Identification of a novel splice variant of the haloacid dehalogenase: PHOSPHO1

PHOSPHO1, a new member of the haloacid dehalogenase superfamily, has recently been implicated in the mineralization process in both osteoblasts and chondrocytes. In this study we describe the identification of a novel, alternatively spliced PHOSPHO1 transcript (PHOSPHO1-3a). This transcript contains the three exons of the previously published variant, however exon 3 contains a retained, 127bp section of intron 2. This forms an in-frame start site, producing an open reading frame of 879bp and predicting a protein of 292 amino acids. The novel 40 amino acid N-terminal region of PHOSPHO1-3a contains a relatively strong secretory signal, however all three domains of the HAD superfamily are retained in exon 3. The expression of this splice variant was confirmed in both human and mouse osteoblast-like cells and also in the chondrogenic ATDC5 cell line. The data within this study indicate a possible function relating to chondrocyte differentiation/mineralization as with the previously published variant

Biomimetic strategies for fracture repair: engineering the cell microenvironment for directed tissue formation

Complications resulting from impaired fracture healing have major clinical implications on fracture management strategies. Novel concepts taken from developmental biology have driven research strategies towards the elaboration of regenerative approaches that can truly harness the complex cellular events involved in tissue formation and repair. Advances in polymer technology and a better understanding of naturally derived scaffolds have given rise to novel biomaterials with an increasing ability to recapitulate native tissue environments. This coupled with advances in the understanding of stem cell biology and technology has opened new avenues for regenerative strategies with true clinical translatability. These advances have provided the impetus to develop alternative approaches to enhance the fracture repair process. We provide an update on these advances, with a focus on the development of novel biomimetic approaches for bone regeneration and their translational potential

Decellularised cartilage ECM culture coatings drive rapid and robust chondrogenic differentiation of human periosteal cells

The control of cell behaviour in an effort to create highly homogeneous cultures is becoming an area of intense research, both to elucidate fundamental biology and for regenerative applications. The extracellular matrix (ECM) controls many cellular processes in vivo, and as such is a rich source of cues that may be translated in vitro. Herein, we describe the creation of cell culture coatings from porcine decellularised hyaline cartilage through enzymatic digestion. Surprisingly, heat-mediated sterilisation created a coating with the capacity to rapidly and robustly induce chondrogenic differentiation of human periosteal cells. This differentiation was validated through the alteration of cell phenotype from a fibroblastic to a cuboidal/cobblestone chondrocyte-like appearance. Moreover, chondrogenic gene expression further supported this observation, where cells cultured on heat sterilised ECM-coated plastic displayed higher expression of COL2A1, ACAN and PRG4 (p 0.05) compared to non-coated plastic cultures. Interestingly, COL2A1 and ACAN expression in this context were sensitive to initial cell density; however, SOX9 expression appeared to be mainly driven by the coating independent of seeding density. The creation of a highly chondrogenic coating may provide a cost-effective solution for the differentiation and/or expansion of human chondrocytes aimed towards cartilage repair strategies

Lee Silverman voice treatment versus standard NHS speech and language therapy versus control in Parkinson's disease (PD COMM pilot):study protocol for a randomized controlled trial

Background: Parkinson’s disease is a common movement disorder affecting approximately 127,000 people in the UK, with an estimated two thirds having speech-related problems. Currently there is no preferred approach to speech and language therapy within the NHS and there is little evidence for the effectiveness of standard NHS therapy or Lee Silverman voice treatment. This trial aims to investigate the feasibility and acceptability of randomizing people with Parkinson’s disease-related speech or voice problems to Lee Silverman voice treatment or standard speech and language therapy compared to a no-intervention control. Methods/Design: The PD COMM pilot is a three arm, assessor-blinded, randomized controlled trial. Randomization will be computer-generated with participants randomized at a ratio of 1:1:1. Participants randomized to intervention arms will be immediately referred to the appropriate speech and language therapist. The target population are patients with a confirmed diagnosis of idiopathic Parkinson’s disease who have problems with their speech or voice. The Lee Silverman voice treatment intervention group will receive the standard regime of 16 sessions between 50 and 60 minutes in length over four weeks, with extra home practice. The standard speech and language therapy intervention group will receive a dose determined by patients’ individual needs, but not exceeding eight weeks of treatment. The control group will receive standard care with no speech and language therapy input for at least six months post-randomization. Outcomes will be assessed at baseline (pre-randomization) and post- randomization at three, six, and 12 months. The outcome measures include patient-reported voice measures, quality of life, resource use, and assessor-rated speech recordings. The recruitment aim is at least 60 participants over 21 months from 11 sites, equating to at least 20 participants in each arm of the trial. This trial is ongoing and recruitment commenced in May 2012. Discussion: This study will provide information on the feasibility and acceptability of randomizing participants to different speech and language therapies or control/deferred treatment. The findings relating to recruitment, treatment compliance, outcome measures, and effect size will inform a future phase III randomized controlled trial

“We can all just get on a bus and go” : Rethinking independent mobility in the context of the universal provision of free bus travel to young Londoners

This paper uses qualitative data from interviews with 118 young Londoners (age 12-18) to examine how the universal provision of free bus travel has affected young people’s independent mobility. Drawing on Sen’s ‘capabilities approach’, we argue that free bus travel enhanced young Londoners’ capability to shape their daily mobility, both directly by increasing financial access and indirectly by facilitating the acquisition of the necessary skills, travelling companions and confidence. These capabilities in turn extended both opportunity freedoms (e.g. facilitating non-“necessary” recreational and social trips) and process freedoms (e.g. feeling more independent by decreasing reliance on parents). Moreover, the universal nature of the entitlement rendered buses a socially inclusive way for groups to travel and spend time together, thereby enhancing group-level capabilities. We believe this attention to individual and group capabilities for self-determination provides the basis for a broader and more child-centred view of ‘independent mobility’ than the typical research focus upon ‘travelling without an adult’ and acquiring parental permissions.Peer reviewe

150,000-year palaeoclimate record from northern Ethiopia supports early, multiple dispersals of modern humans from Africa

Climatic change is widely acknowledged to have played a role in the dispersal of modern humans out of Africa, but the timing is contentious. Dispersal is often linked to climatic change at ~60,000 years ago, despite increasing evidence for earlier presence of modern humans in Asia. Here we report a deep seismic and near-continuous core record of the last 150,000 years from Lake Tana in the Ethiopian highlands, close to the earliest modern human fossil sites and to postulated dispersal routes. The record shows varied climate at the end of the penultimate glacial, followed by an abrupt change to relatively stable moist climate during the last interglacial. These conditions would have favored population growth and range expansion, supporting models of early, multiple dispersals of modern humans from AfricapublishersversionPeer reviewe

Mapping human serum induced gene networks as a basis for the creation of biomimetic periosteum for bone repair

The periosteum is a highly vascularised, collagen-rich tissue that plays a crucial role in directing bone repair. This is orchestrated primarily by its resident progenitor cell population. Indeed, preservation of periosteum integrity is critical for bone healing. Cells extracted from the periosteum retain their osteochondrogenic properties and as such are a promising basis for tissue engineering strategies for the repair of bone defects. However, the culture expansion conditions, and the way in which the cells are reintroduced to the defect site are critical aspects of successful translation. Indeed, expansion in human serum and implantation on biomimetic materials has previously been shown to improve in vivo bone formation. As such, this study aimed to develop a protocol to allow for the expansion of human periosteum derived cells (hPDCs) in a biomimetic periosteal-like environment. The expansion conditions were defined through the investigation of the bioactive cues involved in augmenting hPDC proliferative and multipotency characteristics, based on transcriptomic analysis of cells cultured in human serum. Master regulators of transcriptional networks were identified and an optimised periosteal derived-growth factor cocktail (PD-GFC; containing β-Estradiol, FGF2, TNFα, TGFβ, IGF-1 and PDGF-BB) was generated. Expansion of hPDCs in PD-GFC resulted in serum mimicry with regards to the cell morphology, proliferative capacity and chondrogenic differentiation. When incorporated into a 3D collagen-type-1 matrix and cultured in PD-GFC, the hPDCs migrated to the surface that represented the matrix topography of the periosteum cambium layer. Furthermore, gene expression analysis revealed a downregulated Wnt and TGFβ signature and an upregulation of CREB, which may indicate the hPDCs are recreating their progenitor cell signature. This study highlights the first stage in the development of a biomimetic periosteum which may have applications in bone repair

Cooperative amyloid fibre binding and disassembly by the Hsp70 disaggregase

Although amyloid fibres are highly stable protein aggregates, a specific combination of human Hsp70 system chaperones can disassemble them, including fibres formed of α-synuclein, huntingtin, or Tau. Disaggregation requires the ATPase activity of the constitutively expressed Hsp70 family member, Hsc70, together with the J domain protein DNAJB1 and the nucleotide exchange factor Apg2. Clustering of Hsc70 on the fibrils appears to be necessary for disassembly. Here we use atomic force microscopy to show that segments of in vitro assembled α-synuclein fibrils are first coated with chaperones and then undergo bursts of rapid, unidirectional disassembly. Cryo-electron tomography and total internal reflection fluorescence microscopy reveal fibrils with regions of densely bound chaperones, preferentially at one end of the fibre. Sub-stoichiometric amounts of Apg2 relative to Hsc70 dramatically increase recruitment of Hsc70 to the fibres, creating localised active zones that then undergo rapid disassembly at a rate of ~ 4 subunits per second. The observed unidirectional bursts of Hsc70 loading and unravelling may be explained by differences between the two ends of the polar fibre structure

Author Correction: 150,000-year palaeoclimate record from northern Ethiopia supports early, multiple dispersals of modern humans from Africa

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper