Key Points• Deletion of Gs␣ in osteocytes induces severe osteopenia and a dramatic expansion of cells of the myeloid lineage.• Osteocytes regulate hematopoiesis and specifically contribute to myelopoiesis by secreting proliferative factors such as G-CSF.

Hyperthermia can be produced by near-infrared laser irradiation of gold nanoparticles present in tumors and thus induce tumor cell killing via a bystander effect. To be clinically relevant, however, several problems still need to be resolved. In particular, selective delivery and physical targeting of gold nanoparticles to tumor cells are necessary to improve therapeutic selectivity. Considerable progress has been made with respect to retargeting adenoviral vectors for cancer gene therapy. We therefore hypothesized that covalent coupling of gold nanoparticles to retargeted adenoviral vectors would allow selective delivery of the nanoparticles to tumor cells, thus feasibilizing hyperthermia and gene therapy as a combinatorial therapeutic approach. For this, sulfo-N-hydroxysuccinimide labeled gold nanoparticles were reacted to adenoviral vectors encoding a luciferase reporter gene driven by the cytomegalovirus promoter (AdCMVLuc). We herein demonstrate that covalent coupling could be achieved, while retaining virus infectivity and ability to retarget tumor-associated antigens. These results indicate the possibility of using adenoviral vectors as carriers for gold nanoparticles.

Background: Osteocytes, the most abundant cells in adult bone, express PPR. Results: Mice with constitutive PPR deletion in osteocytes demonstrate blunted anabolic and catabolic bone responses and the inability to recruit osteoblasts and osteoclasts upon PTH administration. Conclusion: PPR in osteocytes is needed for a full skeletal response to PTH administration. Significance: PPR signaling in osteocytes is necessary for PTH-driven anabolic effects during osteoporosis therapy.

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Source code clones are categorized into four types of increasing difficulty of detection, ranging from purely textual (Type-1) to purely semantic (Type-4). Most clone detectors reported in the literature work well up to Type-3, which accounts for syntactic differences. In between Type-3 and Type-4, however, there lies a spectrum of clones that, although still exhibiting some syntactic similarities, are extremely hard to detect -the Twilight Zone. Most clone detectors reported in the literature fail to operate in this zone. We present Oreo, a novel approach to source code clone detection that not only detects Type-1 to Type-3 clones accurately, but is also capable of detecting harder-to-detect clones in the Twilight Zone. Oreo is built using a combination of machine learning, information retrieval, and software metrics. We evaluate the recall of Oreo on BigCloneBench, and perform manual evaluation for precision. Oreo has both high recall and precision. More importantly, it pushes the boundary in detection of clones with moderate to weak syntactic similarity in a scalable manner.

Previous studies have shown that there is a non-trivial amount of duplication in source code. This paper analyzes a corpus of 4.5 million non-fork projects hosted on GitHub representing over 428 million iles written in Java, C++, Python, and JavaScript. We found that this corpus has a mere 85 million unique iles. In other words, 70% of the code on GitHub consists of clones of previously created iles. There is considerable variation between language ecosystems. JavaScript has the highest rate of ile duplication, only 6% of the iles are distinct. Java, on the other hand, has the least duplication, 60% of iles are distinct. Lastly, a project-level analysis shows that between 9% and 31% of the projects contain at least 80% of iles that can be found elsewhere. These rates of duplication have implications for systems built on open source software as well as for researchers interested in analyzing large code bases. As a concrete artifact of this study, we have created DéjàVu, a publicly available map of code duplicates in GitHub repositories. CCS Concepts: • Information systems → Near-duplicate and plagiarism detection; • Software and its engineering → Ultra-large-scale systems;

Cells of the osteoblast lineage are increasingly identified as participants in whole-body metabolism by primarily targeting pancreatic insulin secretion or consuming energy. Osteocytes, the most abundant bone cells, secrete a Wnt-signaling inhibitor called sclerostin. Here we examined three mouse models expressing high sclerostin levels, achieved through constitutive or inducible loss of the stimulatory subunit of G-proteins (Gsα in mature osteoblasts and/or osteocytes). These mice showed progressive loss of white adipose tissue (WAT) with tendency toward increased energy expenditure but no changes in glucose or insulin metabolism. Interestingly beige adipocytes were increased extensively in both gonadal and inguinal WAT and had reduced canonical β-catenin signaling. To determine if sclerostin directly contributes to the increased beige adipogenesis, we engineered an osteocytic cell line lacking Gsα which has high sclerostin secretion. Conditioned media from these cells significantly increased expression of UCP1 in primary adipocytes, and this effect was partially reduced after depletion of sclerostin from the conditioned media. Similarly, treatment of Gsα-deficient animals with sclerostin-neutralizing antibody partially reduced the increased UCP1 expression in WAT. Moreover, direct treatment of sclerostin to wild-type mice significantly increased UCP1 expression in WAT. These results show that osteocytes and/or osteoblasts secrete factors regulating beige adipogenesis, at least in part, through the Wnt-signaling inhibitor sclerostin. Further studies are needed to assess metabolic effects of sclerostin on adipocytes and other metabolic tissues.

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