The effect of habitat composition on sexual conflict in the seaweed flies Coelopa frigida and C. pilipes

Despite the recent explosion of interest in sexual conflict, the effect of environmental conditions on the intensity of sexual conflict within populations has been largely ignored. Reproductive encounters within coelopids are characterized by sexual conflict in the form of intense harassment by males, usually resulting in a vigorous premating struggle. We investigated the effect of habitat composition and duration of exposure to oviposition sites on the level of sexual harassment by males and mating success in two species of European seaweed flies, Coelopa frigida and C. pilipes. The wrack beds inhabited by these two species are dominated by two genera of brown algae, Fucus and Laminaria, the relative proportions of which can vary considerably between wrack beds. Fucus is known to stimulate harassment by males, increase copulation duration and induce females to oviposit in both species. In this study Laminaria stimulated a higher level of harassment by male C. frigida than Fucus did. However, a similar effect was not observed in C. pilipes, with the main additional factor affecting harassment in this species being the age of the male. Our study highlights the potential importance of environmental conditions on the intensity of sexual conflict within a population. We discuss the evolutionary significance of these observed effects in seaweed flies

Cell adhesion molecule CD166 drives malignant progression and osteolytic disease in multiple myeloma

Multiple myeloma (MM) is incurable once osteolytic lesions have seeded at skeletal sites, but factors mediating this deadly pathogenic advance remain poorly understood. Here we report evidence of a major role for the cell adhesion molecule CD166, which we discovered to be highly expressed in MM cell lines and primary bone marrow (BM) cells from patients. CD166+ MM cells homed more efficiently than CD166− cells to the BM of engrafted immunodeficient NSG mice. CD166 silencing in MM cells enabled longer survival, a smaller tumor burden and less osteolytic lesions, as compared to mice bearing control cells. CD166 deficiency in MM cell lines or CD138+ BM cells from MM patients compromised their ability to induce bone resorption in an ex vivo organ culture system. Further, CD166 deficiency in MM cells also reduced formation of osteolytic disease in vivo after intra-tibial engraftment. Mechanistic investigation revealed that CD166 expression in MM cells inhibited osteoblastogenesis of BM-derived osteoblast progenitors by suppressing RUNX2 gene expression. Conversely, CD166 expression in MM cells promoted osteoclastogenesis by activating TRAF6-dependent signaling pathways in osteoclast progenitors. Overall, our results define CD166 as a pivotal director in MM cell homing to the BM and MM progression, rationalizing its further study as a candidate therapeutic target for MM treatment

ROLE OF CD166 IN MULTIPLE MYELOMA CELL HOMING TO THE BONE MARROW MICROENVIRONMENT AND DISEASE PROGRESSION

poster abstractMultiple myeloma (MM) is a plasma cell malignancy characterized by multiple lytic lesions throughout the skeleton, suggesting that trafficking of MM cells from the bone marrow (BM) and lodgment of these cells at secondary sites is important in disease progression. CD38+CD138- MM cells were previously characterized as putative MM stem cells (MMSC, Cancer Res. 2008; 68(1):190-7.). We analyzed CD38+CD138- cells contained within the MM cell line H929 and determined that a fraction of these cells (29.9%±1.4%) expresses CD166. CD166 is a member of the immunoglobulin superfamily capable of mediating both homophilic and heterophilic (CD6) interactions and has been shown to enhance metastasis and invasion in several tumors including breast cancer and melanoma. Studies from our laboratory suggest that CD38+CD138-CD166+ MM cells possess many functional properties commonly associated with MMSC including cell cycle quiescence, maintenance and propagation of daughter cells on a stromal substrate and gene expression profile. We hypothesized that CD166 promotes MM cell trafficking to the BM and is critical for disease progression. To test this hypothesis, H929-GFP myeloma cells were injected intravenously into NSG mice and GFP cells were recovered from the BM 14hr later. While only 3.3%±1.5% of total H929-GFP cells express the CD38+CD138- phenotype, the frequency of CD38+CD138- cells contained in BM-homed H929-GFP cells was significantly higher (53.4%±3.7%, n=3, p<0.01), suggesting a preferential homing of MMSC to the marrow microenvironment. Interestingly, whereas only 29.9%±1.4% of CD38+CD138- cells expressed CD166 prior to injection, 84.1%±10.8% of BM-homed H929-GFP CD38+CD138- cells expressed CD166 (n=3, p<0.01), suggesting that CD166 plays a critical role in directing homing of MM cells to the BM. Next, CD166 expression on H929-GFP cells was knocked down (KD) with shRNA in order to examine if reduced CD166 expression inhibit the homing of MM cells to the BM. The number of BM-homed GFP cells was significantly decreased for CD166KD cells (5658±904, n=6) compared to mock control (8551±848, n=6; p<0.05). Interestingly, cells in which suppression of CD166 expression was not achieved with shRNA homed preferentially to the BM (4.3%±0.3% CD166+cells in CD166 KD H929-GFP before injection versus 29.3%±3.6% in BM-homed GFP cells). Then we compared the progression of MM in NSG mice initiated with mock control or CD166 KD H929-GFP cells. Disease progression in mice receiving control cells was more rapid compared to that in mice receiving CD166KD cells as evidenced by serum levels of human IgA (kappa) at 4 weeks posttransplantation (240.5±67.1ng/ml versus 45.1±33.0ng/ml, n=3; p<0.05). We next examined the potential role of CD166 in osteolytic lesions using a novel Ex Vivo Organ Culture Assay (EVOCA) in which MM cells are co-cultured over calvariae from 10d-old pups for 7 days creating an in vitro 3D system for the interaction of MM cells with bone microenvironment. Data from EVOCA with H929 cells showed that bone osteolytic lesions are substantially reduced when CD166 is absent on either MM (CD166- fraction) or osteoblast lineage cells (calvariae from CD166-/- mice). Furthermore, co-culturing CD166+ or CD166- H929 cells with bone marrow stromal cells (BMSC) from WT or CD166-/- mice revealed that mRNA levels of receptor activator of NF-κB ligand (RANKL) are decreased when CD166 is absent on either MM or stromal cells while mRNA levels of osteoprotegerin (OPG), an important inhibitor of osteoclastogenesis, are not altered. This resulted in decreased RANKL/OPG ratios in cultures containing a CD166- component suggesting reduced MM-induced osteoclastogenesis in the absence of CD166. Interestingly, levels of M-CSF and IL-6 were similar in all these cultures suggesting that loss of CD166 may mediate suppression of osteolytic lesions through the downregulation of RANKL. Together, these results suggest that CD166 plays an important role in homing and retention of MM cells in the BM and promotes MM disease progression as well as bone-lytic disease and that CD166 may serve as a therapeutic target in the treatment of MM

Software Development Standard Processes (SDSP)

A JPL-created set of standard processes is to be used throughout the lifecycle of software development. These SDSPs cover a range of activities, from management and engineering activities, to assurance and support activities. These processes must be applied to software tasks per a prescribed set of procedures. JPL s Software Quality Improvement Project is currently working at the behest of the JPL Software Process Owner to ensure that all applicable software tasks follow these procedures. The SDSPs are captured as a set of 22 standards in JPL s software process domain. They were developed in-house at JPL by a number of Subject Matter Experts (SMEs) residing primarily within the Engineering and Science Directorate, but also from the Business Operations Directorate and Safety and Mission Success Directorate. These practices include not only currently performed best practices, but also JPL-desired future practices in key thrust areas like software architecting and software reuse analysis. Additionally, these SDSPs conform to many standards and requirements to which JPL projects are beholden

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase&nbsp;1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation&nbsp;disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age&nbsp; 6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score&nbsp; 652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc&nbsp;= 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N&nbsp;= 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in&nbsp;Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in&nbsp;Asia&nbsp;and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701