Guest editorial: special issue on bone tissue engineering

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Bioactive composites for bone tissue engineering

One of the major challenges of bone tissue engineering is the production of a suitable scaffold material. In this review the current composite materials options available are considered covering both the methods of both production and assessing the scaffolds. A range of production routes have been investigated ranging from the use of porogens to produce the porosity through to controlled deposition methods. The testing regimes have included mechanical testing of the materials produced through to in vivo testing of the scaffolds. While the ideal scaffold material has not yet been produced, progress is being made

Genome sequence of Acetomicrobium hydrogeniformans OS1

Acetomicrobium hydrogeniformans, an obligate anaerobe of the phylum Synergistetes, was isolated from oil production water. It has the unusual ability to produce almost 4 molecules H2/molecule glucose. The draft genome of A. hydrogeniformans OS1 (DSM 22491T) is 2,123,925 bp, with 2,068 coding sequences and 60 RNA genes

Hybrid Core-Shell Scaffolds for Bone Tissue Engineering

The tissue engineering applications of coaxial electrospinning are growing due to the potential increased functionality of the fibres compared to basic electrospinning. Previous studies of core and shell scaffolds have placed the active elements in the core, however, the surface response to a biomaterial affects the subsequent behaviour, thus here hydroxyapatite (HA) was added to the shell. Coaxial electrospun polycaprolactone (PCL)-polylactic acid (PLA)/HA (core-shell) scaffolds were produced in 2D sheets using a plate collector, or 3D tubes for bone tissue engineering using a rotating needle collector. The scaffolds include high hydroxyapatite content while retaining their structural and mechanical integrity. The effect of the collector type on fibre diameter, fibre alignment and mechanical properties have been evaluated, and the impact of HA incorporation on bioactivity, BMP-2 release, cell behaviour and mechanical properties for up to 12 weeks degradation were assessed. Fibre uniformity in coaxial electrospinning depends on the relative flow rate of the core and shell solutions. Using a rotating needle collector increased fibre alignment compared to a stationary collector, without affecting fibre diameter significantly, while HA content increased fibre non-uniformity. Coaxial PCL-PLA/HA fibres exhibited significantly higher bioactivity compared to PCL-PLA scaffolds due to the surface exposure of the HA particles. Apatite formation increased with increasing SBF immersion time. Coaxial tubular scaffolds with and without HA incorporation showed gradual reductions in their mechanical properties over 12 weeks in PBS or SBF but still retained their structural integrity. Coaxial scaffolds with and without HA exhibited gradual and sustained BMP-2 release and supported MSCs proliferation and differentiation with no significant difference between the two scaffolds types. These materials therefore show potential applications as bone tissue engineering scaffolds

Transient Thresholding: A Mechanism Enabling Noncooperative Transcriptional Circuitry to Form a Switch

Threshold generation in fate-selection circuits is often achieved through deterministic bistability, which requires cooperativity (i.e., nonlinear activation) and associated hysteresis. However, the Tat positive-feedback loop that controls HIV’s fate decision between replication and proviral latency lacks self-cooperativity and deterministic bistability. Absent cooperativity, it is unclear how HIV can temporarily remain in an off-state long enough for the kinetically slower epigenetic silencing mechanisms to act—expression fluctuations should rapidly trigger active positive feedback and replication, precluding establishment of latency. Here, using flow cytometry and single-cell imaging, we find that the Tat circuit exhibits a transient activation threshold. This threshold largely disappears after ∼40 h—accounting for the lack of deterministic bistability—and promoter activation shortens the lifetime of this transient threshold. Continuous differential equation models do not recapitulate this phenomenon. However, chemical reaction (master equation) models where the transcriptional transactivator and promoter toggle between inactive and active states can recapitulate the phenomenon because they intrinsically create a single-molecule threshold transiently requiring excess molecules in the inactive state to achieve at least one molecule (rather than a continuous fractional value) in the active state. Given the widespread nature of promoter toggling and transcription factor modifications, transient thresholds may be a general feature of inducible promoters

Web-Based Genome-Wide Association Study Identifies Two Novel Loci and a Substantial Genetic Component for Parkinson's Disease

Although the causes of Parkinson's disease (PD) are thought to be primarily environmental, recent studies suggest that a number of genes influence susceptibility. Using targeted case recruitment and online survey instruments, we conducted the largest case-control genome-wide association study (GWAS) of PD based on a single collection of individuals to date (3,426 cases and 29,624 controls). We discovered two novel, genome-wide significant associations with PD–rs6812193 near SCARB2 (, ) and rs11868035 near SREBF1/RAI1 (, )—both replicated in an independent cohort. We also replicated 20 previously discovered genetic associations (including LRRK2, GBA, SNCA, MAPT, GAK, and the HLA region), providing support for our novel study design. Relying on a recently proposed method based on genome-wide sharing estimates between distantly related individuals, we estimated the heritability of PD to be at least 0.27. Finally, using sparse regression techniques, we constructed predictive models that account for 6%–7% of the total variance in liability and that suggest the presence of true associations just beyond genome-wide significance, as confirmed through both internal and external cross-validation. These results indicate a substantial, but by no means total, contribution of genetics underlying susceptibility to both early-onset and late-onset PD, suggesting that, despite the novel associations discovered here and elsewhere, the majority of the genetic component for Parkinson's disease remains to be discovered

Adultery and the Rumor Mill: les bourgeois de Molinchart and El gran galeoto

This article seeks to challenge interpretations of the adultery plot as a subversive current in nineteenth-century literature by examining two texts that are often dismissed by contemporary critics: Les bourgeois de Molinchart (1854), a novel by the French writer Champfleury (the pseudonym of Jules Husson), and El gran Galeoto (1881), a play by the Spanish playwright Jos, Echegaray. In each of these works, the rumor of the adultery precedes and to a large extent precipitates the infidelity at the end of the work. In committing adultery, therefore, the protagonists are not rising up against social norms so much as capitulating to the expectations of society, enacting a plot that has been projected upon them. The essay compares and contrasts the treatment of the rumor mill in the two works and examines the literary strategies that the writers use to undercut a transgressive reading of the infidelity plot

The skeletal phenotype of chondroadherin deficient mice

Chondroadherin, a leucine rich repeat extracellular matrix protein with functions in cell to matrix interactions, binds cells via their a2b1 integrin as well as via cell surface proteoglycans, providing for different sets of signals to the cell. Additionally, the protein acts as an anchor to the matrix by binding tightly to collagens type I and II as well as type VI. We generated mice with inactivated chondroadherin gene to provide integrated studies of the role of the protein. The null mice presented distinct phenotypes with affected cartilage as well as bone. At 3–6 weeks of age the epiphyseal growth plate was widened most pronounced in the proliferative zone. The proteome of the femoral head articular cartilage at 4 months of age showed some distinct differences, with increased deposition of cartilage intermediate layer protein 1 and fibronectin in the chondroadherin deficient mice, more pronounced in the female. Other proteins show decreased levels in the deficient mice, particularly pronounced for matrilin-1, thrombospondin-1 and notably the members of the a1-antitrypsin family of proteinase inhibitors as well as for a member of the bone morphogenetic protein growth factor family. Thus, cartilage homeostasis is distinctly altered. The bone phenotype was expressed in several ways. The number of bone sialoprotein mRNA expressing cells in the proximal tibial metaphysic was decreased and the osteoid surface was increased possibly indicating a change in mineral metabolism. Micro-CT revealed lower cortical thickness and increased structure model index, i.e. the amount of plates and rods composing the bone trabeculas. The structural changes were paralleled by loss of function, where the null mice showed lower femoral neck failure load and tibial strength during mechanical testing at 4 months of age. The skeletal phenotype points at a role for chondroadherin in both bone and cartilage homeostasis, however, without leading to altered longitudinal growth

Expression of the Splicing Factor Gene SFRS10 Is Reduced in Human Obesity and Contributes to Enhanced Lipogenesis

SummaryAlternative mRNA splicing provides transcript diversity and may contribute to human disease. We demonstrate that expression of several genes regulating RNA processing is decreased in both liver and skeletal muscle of obese humans. We evaluated a representative splicing factor, SFRS10, downregulated in both obese human liver and muscle and in high-fat-fed mice, and determined metabolic impact of reduced expression. SFRS10-specific siRNA induces lipogenesis and lipid accumulation in hepatocytes. Moreover, Sfrs10 heterozygous mice have increased hepatic lipogenic gene expression, VLDL secretion, and plasma triglycerides. We demonstrate that LPIN1, a key regulator of lipid metabolism, is a splicing target of SFRS10; reduced SFRS10 favors the lipogenic β isoform of LPIN1. Importantly, LPIN1β-specific siRNA abolished lipogenic effects of decreased SFRS10 expression. Together, our results indicate that reduced expression of SFRS10, as observed in tissues from obese humans, alters LPIN1 splicing, induces lipogenesis, and therefore contributes to metabolic phenotypes associated with obesity