Emulsion Inks: A New Class of Materials for 3D Printing Porous Tissue Engineered Grafts

Tissue grafts are often crucial in restoring function and promoting healing after traumatic injury. Many synthetic materials have been developed, but these often suffer from inadequate tissue integration, limited biodegradability, and mechanical mismatch with the target tissue. Recent advances in 3D printing technologies have enabled the fabrication of custom-fit scaffolds that resemble native tissue. Although these scaffolds can more closely mimic defect shape, new inks are needed to provide tunable control over multiple levels of scaffold structure and function. To address these limitations, we have developed an extensible system for printing complex tissue engineered scaffolds by creating emulsion templated inks. These emulsion inks exhibit tunable pore sizes, modulus, and strength. Formulation of inks with viscous, reactive macromers results in extruded material that holds its shape after extrusion and polymerizes rapidly upon exposure to UV light. New methodology was developed to permit the rational design of emulsion inks based on rheological and cure properties, and these inks were able to successfully create high fidelity scaffolds with customizable, hierarchical porosity. Emulsion inks are compatible with nearly any hydrophobic macromer allowing development of inks with limitless chemical and material properties. Next, a hybrid printing system was developed for extrusion of thermoplastic PCL and PLA along with emulsion inks to provide mechanical reinforcement. Scaffolds without reinforcement exhibited an increase in permeability with a decrease in infill density, with detriment to their modulus and strength. Mechanical reinforcement with PLA, however, resulted in a significant increase in modulus and strength in all cases. The creation of novel emulsion inks from existing biomaterial systems opens the door to the creation of scaffolds with a wide range of physical and chemical properties. Finally, this system was extended to oil-in-water emulsions, termed hydrocolloid inks, to facilitate printing of hydrogels. Due to their low viscosity, high fidelity printing of hydrogels has typically been limited to SLA methods. SFF printing of hydrogel scaffolds frequently relies on thickeners and additives, but we have refined the rheological properties without modification of the hydrogel makeup by emulsifying with innocuous mineral oil. These 3D printed hydrogel scaffolds represent some of the highest fidelity reproductions of complex anatomical geometries in the literature to date. Additionally, this system provides a methodology for creating hydrocolloid inks from nearly any hydrogel biomaterial. In summary, we have developed a library of porous materials that can be used to improve tissue regeneration. Furthermore, the emulsion structure-property relationships explored here can be used in designing future emulsion inks. A combinatorial approach of tuning the ink and fabrication system allows for creation of complex scaffolds with improved biomimicry, allowing for a new generation of hierarchically porous tissue engineered constructs

A stromal lysolipid-autotaxin signaling axis promotes pancreatic tumor progression

Pancreatic ductal adenocarcinoma (PDAC) develops a pronounced stromal response reflecting an aberrant wound-healing process. This stromal reaction features transdifferentiation of tissue-resident pancreatic stellate cells (PSC) into activated cancer-associated fibroblasts, a process induced by PDAC cells but of unclear significance for PDAC progression. Here, we show that PSCs undergo a dramatic lipid metabolic shift during differentiation in the context of pancreatic tumorigenesis, including remodeling of the intracellular lipidome and secretion of abundant lipids in the activated, fibroblastic state. Specifically, stroma-derived lysophosphatidylcholines support PDAC cell synthesis of phosphatidylcholines, key components of cell membranes, and also facilitate production of the potent wound-healing mediator lysophosphatidic acid (LPA) by the extracellular enzyme autotaxin, which is overexpressed in PDAC. The autotaxin–LPA axis promotes PDAC cell proliferation, migration, and AKT activation, and genetic or pharmacologic autotaxin inhibition suppresses PDAC growth in vivo. Our work demonstrates how PDAC cells exploit the local production of wound-healing mediators to stimulate their own growth and migration. Significance: Our work highlights an unanticipated role for PSCs in producing the oncogenic LPA signaling lipid and demonstrates how PDAC tumor cells co-opt the release of wound-healing mediators by neighboring PSCs to promote their own proliferation and migration

The role of political trust in conditioning perceptions of corruption

Political trust and corruption have both elicited considerable academic and popular commentary in recent years. Much attention has been focused on the extent to which corruption has contributed to citizens’ increasing distrust of their politicians. But little attention has been paid to the possibility that distrust may condition responses to alleged corruption, and no work has hitherto demonstrated the veracity of this relationship in a mature democracy. Drawing on data from the United Kingdom, this paper finds that less trusting individuals are consistently more censorious of politicians’ misbehaviour and more likely to perceive the presence of corruption than are their more trusting peers. The paper further demonstrates that people who are less trusting become relatively more critical (compared with the more trusting) as the generally perceived corruptness of a certain scenariodeclines. It also demonstrates how trust increases in importance as a predictor of ethical judgements when behaviour is generally reckoned to be less corrupt. Further analysis suggests that this effect is partly connected to uncertainty. Less obviously corrupt acts are associated with higher levels of uncertainty, which appears to open up a space for trust to play an even more significant role in shaping individual's judgements of politicians’ behaviour.</jats:p

A composite biochemical system for bacterial nitrate and nitrite assimilation as exemplified by Paracoccus denitrificans

The denitrifying bacterium Paracoccus denitrificans can grow aerobically or anaerobically using nitrate or nitrite as the sole nitrogen source. The biochemical pathway responsible is expressed from a gene cluster comprising a nitrate/nitrite transporter (NasA), nitrite transporter (NasH), nitrite reductase (NasB), ferredoxin (NasG) and nitrate reductase (NasC). NasB and NasG are essential for growth with nitrate or nitrite as the nitrogen source. NADH serves as the electron donor for nitrate and nitrite reduction, but only NasB has a NADH-oxidizing domain. Nitrate and nitrite reductase activities show the same Km for NADH and can be separated by anion-exchange chromatography, but only fractions containing NasB retain the ability to oxidize NADH. This implies that NasG mediates electron flux from the NADH-oxidizing site in NasB to the sites of nitrate and nitrite reduction in NasC and NasB respectively. Delivery of extracellular nitrate to NasBGC is mediated by NasA, but both NasA and NasH contribute to nitrite uptake. The roles of NasA and NasC can be substituted during anaerobic growth by the biochemically distinct membrane-bound respiratory nitrate reductase (Nar), demonstrating functional overlap. nasG is highly conserved in nitrate/nitrite assimilation gene clusters, which is consistent with a key role for the NasG ferredoxin, as part of a phylogenetically widespread composite nitrate and nitrite reductase system

MYC regulates ductal-neuroendocrine lineage plasticity in pancreatic ductal adenocarcinoma associated with poor outcome and chemoresistance

Neuroendocrine differentiation of epithelial tumor cells can contribute to cancer cell resistance and survival. Here, the authors show that dysregulated c-Myc promotes neuroendocrine differentiation in pancreatic ductal adenocarcinoma, leading to poor survival and chemoresistance

Blood-brain barrier dysfunction precedes cognitive decline and neurodegeneration in diabetic insulin resistant mouse model: An implication for causal link

© 2017 Takechi, Lam, Brook, Giles, Fimognari, Mooranian, Al-Salami, Coulson, Nesbit and Mamo. Diabetic insulin resistance and pro-diabetic diet are reported to increase dementia risk through unknown mechanisms. Emerging evidence suggests that the integrity of blood-brain barrier (BBB) is central to the onset and progression of neurodegeneration and cognitive impairment. Therefore, the current study investigated the effect of pro-diabetic diets on cognitive dysfunction in association to BBB integrity and its putative mechanisms. In C57BL/6J mice chronically ingested with a diet enriched in fat and fructose (HFF), Morris Water Maze (MWM) test indicated no significant cognitive decline after 4 weeks of HFF feeding compared to low-fat (LF) fed control. However, at this stage, BBB dysfunction accompanied by heightened neuroinflammation in cortex and hippocampal regions was already evident. After 24 weeks, HFF fed mice showed significantly deteriorated cognitive function concomitant with substantial neurodegeneration, which both showed significant associations with increased BBB permeability. In addition, the data indicated that the loss of BBB tight junctions was significantly associated with heightened inflammation and leukocyte infiltration. The data collectively suggest that in mice maintained on pro-diabetic diet, the dysfunctional BBB associated to inflammation and leukocyte recruitment precedes the neurodegeneration and cognitive decline, possibly indicating causal association

Harnessing the immune system in glioblastoma.

Glioblastoma is the most common primary malignant brain tumour. Survival is poor and improved treatment options are urgently needed. Although immunotherapies have emerged as effective treatments for a number of cancers, translation of these through to brain tumours is a distinct challenge, particularly due to the blood-brain barrier and the unique immune tumour microenvironment afforded by CNS-specific cells. This review discusses the immune system within the CNS, mechanisms of immune escape employed by glioblastoma, and the immunological effects of conventional glioblastoma treatments. Novel therapies for glioblastoma that harness the immune system and their current clinical progress are outlined, including cancer vaccines, T-cell therapies and immune checkpoint modulators.N.B. is funded by Cancer Research UK. T.C. is funded by the University College London Hospitals Charity. P.M. is supported by the University College Hospital/University College London Biomedical Research Centre and the National Brain Appeal