With the limited capacity for self‐repair in the adult CNS, efforts to stimulate quiescent stem cell populations within discrete brain regions, as well as harness the potential of stem cell ...transplants, offer significant hope for neural repair. These new cells are capable of providing trophic cues to support residual host populations and/or replace those cells lost to the primary insult. However, issues with low‐level adult neurogenesis, cell survival, directed differentiation and inadequate reinnervation of host tissue have impeded the full potential of these therapeutic approaches and their clinical advancement. Biomaterials offer novel approaches to stimulate endogenous neurogenesis, as well as for the delivery and support of neural progenitor transplants, providing a tissue‐appropriate physical and trophic milieu for the newly integrating cells. In this review, we will discuss the various approaches by which bioengineered scaffolds may improve stem cell‐based therapies for repair of the CNS.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Injectable biomimetic hydrogels have great potential for use in regenerative medicine as cellular delivery vectors. However, they can suffer from issues relating to hypoxia, including poor cell ...survival, differentiation, and functional integration owing to the lack of an established vascular network. Here we engineer a hybrid myoglobin:peptide hydrogel that can concomitantly deliver stem cells and oxygen to the brain to support engraftment until vascularisation can occur naturally. We show that this hybrid hydrogel can modulate cell fate specification within progenitor cell grafts, resulting in a significant increase in neuronal differentiation. We find that the addition of myoglobin to the hydrogel results in more extensive innervation within the host tissue from the grafted cells, which is essential for neuronal replacement strategies to ensure functional synaptic connectivity. This approach could result in greater functional integration of stem cell-derived grafts for the treatment of neural injuries and diseases affecting the central and peripheral nervous systems.
Donor cell age can have a significant impact on transplantation outcomes. Despite the rapid advancement of human pluripotent stem cell (hPSC)-derived dopaminergic (DA) progenitors to the clinic for ...transplantation into Parkinson's Disease (PD), surprisingly limited data exists regarding the influence of cellular age on neural graft survival, composition, and integration. Here we examined the impact of transplanting ventral midbrain (VM) progenitors at varying days of differentiation (from day 13–30) into a rodent PD model, comparing two hPSC lines (an embryonic and an induced pluripotent cell line, hESC and hiPSC, respectively). Both hPSC lines expressed GFP under the promoter PITX3 enabling specific tracking of graft-derived DA neurons. Post-mortem analysis at 6 months revealed larger grafts from Day19 (D19), D22 and D25 progenitors, yet contained a higher proportion of non-DA and poorly specified (FOXA2-) cells. While D13 and D30 progenitors yielded smaller grafts. D13-derived grafts had the highest DA neuron proportion and proportionally more GIRK2+ DA neurons, the subpopulation critical for motor function. These younger progenitor grafts maintained their capacity to innervate developmentally relevant DA targets, with increased innervation capacity per DA neuron, collectively resulting in restoration of motor deficits with equal or greater proficiency than older donor cells. While donor age effects were reproducible for a given hPSC line and trends were similar between the two hPSC lines, grafts of D13 hiPSC-derived progenitors showed a 6-fold greater density of DA neurons compared to D13 hESC-derived grafts, highlighting between-line variability. These findings show that hPSC-derived VM donor age has a direct impact on graft survival, composition and maturation, and that careful assessment, on a line-to-line basis is required prior to translation.
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•Varying neural progenitor age, derived from human PSCs, majorly impacts graft outcomes.•Young progenitors generate small grafts, enriched with A9-like dopamine neurons.•Young progenitors show greater innervation capacity to reverse motor deficits in PD.•Graft outcomes are reproducible within, but variable across pluripotent stem cell lines.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Seawater sulfate is a major carrier of oxidizing capacity and influences the redox budget of the Earth’s surface on geologic timescales. Records of oxygen and sulfur isotopes in seawater sulfate are ...used to track changes in sulfate cycling through geologic time. Interpretations of these records are typically based on models that describe the seawater sulfate reservoir as a mass balance between microbial, riverine and sedimentary sulfate fluxes. Here, we investigate the influence of hydrothermal sulfate cycling, which remains an unconstrained but potentially significant additional flux in this mass balance. We find that anhydrite (CaSO4) from eight submarine hydrothermal vent fields is consistently offset from seawater sulfate in δ18O but not Δ’17O or δ34S. Experiments at hydrothermal pressure–temperature conditions indicate that this δ18O offset is driven by oxygen isotope exchange between sulfate and hydrothermal H2O at high temperature. An updated isotope mass balance model shows that a flux of hydrothermal sulfate into seawater, derived from retrograde dissolution of hydrothermal anhydrite, could cause high-temperature oxygen isotope exchange to buffer seawater sulfate δ18O and Δ’17O by as much as 25%. Hydrothermal sulfate preserved in the Troodos Ophiolite (Cretaceous) also records a δ18O and Δ’17O signal of high-temperature oxygen isotope exchange, supporting the conclusion that geologic records of seawater sulfate oxygen isotopes may include a hydrothermal component.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The present study investigated whether a battery of tests designed to measure different levels of emotional intelligence could differentiate adolescent sex offenders from a non-offender control ...group. Fifteen male adolescent sex offenders ranging in age from 14 to 17 years were recruited through Health and Community Services (VIC, Australia) and 49 non-offender males, matched for age, completed the battery. The battery comprised the Trait Meta-Mood Scale (TMMS), Davis' Interpersonal Reactivity Index (IRI), the Inventory of Interpersonal Problems (IIP-32), the Revised Toronto Alexithymia Scale (TAS-20) and the Openness to Feelings facet of the NEO PI-R. Discriminant analyses using all five tests showed that 89·9 per cent of the sample were correctly allocated their respective groups. Overall the sex offenders were higher on aggression and attention to feelings, less clear about their feelings and less capable to repair unpleasant moods and prolong positive ones. It was concluded that these findings could be the focus of treatment approaches for adolescent sex offenders.
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FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UL, UM, UPCLJ, UPUK
The advent of structural genomics initiatives has led to a pressing need for high‐throughput macromolecular structure determination. To accomplish this, new methods and inevitably new software must ...be developed to accelerate the process of structure solution. To minimize duplication of effort and to generate maintainable code efficiently, a toolbox of basic crystallographic software components is required. The development of the Computational Crystallography Toolbox (cctbx) has been undertaken for this purpose. In this paper, the fundamental requirements for the cctbx are outlined and the decisions that have lead to its implementation are explained. The cctbx currently contains algorithms for the handling of unit cells, space groups and atomic scatterers, and is released under an Open Source license to allow unrestricted use and continued development. It will be developed further to become a comprehensive library of crystallographic tools useful to the entire community of software developers.
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BFBNIB, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
A new software system called PHENIX (Python‐based Hierarchical ENvironment for Integrated Xtallography) is being developed for the automation of crystallographic structure solution. This will provide ...the necessary algorithms to proceed from reduced intensity data to a refined molecular model, and facilitate structure solution for both the novice and expert crystallographer. Here, the features of PHENIXare reviewed and the recent advances in infrastructure and algorithms are briefly described.
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BFBNIB, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
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