A clinically relevant model of osteoinduction: a process requiring calcium phosphate and BMP/Wnt signalling

In this study, we investigated a clinically relevant model of in vivo ectopic bone formation utilizing human periosteum derived cells (HPDCs) seeded in a Collagraft carrier and explored the mechanisms by which this process is driven. Bone formation occurred after eight weeks when a minimum of one million HPDCs was loaded on Collagraft carriers and implanted subcutaneously in NMRI nu/nu mice. De novo bone matrix, mainly secreted by the HPDCs, was found juxta-proximal of the calcium phosphate (CaP) granules suggesting that CaP may have triggered the 'osteoinductive program'. Indeed, removal of the CaP granules by ethylenediaminetetraacetic acid decalcification prior to cell seeding and implantation resulted in loss of bone formation. In addition, inhibition of endogenous bone morphogenetic protein and Wnt signalling by overexpression of the secreted antagonists Noggin and Frzb, respectively, also abrogated osteoinduction. Proliferation of the engrafted HPDCs was strongly reduced in the decalcified scaffolds or when seeded with adenovirus-Noggin/Frzb transduced HPDCs indicating that cell division of the engrafted HPDCs is required for the direct bone formation cascade. These data suggest that this model of bone formation is similar to that observed during physiological intramembranous bone development and may be of importance when investigating tissue engineering strategies.Published versio

A biomimetic pancreatic cancer on-chip reveals endothelial ablation via ALK7 signaling

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, lethal malignancy that invades adjacent vasculatures and spreads to distant sites before clinical detection. Although invasion into the peripancreatic vasculature is one of the hallmarks of PDAC, paradoxically, PDAC tumors also exhibit hypovascularity. How PDAC tumors become hypovascular is poorly understood. We describe an organotypic PDAC-on-a-chip culture model that emulates vascular invasion and tumor-blood vessel interactions to better understand PDAC-vascular interactions. The model features a 3D matrix containing juxtaposed PDAC and perfusable endothelial lumens. PDAC cells invaded through intervening matrix, into vessel lumen, and ablated the endothelial cells, leaving behind tumor-filled luminal structures. Endothelial ablation was also observed in in vivo PDAC models. We also identified the activin-ALK7 pathway as a mediator of endothelial ablation by PDAC. This tumor-on-a-chip model provides an important in vitro platform for investigating the process of PDAC-driven endothelial ablation and may provide a mechanism for tumor hypovascularity.R01 EB000262 - NIBIB NIH HHS; TL1 TR001410 - NCATS NIH HHS; UC4 DK104196 - NIDDK NIH HHS; UH3 EB017103 - NIBIB NIH HHSPublished versio

Simulating a sequential coalition formation process for the climate change problem: first come, but second served?

We analyze stability of self-enforcing climate agreements, considering a sequential coalition formation process of heterogeneous and farsighted players. Players can make proposals which are either accepted or countered by alternative proposals. We discuss the conceptual difficulties of implementing and solving such a game and the strategic options arising in a sequential process. This is illustrated with simple examples and with numerical simulations using the CLIMNEG world simulation model (CWSM)

A CMOS Time to Digital Converter IC with 2 Level Analog CAM

A time to charge converter IC with an analog memory unit (TCCAMU) has been designed and fabricated in HP\u27s CMOS 1.2-µm n-well process. The TCCAMU is an event driven system designed for front end data acquisition in high energy physics experiments. The chip includes a time to charge converter, analog Level 1 and Level 2 associative memories for input pipelining and data filtering, and an A/D converter. The intervals measured and digitized range from 8-24 ns. Testing of the fabricated chip resulted in an LSB width of 107 ps, a typical differential nonlinearity of \u3c 35 ps, and a typical integral nonlinearity of \u3c 200 ps. The average power dissipation is 8.28 mW per channel. By counting the reference clock, a time resolution of 107 ps over ~ 1 s range could be realized

Cellular forces and matrix assembly coordinate fibrous tissue repair

Planar in vitro models have been invaluable tools to identify the mechanical basis of wound closure. Although these models may recapitulate closure dynamics of epithelial cell sheets, they fail to capture how a wounded fibrous tissue rebuilds its 3D architecture. Here we develop a 3D biomimetic model for soft tissue repair and demonstrate that fibroblasts ensconced in a collagen matrix rapidly close microsurgically induced defects within 24 h. Traction force microscopy and time-lapse imaging reveal that closure of gaps begins with contractility-mediated whole-tissue deformations. Subsequently, tangentially migrating fibroblasts along the wound edge tow and assemble a progressively thickening fibronectin template inside the gap that provide the substrate for cells to complete closure. Unlike previously reported mechanisms based on lamellipodial protrusions and purse-string contraction, our data reveal a mode of stromal closure in which coordination of tissue-scale deformations, matrix assembly and cell migration act together to restore 3D tissue architecture