P-Element Homing Is Facilitated by engrailed Polycomb-Group Response Elements in Drosophila melanogaster

P-element vectors are commonly used to make transgenic Drosophila and generally insert in the genome in a nonselective manner. However, when specific fragments of regulatory DNA from a few Drosophila genes are incorporated into P-transposons, they cause the vectors to be inserted near the gene from which the DNA fragment was derived. This is called P-element homing. We mapped the minimal DNA fragment that could mediate homing to the engrailed/invected region of the genome. A 1.6 kb fragment of engrailed regulatory DNA that contains two Polycomb-group response elements (PREs) was sufficient for homing. We made flies that contain a 1.5kb deletion of engrailed DNA (enΔ1.5) in situ, including the PREs and the majority of the fragment that mediates homing. Remarkably, homing still occurs onto the enΔ1. 5 chromosome. In addition to homing to en, P[en] inserts near Polycomb group target genes at an increased frequency compared to P[EPgy2], a vector used to generate 18,214 insertions for the Drosophila gene disruption project. We suggest that homing is mediated by interactions between multiple proteins bound to the homing fragment and proteins bound to multiple areas of the engrailed/invected chromatin domain. Chromatin structure may also play a role in homing

Dust Emission from Evolved and Unevolved HII Regions in the Large Magellanic Cloud

We present a study of the dust properties of 12 classical and superbubble HII regions in the Large Magellanic Cloud. We use infrared photometry from Spitzer (8, 24, 70, and 160 \mum bands), obtained as part of the Surveying the Agents of a Galaxy's Evolution (SAGE) program, along with archival spectroscopic classifications of the ionizing stars to examine the role of stellar sources on dust heating and processing. Our infrared observations show surprisingly little correlation between the emission properties of the dust and the effective temperatures or bolometric magnitudes of stars in the HII regions, suggesting that the HII region evolutionary timescale is not on the order of the dust processing timescale. We find that the infrared emission of superbubbles and classical HII regions shows little differentiation between the two classes, despite the significant differences in age and morphology. We do detect a correlation of the 24 \mum emission from hot dust with the ratio of 70 to 160 \mum flux. This correlation can be modeled as a trend in the temperature of a minority hot dust component, while a majority of the dust remains significantly cooler.Comment: 15 pages, 5 figures. Accepted to Ap

A contemporaneous infrared flash from a long gamma-ray burst: an echo from the central engine

The explosion that results in a cosmic gamma-ray burst (GRB) is thought to produce emission from two physical processes -- the activity of the central engine gives rise to the high-energy emission of the burst through internal shocking and the subsequent interaction of the flow with the external environment produces long-wavelength afterglow. While afterglow observations continue to refine our understanding of GRB progenitors and relativistic shocks, gamma-ray observations alone have not yielded a clear picture of the origin of the prompt emission nor details of the central engine. Only one concurrent visible-light transient has been found and was associated with emission from an external shock. Here we report the discovery of infrared (IR) emission contemporaneous with a GRB, beginning 7.2 minutes after the onset of GRB 041219a. Our robotic telescope acquired 21 images during the active phase of the burst, yielding the earliest multi-colour observations of any long-wavelength emission associated with a GRB. Analysis of an initial IR pulse suggests an origin consistent with internal shocks. This opens a new possibility to study the central engine of GRBs with ground-based observations at long wavelengths.Comment: Accepted to Nature on March 1, 2005. 9 pages, 4 figures, nature12.cls and nature1.cls files included. This paper is under press embargo until print publicatio

Keck-I MOSFIRE spectroscopy of compact star-forming galaxies at z≳\gtrsim2: High velocity dispersions in progenitors of compact quiescent galaxies

We present Keck-I MOSFIRE near-infrared spectroscopy for a sample of 13 compact star-forming galaxies (SFGs) at redshift $2\leq z \leq2.5$ with star formation rates of SFR$\sim$100M$_{\odot}$ y$^{-1}$ and masses of log(M/M$_{\odot}$)$\sim10.8$. Their high integrated gas velocity dispersions of $\sigma_{\rm{int}}$=230$^{+40}_{-30}$ km s$^{-1}$, as measured from emission lines of H$_{\alpha}$ and [OIII], and the resultant M$_{\star}-\sigma_{\rm{int}}$ relation and M$_{\star}$$-$M$_{\rm{dyn}}$ all match well to those of compact quiescent galaxies at $z\sim2$, as measured from stellar absorption lines. Since log(M$_{\star}$/M$_{\rm{dyn}}$)$=-0.06\pm0.2$ dex, these compact SFGs appear to be dynamically relaxed and more evolved, i.e., more depleted in gas and dark matter ($<$13$^{+17}_{-13}$\%) than their non-compact SFG counterparts at the same epoch. Without infusion of external gas, depletion timescales are short, less than $\sim$300 Myr. This discovery adds another link to our new dynamical chain of evidence that compact SFGs at $z\gtrsim2$ are already losing gas to become the immediate progenitors of compact quiescent galaxies by $z\sim2$.Comment: 12 pages, 7 figures, submitted to Ap

Inhibition of Y1 receptor signaling improves islet transplant outcome

Failure to secrete sufficient quantities of insulin is a pathological feature of type-1 and type-2 diabetes, and also reduces the success of islet cell transplantation. Here we demonstrate that Y1 receptor signaling inhibits insulin release in β-cells, and show that this can be pharmacologically exploited to boost insulin secretion. Transplanting islets with Y1 receptor deficiency accelerates the normalization of hyperglycemia in chemically induced diabetic recipient mice, which can also be achieved by short-term pharmacological blockade of Y1 receptors in transplanted mouse and human islets. Furthermore, treatment of non-obese diabetic mice with a Y1 receptor antagonist delays the onset of diabetes. Mechanistically, Y1 receptor signaling inhibits the production of cAMP in islets, which via CREB mediated pathways results in the down-regulation of several key enzymes in glycolysis and ATP production. Thus, manipulating Y1 receptor signaling in β-cells offers a unique therapeutic opportunity for correcting insulin deficiency as it occurs in the pathological state of type-1 diabetes as well as during islet transplantation.Islet transplantation is considered one of the potential treatments for T1DM but limited islet survival and their impaired function pose limitations to this approach. Here Loh et al. show that the Y1 receptor is expressed in β- cells and inhibition of its signalling, both genetic and pharmacological, improves mouse and human islet function.info:eu-repo/semantics/publishe

Homocysteine metabolism pathway is involved in the control of glucose homeostasis: a cystathionine beta synthase deficiency study in mouse

Cystathionine beta synthase (CBS) catalyzes the first step of the transsulfuration pathway from homocysteine to cystathionine, and its deficiency leads to hyperhomocysteinemia (HHcy) in humans and rodents. To date, scarce information is available about the HHcy effect on insulin secretion, and the link between CBS activity and the setting of type 2 diabetes is still unknown. We aimed to decipher the consequences of an inborn defect in CBS on glucose homeostasis in mice. We used a mouse model heterozygous for CBS (CBS+/-) that presented a mild HHcy. Other groups were supplemented with methionine in drinking water to increase the mild to intermediate HHcy, and were submitted to a high-fat diet (HFD). We measured the food intake, body weight gain, body composition, glucose homeostasis, plasma homocysteine level, and CBS activity. We evidenced a defect in the stimulated insulin secretion in CBS+/- mice with mild and intermediate HHcy, while mice with intermediate HHcy under HFD presented an improvement in insulin sensitivity that compensated for the decreased insulin secretion and permitted them to maintain a glucose tolerance similar to the CBS+/+ mice. Islets isolated from CBS+/- mice maintained their ability to respond to the elevated glucose levels, and we showed that a lower parasympathetic tone could, at least in part, be responsible for the insulin secretion defect. Our results emphasize the important role of Hcy metabolic enzymes in insulin secretion and overall glucose homeostasis

Operational Performance of MOSFIRE with Its Cryogenic Configurable Slitmask Unit at the W. M. Keck Observatory

The Multi-Object Spectrograph for Infrared Exploration (MOSFIRE) achieved first light on the W. M. Keck Observatory’s Keck I telescope on 4 April 2012 and quickly became the most popular Keck I instrument. One of the primary reasons for the instrument’s popularity is that it uses a configurable slitmask unit developed by the Centre Suisse d’Electronique et Microtechnique (CSEM SA) to isolate the light from up to 46 objects simultaneously. In collaboration with the instrument development team and CSEM engineers, the Keck observatory staff present how MOSFIRE is successfully used, and we identify what contributed to routine and trouble free nighttime operations

A Small Molecule Inhibitor of PDK1/PLC gamma 1 Interaction Blocks Breast and Melanoma Cancer Cell Invasion

Strong evidence suggests that phospholipase Cγ1 (PLCγ1) is a suitable target to counteract tumourigenesis and metastasis dissemination. We recently identified a novel signalling pathway required for PLCγ1 activation which involves formation of a protein complex with 3-phosphoinositide-dependent protein kinase 1 (PDK1). In an effort to define novel strategies to inhibit PLCγ1-dependent signals we tested here whether a newly identified and highly specific PDK1 inhibitor, 2-O-benzyl-myo-inositol 1,3,4,5,6-pentakisphosphate (2-O-Bn-InsP5), could affect PDK1/PLCγ1 interaction and impair PLCγ1-dependent cellular functions in cancer cells. Here, we demonstrate that 2-O-Bn-InsP5 interacts specifically with the pleckstrin homology domain of PDK1 and impairs formation of a PDK1/PLCγ1 complex. 2-O-Bn-InsP5 is able to inhibit the epidermal growth factor-induced PLCγ1 phosphorylation and activity, ultimately resulting in impaired cancer cell migration and invasion. Importantly, we report that 2-O-Bn-InsP5 inhibits cancer cell dissemination in zebrafish xenotransplants. This work demonstrates that the PDK1/PLCγ1 complex is a potential therapeutic target to prevent metastasis and it identifies 2-O-Bn-InsP5 as a leading compound for development of anti-metastatic drugs

Machine learning methods applied to genotyping data capture interactions between single nucleotide variants in late onset Alzheimer's disease

Introduction Genome-wide association studies (GWAS) in late onset Alzheimer's disease (LOAD) provide lists of individual genetic determinants. However, GWAS do not capture the synergistic effects among multiple genetic variants and lack good specificity. Methods We applied tree-based machine learning algorithms (MLs) to discriminate LOAD (>700 individuals) and age-matched unaffected subjects in UK Biobank with single nucleotide variants (SNVs) from Alzheimer's disease (AD) studies, obtaining specific genomic profiles with the prioritized SNVs. Results MLs prioritized a set of SNVs located in genes PVRL2, TOMM40, APOE, and APOC1, also influencing gene expression and splicing. The genomic profiles in this region showed interaction patterns involving rs405509 and rs1160985, also present in the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. rs405509 located in APOE promoter interacts with rs429358 among others, seemingly neutralizing their predisposing effect. Discussion Our approach efficiently discriminates LOAD from controls, capturing genomic profiles defined by interactions among SNVs in a hot-spot region