. An iterative local method was developed and used as well. We present the results obtained for the ITS alignment using about 10^5 charged tracks from cosmic rays that have been collected during summer 2008, with the ALICE solenoidal magnet switched off.Peer reviewe

Star-forming cores embedded in a massive cold clump: Fragmentation, collapse and energetic outflows

The fate of massive cold clumps, their internal structure and collapse need to be characterised to understand the initial conditions for the formation of high-mass stars, stellar systems, and the origin of associations and clusters. We explore the onset of star formation in the 75 M_sun SMM1 clump in the region ISOSS J18364-0221 using infrared and (sub-)millimetre observations including interferometry. This contracting clump has fragmented into two compact cores SMM1 North and South of 0.05 pc radius, having masses of 15 and 10 M_sun, and luminosities of 20 and 180 L_sun. SMM1 South harbours a source traced at 24 and 70um, drives an energetic molecular outflow, and appears supersonically turbulent at the core centre. SMM1 North has no infrared counterparts and shows lower levels of turbulence, but also drives an outflow. Both outflows appear collimated and parsec-scale near-infrared features probably trace the outflow-powering jets. We derived mass outflow rates of at least 4E-5 M_sun/yr and outflow timescales of less than 1E4 yr. Our HCN(1-0) modelling for SMM1 South yielded an infall velocity of 0.14 km/s and an estimated mass infall rate of 3E-5 M_sun/yr. Both cores may harbour seeds of intermediate- or high-mass stars. We compare the derived core properties with recent simulations of massive core collapse. They are consistent with the very early stages dominated by accretion luminosity.Comment: Accepted for publication in ApJ, 14 pages, 7 figure

Survival of the Fittest: Positive Selection of CD4+ T Cells Expressing a Membrane-Bound Fusion Inhibitor Following HIV-1 Infection

Although a variety of genetic strategies have been developed to inhibit HIV replication, few direct comparisons of the efficacy of these inhibitors have been carried out. Moreover, most studies have not examined whether genetic inhibitors are able to induce a survival advantage that results in an expansion of genetically-modified cells following HIV infection. We evaluated the efficacy of three leading genetic strategies to inhibit HIV replication: 1) an HIV-1 tat/rev-specific small hairpin (sh) RNA; 2) an RNA antisense gene specific for the HIV-1 envelope; and 3) a viral entry inhibitor, maC46. In stably transduced cell lines selected such that >95% of cells expressed the genetic inhibitor, the RNA antisense envelope and viral entry inhibitor maC46 provided the strongest inhibition of HIV-1 replication. However, when mixed populations of transduced and untransduced cells were challenged with HIV-1, the maC46 fusion inhibitor resulted in highly efficient positive selection of transduced cells, an effect that was evident even in mixed populations containing as few as 1% maC46-expressing cells. The selective advantage of the maC46 fusion inhibitor was also observed in HIV-1-infected cultures of primary T lymphocytes as well as in HIV-1-infected humanized mice. These results demonstrate robust inhibition of HIV replication with the fusion inhibitor maC46 and the antisense Env inhibitor, and importantly, a survival advantage of cells expressing the maC46 fusion inhibitor both in vitro and in vivo. Evaluation of the ability of genetic inhibitors of HIV-1 replication to confer a survival advantage on genetically-modified cells provides unique information not provided by standard techniques that may be important in the in vivo efficacy of these genes

Functional conservation of the Drosophila hybrid incompatibility gene Lhr

<p>Abstract</p> <p>Background</p> <p>Hybrid incompatibilities such as sterility and lethality are commonly modeled as being caused by interactions between two genes, each of which has diverged separately in one of the hybridizing lineages. The gene <it>Lethal hybrid rescue </it>(<it>Lhr</it>) encodes a rapidly evolving heterochromatin protein that causes lethality of hybrid males in crosses between <it>Drosophila melanogaster </it>females and <it>D. simulans </it>males. Previous genetic analyses showed that hybrid lethality is caused by <it>D. simulans Lhr </it>but not by <it>D. melanogaster Lhr</it>, confirming a critical prediction of asymmetry in the evolution of a hybrid incompatibility gene.</p> <p>Results</p> <p>Here we have examined the functional properties of <it>Lhr </it>orthologs from multiple Drosophila species, including interactions with other heterochromatin proteins, localization to heterochromatin, and ability to complement hybrid rescue in <it>D. melanogaster</it>/<it>D. simulans </it>hybrids. We find that these properties are conserved among most <it>Lhr </it>orthologs, including <it>Lhr </it>from <it>D. melanogaster</it>, <it>D. simulans </it>and the outgroup species <it>D. yakuba</it>.</p> <p>Conclusions</p> <p>We conclude that evolution of the hybrid lethality properties of <it>Lhr </it>between <it>D. melanogaster </it>and <it>D. simulans </it>did not involve extensive loss or gain of functions associated with protein interactions or localization to heterochromatin.</p

Screening of the DNA mismatch repair genes MLH1, MSH2 and MSH6 in a Greek cohort of Lynch syndrome suspected families

<p>Abstract</p> <p>Background</p> <p>Germline mutations in the DNA mismatch repair genes predispose to Lynch syndrome, thus conferring a high relative risk of colorectal and endometrial cancer. The <it>MLH1, MSH2 </it>and <it>MSH6 </it>mutational spectrum reported so far involves minor alterations scattered throughout their coding regions as well as large genomic rearrangements. Therefore, a combination of complete sequencing and a specialized technique for the detection of genomic rearrangements should be conducted during a proper DNA-testing procedure. Our main goal was to successfully identify Lynch syndrome families and determine the spectrum of <it>MLH1</it>, <it>MSH2 </it>and <it>MSH6 </it>mutations in Greek Lynch families in order to develop an efficient screening protocol for the Greek colorectal cancer patients' cohort.</p> <p>Methods</p> <p>Forty-two samples from twenty-four families, out of which twenty two of Greek, one of Cypriot and one of Serbian origin, were screened for the presence of germline mutations in the major mismatch repair genes through direct sequencing and MLPA. Families were selected upon Amsterdam criteria or revised Bethesda guidelines.</p> <p>Results</p> <p>Ten deleterious alterations were detected in twelve out of the twenty-four families subjected to genetic testing, thus our detection rate is 50%. Four of the pathogenic point mutations, namely two nonsense, one missense and one splice site change, are novel, whereas the detected genomic deletion encompassing exon 6 of the <it>MLH1 </it>gene has been described repeatedly in the LOVD database. The average age of onset for the development of both colorectal and endometrial cancer among mutation positive families is 43.2 years.</p> <p>Conclusion</p> <p>The mutational spectrum of the MMR genes investigated as it has been shaped by our analysis is quite heterogeneous without any strong indication for the presence of a founder effect.</p

Cis-by-Trans Regulatory Divergence Causes the Asymmetric Lethal Effects of an Ancestral Hybrid Incompatibility Gene

The Dobzhansky and Muller (D-M) model explains the evolution of hybrid incompatibility (HI) through the interaction between lineage-specific derived alleles at two or more loci. In agreement with the expectation that HI results from functional divergence, many protein-coding genes that contribute to incompatibilities between species show signatures of adaptive evolution, including Lhr, which encodes a heterochromatin protein whose amino acid sequence has diverged extensively between Drosophila melanogaster and D. simulans by natural selection. The lethality of D. melanogaster/D. simulans F1 hybrid sons is rescued by removing D. simulans Lhr, but not D. melanogaster Lhr, suggesting that the lethal effect results from adaptive evolution in the D. simulans lineage. It has been proposed that adaptive protein divergence in Lhr reflects antagonistic coevolution with species-specific heterochromatin sequences and that defects in LHR protein localization cause hybrid lethality. Here we present surprising results that are inconsistent with this coding-sequence-based model. Using Lhr transgenes expressed under native conditions, we find no evidence that LHR localization differs between D. melanogaster and D. simulans, nor do we find evidence that it mislocalizes in their interspecific hybrids. Rather, we demonstrate that Lhr orthologs are differentially expressed in the hybrid background, with the levels of D. simulans Lhr double that of D. melanogaster Lhr. We further show that this asymmetric expression is caused by cis-by-trans regulatory divergence of Lhr. Therefore, the non-equivalent hybrid lethal effects of Lhr orthologs can be explained by asymmetric expression of a molecular function that is shared by both orthologs and thus was presumably inherited from the ancestral allele of Lhr. We present a model whereby hybrid lethality occurs by the interaction between evolutionarily ancestral and derived alleles

RNA interference approaches for treatment of HIV-1 infection

HIV/AIDS is a chronic and debilitating disease that cannot be cured with current antiretroviral drugs. While combinatorial antiretroviral therapy (cART) can potently suppress HIV-1 replication and delay the onset of AIDS, viral mutagenesis often leads to viral escape from multiple drugs. In addition to the pharmacological agents that comprise cART drug cocktails, new biological therapeutics are reaching the clinic. These include gene-based therapies that utilize RNA interference (RNAi) to silence the expression of viral or host mRNA targets that are required for HIV-1 infection and/or replication. RNAi allows sequence-specific design to compensate for viral mutants and natural variants, thereby drastically expanding the number of therapeutic targets beyond the capabilities of cART. Recent advances in clinical and preclinical studies have demonstrated the promise of RNAi therapeutics, reinforcing the concept that RNAi-based agents might offer a safe, effective, and more durable approach for the treatment of HIV/AIDS. Nevertheless, there are challenges that must be overcome in order for RNAi therapeutics to reach their clinical potential. These include the refinement of strategies for delivery and to reduce the risk of mutational escape. In this review, we provide an overview of RNAi-based therapies for HIV-1, examine a variety of combinatorial RNAi strategies, and discuss approaches for ex vivo delivery and in vivo delivery