High-mass Starless Clumps in the inner Galactic Plane: the Sample and Dust Properties

We report a sample of 463 high-mass starless clump (HMSC) candidates within $-60\deg<l<60\deg$ and $-1\deg<b<1\deg$. This sample has been singled out from 10861 ATLASGAL clumps. All of these sources are not associated with any known star-forming activities collected in SIMBAD and young stellar objects identified using color-based criteria. We also make sure that the HMSC candidates have neither point sources at 24 and 70 \micron~nor strong extended emission at 24 $\mu$m. Most of the identified HMSCs are infrared ($\le24$ $\mu$m) dark and some are even dark at 70 $\mu$m. Their distribution shows crowding in Galactic spiral arms and toward the Galactic center and some well-known star-forming complexes. Many HMSCs are associated with large-scale filaments. Some basic parameters were attained from column density and dust temperature maps constructed via fitting far-infrared and submillimeter continuum data to modified blackbodies. The HMSC candidates have sizes, masses, and densities similar to clumps associated with Class II methanol masers and HII regions, suggesting they will evolve into star-forming clumps. More than 90% of the HMSC candidates have densities above some proposed thresholds for forming high-mass stars. With dust temperatures and luminosity-to-mass ratios significantly lower than that for star-forming sources, the HMSC candidates are externally heated and genuinely at very early stages of high-mass star formation. Twenty sources with equivalent radius $r_\mathrm{eq}<0.15$ pc and mass surface density $\Sigma>0.08$ g cm$^{-2}$ could be possible high-mass starless cores. Further investigations toward these HMSCs would undoubtedly shed light on comprehensively understanding the birth of high-mass stars.Comment: 16 pages, 15 figures, and 5 tables. Accepted for publication in ApJS. FITS images for the far-IR to sub-mm data, H2 column density and dust temperature maps of all the HMSC candidates are available at https: //yuanjinghua.github.io/hmscs.html. Codes used for this work are publicly available from https://github.com/yuanjinghua/HMSCs_ca

The Oracle Problem When Testing from MSCs

Message Sequence Charts (MSCs) form a popular language in which scenario-based specifications and models can be written. There has been significant interest in automating aspects of testing from MSCs. This paper concerns the Oracle Problem, in which we have an observation made in testing and wish to know whether this is consistent with the specification. We assume that there is an MSC specification and consider the case where we have entirely independent local testers (local observability) and where the observations of the local testers are logged and brought together (tester observability). It transpires that under local observability the Oracle Problem can be solved in low-order polynomial time if we use sequencing, loops and choices but becomes NP-complete if we also allow parallel components; if we place a bound on the number of parallel components then it again can be solved in polynomial time. For tester observability, the problem is NP-complete when we have either loops or choices. However, it can be solved in low-order polynomial time if we have only one loop, no choices, and no parallel components. If we allow parallel components then the Oracle Problem is NP-complete for tester observability even if we restrict to the case where there are at most two processes

Anti-Tumor Effects of TRAIL-Expressing Mesenchymal Stromal Cells in a Mouse Xenograft Model of Human Mesothelioma

Malignant mesothelioma (MM) remains a highly deadly malignancy with poor treatment option. The MM cells further promote a highly inflammatory microenvironment which contributes to tumor initiation, development, severity, and propagation. We reasoned that the anti-inflammatory actions of mesenchymal stromal cells (MSCs) and further anti-tumor effects of MSCs engineered to over-express TNF-related apoptosis inducing ligand (TRAIL) protein (MSC-TRAIL) would effectively inhibit mesothelioma growth. Using a mouse xenograft model of intraperitoneal human mesothelioma, native mouse (mMSC) or human (hMSC) MSCs were administered either systemically (IV) or intraperitoneally (IP) at various times following tumor inoculation. Both mMSCs and hMSCs localized at sites of MM tumor growth in vivo and decreased local inflammation. Further, a trend towards decrease in tumor burden was observed. Parallel studies of in vitro exposure of nine primary human mesothelioma cell lines to mMSCs or hMSCs demonstrated reduced tumor cell migration. In contrast MSC-TRAIL exposure induced apoptosis of TRAIL sensitive MM cells in vitro and both mouse and human MSC-TRAIL significantly reduced the inflammatory tumor environment in vivo. Moreover human MSC-TRAIL administration significantly reduced peritoneal tumor burden in vivo and increased tumor cell apoptosis. These proof-of-concept studies suggest that TRAIL-expressing MSCs may be useful against malignant mesothelioma

Osteoprotegerin reduces osteoclast resorption activity without affecting osteogenesis on nanoparticulate mineralized collagen scaffolds.

The instructive capabilities of extracellular matrix-inspired materials for osteoprogenitor differentiation have sparked interest in understanding modulation of other cell types within the bone regenerative microenvironment. We previously demonstrated that nanoparticulate mineralized collagen glycosaminoglycan (MC-GAG) scaffolds efficiently induced osteoprogenitor differentiation and bone healing. In this work, we combined adenovirus-mediated delivery of osteoprotegerin (AdOPG), an endogenous anti-osteoclastogenic decoy receptor, in primary human mesenchymal stem cells (hMSCs) with MC-GAG to understand the role of osteoclast inactivation in augmentation of bone regeneration. Simultaneous differentiation of osteoprogenitors on MC-GAG and osteoclast progenitors resulted in bidirectional positive regulation. AdOPG expression did not affect osteogenic differentiation alone. In the presence of both cell types, AdOPG-transduced hMSCs on MC-GAG diminished osteoclast-mediated resorption in direct contact; however, osteoclast-mediated augmentation of osteogenic differentiation was unaffected. Thus, the combination of OPG with MC-GAG may represent a method for uncoupling osteogenic and osteoclastogenic differentiation to augment bone regeneration

Utilizing osteocyte derived factors to enhance cell viability and osteogenic matrix deposition within IPN hydrogels

Many bone defects arising due to traumatic injury, disease, or surgery are unable to regenerate, requiring intervention. More than four million graft procedures are performed each year to treat these defects making bone the second most commonly transplanted tissue worldwide. However, these types of graft suffer from a limited supply, a second surgical site, donor site morbidity, and pain. Due to the unmet clinical need for new materials to promote skeletal repair, this study aimed to produce novel biomimetic materials to enhance stem/stromal cell osteogenesis and bone repair by recapitulating aspects of the biophysical and biochemical cues found within the bone microenvironment. Utilizing a collagen type I-alginate interpenetrating polymer network we fabricated a material which mirrors the mechanical and structural properties of unmineralized bone, consisting of a porous fibrous matrix with a young's modulus of 64 kPa, both of which have been shown to enhance mesenchymal stromal/stem cell (MSC) osteogenesis. Moreover, by combining this material with biochemical paracrine factors released by statically cultured and mechanically stimulated osteocytes, we further mirrored the biochemical environment of the bone niche, enhancing stromal/stem cell viability, differentiation, and matrix deposition. Therefore, this biomimetic material represents a novel approach to promote skeletal repair

Reliability prediction in model driven development

Evaluating the implications of an architecture design early in the software development lifecycle is important in order to reduce costs of development. Reliability is an important concern with regard to the correct delivery of software system service. Recently, the UML Profile for Modeling Quality of Service has defined a set of UML extensions to represent dependability concerns (including reliability) and other non-functional requirements in early stages of the software development lifecycle. Our research has shown that these extensions are not comprehensive enough to support reliability analysis for model-driven software engineering, because the description of reliability characteristics in this profile lacks support for certain dynamic aspects that are essential in modeling reliability. In this work, we define a profile for reliability analysis by extending the UML 2.0 specification to support reliability prediction based on scenario specifications. A UML model specified using the profile is translated to a labelled transition system (LTS), which is used for automated reliability prediction and identification of implied scenarios; the results of this analysis are then fed back to the UML model. The result is a comprehensive framework for addressing software reliability modeling, including analysis and evolution of reliability predictions. We exemplify our approach using the Boiler System used in previous work and demonstrate how reliability analysis results can be integrated into UML models

Tissue inhibitor of metalloproteinase-1 (TIMP-1) regulates mesenchymal stem cells through let-7f microRNA and Wnt/β-catenin signaling

Tissue inhibitor of metalloproteinases 1 (TIMP-1) is a matrix metalloproteinase (MMP)-independent regulator of growth and apoptosis in various cell types. The receptors and signaling pathways that are involved in the growth factor activities of TIMP-1, however, remain controversial. RNA interference of TIMP-1 has revealed that endogenous TIMP-1 suppresses the proliferation, metabolic activity, and osteogenic differentiation capacity of human mesenchymal stem cells (hMSCs). The knockdown of TIMP-1 in hMSCs activated the Wnt/β-catenin signaling pathway as indicated by the increased stability and nuclear localization of β-catenin in TIMP-1–deficient hMSCs. Moreover, TIMP-1 knockdown cells exhibited enhanced β-catenin transcriptional activity, determined by Wnt/β-catenin target gene expression analysis and a luciferase-based β-catenin– activated reporter assay. An analysis of a mutant form of TIMP-1 that cannot inhibit MMP indicated that the effect of TIMP-1 on β-catenin signaling is MMP independent. Furthermore, the binding of CD63 to TIMP-1 on the surface of hMSCs is essential for the TIMP-1–mediated effects on Wnt/β-catenin signaling. An array analysis of microRNAs (miRNAs) and transfection studies with specific miRNA inhibitors and mimics showed that let-7f miRNA is crucial for the regulation of β-catenin activity and osteogenic differentiation by TIMP-1. Let-7f was up-regulated in TIMP-1–depleted hMSCs and demonstrably reduced axin 2, an antagonist of β-catenin stability. Our results demonstrate that TIMP-1 is a direct regulator of hMSC functions and reveal a regulatory network in which let-7f modulates Wnt/β-catenin activity

Efficient generation of neural stem cell-like cells from adult human bone marrow stromal cells

Clonogenic neural stem cells (NSCs) are self-renewing cells that maintain the capacity to differentiate into brain-specific cell types, and may also replace or repair diseased brain tissue. NSCs can be directly isolated from fetal or adult nervous tissue, or derived from embryonic stem cells. Here, we describe the efficient conversion of human adult bone marrow stromal cells (hMSC) into a neural stem cell-like population (hmNSC, for human marrow-derived NSC-like cells). These cells grow in neurosphere-like structures, express high levels of early neuroectodermal markers, such as the proneural genes NeuroD1, Neurog2, MSl1 as well as otx1 and nestin, but lose the characteristics of mesodermal stromal cells. In the presence of selected growth factors, hmNSCs can be differentiated into the three main neural phenotypes: astroglia, oligodendroglia and neurons. Clonal analysis demonstrates that individual hmNSCs are multipotent and retain the capacity to generate both glia and neurons. Our cell culture system provides a powerful tool for investigating the molecular mechanisms of neural differentiation in adult human NSCs. hmNSCs may therefore ultimately help to treat acute and chronic neurodegenerative diseases