Biofabrication of vasculature in microphysiological models of bone

Bone contains a dense network of blood vessels that are essential to its homoeostasis, endocrine function, mineral metabolism and regenerative functions. In addition, bone vasculature is implicated in a number of prominent skeletal diseases, and bone has high affinity for metastatic cancers. Despite vasculature being an integral part of bone physiology and pathophysiology, it is often ignored or oversimplified in in vitro bone models. However, 3D physiologically relevant vasculature can now be engineered in vitro, with microphysiological systems (MPS) increasingly being used as platforms for engineering this physiologically relevant vasculature. In recent years, vascularised models of bone in MPSs systems have been reported in the literature, representing the beginning of a possible technological step change in how bone is modelled in vitro. Vascularised bone MPSs is a subfield of bone research in its nascency, however given the impact of MPSs has had in in vitro organ modelling, and the crucial role of vasculature to bone physiology, these systems stand to have a substantial impact on bone research. However, engineering vasculature within the specific design restraints of the bone niche is significantly challenging given the different requirements for engineering bone and vasculature. With this in mind, this paper aims to serve as technical guidance for the biofabrication of vascularised bone tissue within MPS devices. We first discuss the key engineering and biological considerations for engineering more physiologically relevant vasculature in vitro within the specific design constraints of the bone niche. We next explore emerging applications of vascularised bone MPSs, and conclude with a discussion on the current status of vascularised bone MPS biofabrication and suggest directions for development of next generation vascularised bone MPSs

Centriole splitting caused by loss of the centrosomal linker protein C-NAP1 reduces centriolar satellite density and impedes centrosome amplification

Duplication of the centrosomes is a tightly regulated process. Abnormal centrosome numbers can impair cell division and cause changes in how cells migrate. Duplicated centrosomes are held together by a proteinaceous linker made up of rootletin filaments anchored to the centrioles by C-NAP1. This linker is removed in a NEK2A kinase-dependent manner as mitosis begins. To explore C-NAP1 activities in regulating centrosome activities, we used genome editing to ablate it. C-NAP1–null cells were viable and had an increased frequency of premature centriole separation, accompanied by reduced density of the centriolar satellites, with reexpression of C-NAP1 rescuing both phenotypes. We found that the primary cilium, a signaling structure that arises from the mother centriole docked to the cell membrane, was intact in the absence of C-NAP1, although components of the ciliary rootlet were aberrantly localized away from the base of the cilium. C-NAP1–deficient cells were capable of signaling through the cilium, as determined by gene expression analysis after fluid flow–induced shear stress and the relocalization of components of the Hedgehog pathway. Centrosome amplification induced by DNA damage or by PLK4 or CDK2 overexpression was markedly reduced in the absence of C-NAP1. We conclude that centriole splitting reduces the local density of key centriolar precursors to impede overduplication

Recent advances in understanding the effects of climate change on coral reefs

Climate change is one of the greatest threats to the persistence of coral reefs. Sustained and ongoing increases in ocean temperatures and acidification are altering the structure and function of reefs globally. Here, we summarise recent advances in our understanding of the effects of climate change on scleractinian corals and reef fish. Although there is considerable among-species variability in responses to increasing temperature and seawater chemistry, changing temperature regimes are likely to have the greatest influence on the structure of coral and fish assemblages, at least over short–medium timeframes. Recent evidence of increases in coral bleaching thresholds, local genetic adaptation and inheritance of heat tolerance suggest that coral populations may have some capacity to respond to warming, although the extent to which these changes can keep pace with changing environmental conditions is unknown. For coral reef fishes, current evidence indicates increasing seawater temperature will be a major determinant of future assemblages, through both habitat degradation and direct effects on physiology and behaviour. The effects of climate change are, however, being compounded by a range of anthropogenic disturbances, which may undermine the capacity of coral reef organisms to acclimate and/or adapt to specific changes in environmental conditions

Doping, European Law and the Implications of Meca-Medina

The ruling of the European Court of Justice in the anti-doping case of Meca Medina v. The Commission has important implications for athletes, domestic governing bodies, international federations and supra-national actors such as WADA and the Court of Arbitration for Sport. Meca-Medina has been criticised as an unwelcome interference by the courts in the legitimate activities of sporting organisations, but after Bosman it was fanciful to argue that those organisations should be ‘above the law’ and the courts should have no jurisdiction over their activities. That said, there is a stark difference between the courts having jurisdiction over sports’ decisions and being willing to overturn them - the courts have been, and remain, willing to defer to the expertise of sporting organisations. However, the ECJ’s ruling in MOTOE confirms that the courts will intervene in appropriate circumstances. In order to avoid sanction on competition law grounds sports organisations must thus be able to justify their provisions on (for example) what is an unacceptable level of nandrolone, show that athletes’ fundamental rights such as the right to a fair hearing have been respected, and ensure that any sanctions imposed upon athletes who fall foul of doping regulations are proportionate to the offence committed

The effect of metabolic phenotype on sociability and social group size preference in a coral reef fish

Although individuals within social groups experience reduced predation risk and find food patches more consistently, there can be competition for food among groupmates. Individuals with a higher standard metabolic rate (SMR) may be less social, to prioritize food acquisition over defense, while a greater maximum metabolic rate (MMR) may modulate sociability through increased competitive ability. Therefore, in theory, individuals with a higher SMR may prefer smaller groups and those with greater MMR may prefer larger groups. We examined links among metabolic phenotype, sociability, and choice of group size in the redbelly yellowtail fusilier Caesio cuning. Individuals were exposed to three association tests: (a) a choice between two fish or zero fish; (b) a choice between five fish or zero fish; and (c) a choice between two fish and five fish. The first two tests quantified sociability while the third measured relative group size choice. Although there was no link between SMR and sociability, fish with a higher MMR were more social than those individuals with a lower MMR. While no correlation was found between MMR and group size choice, there was weak evidence that, if anything, individuals with a higher SMR preferred larger groups, contrary to our hypothesis. As C. cuning is an active fish that spends a large proportion of time operating above SMR, this result could suggest that the links between sociability and SMR may shift depending on a species’ routine behavior. Links between sociability and MMR may arise if competitive ability allows individuals to obtain resources within groups. Although metabolic traits had no significant influence on group size choice, variation in food availability or predation risk could alter the effects of metabolism on group size choice

Body Size and Substrate Type Modulate Movement by the Western Pacific Crown-Of-Thorns Starfish, Acanthaster solaris

The movement capacity of the crown-of-thorns starfishes (Acanthaster spp.) is a primary determinant of both their distribution and impact on coral assemblages. We quantified individual movement rates for the Pacific crown-of-thorns starfish (Acanthaster solaris) ranging in size from 75–480 mm total diameter, across three different substrates (sand, flat consolidated pavement, and coral rubble) on the northern Great Barrier Reef. The mean (±SE) rate of movement for smaller (diameter) A. solaris was 23.99 ± 1.02 cm/ min and 33.41 ± 1.49 cm/ min for individuals \u3e350 mm total diameter. Mean (±SE) rates of movement varied with substrate type, being much higher on sand (36.53 ± 1.31 cm/ min) compared to consolidated pavement (28.04 ± 1.15 cm/ min) and slowest across coral rubble (17.25 ± 0.63 cm/ min). If average rates of movement measured here can be sustained, in combination with strong directionality, displacement distances of adult A. solaris could range from 250–520 m/ day, depending on the prevailing substrate. Sustained movement of A. solaris is, however, likely to be highly constrained by habitat heterogeneity, energetic constraints, resource availability, and diurnal patterns of activity, thereby limiting their capacity to move between reefs or habitats

Maximizing regional biodiversity requires a mosaic of protection levels

Protected areas are the flagship management tools to secure biodiversity from anthropogenic impacts. However, the extent to which adjacent areas with distinct protection levels host different species numbers and compositions remains uncertain. Here, using reef fishes, European alpine plants, and North American birds, we show that the composition of species in adjacent Strictly Protected, Restricted, and Non-Protected areas is highly dissimilar, whereas the number of species is similar, after controlling for environmental conditions, sample size, and rarity. We find that between 12% and 15% of species are only recorded in Non-Protected areas, suggesting that a non-negligible part of regional biodiversity occurs where human activities are less regulated. For imperiled species, the proportion only recorded in Strictly Protected areas reaches 58% for fishes, 11% for birds, and 7% for plants, highlighting the fundamental and unique role of protected areas and their environmental conditions in biodiversity conservation

Validation of Continuous Glucose Monitoring in Children and Adolescents With Cystic Fibrosis: A prospective cohort study

OBJECTIVE: To validate continuous glucose monitoring (CGM) in children and adolescents with cystic fibrosis. RESEARCH DESIGN AND METHODS: Paired oral glucose tolerance tests (OGTTs) and CGM monitoring was undertaken in 102 children and adolescents with cystic fibrosis (age 9.5-19.0 years) at baseline (CGM1) and after 12 months (CGM2). CGM validity was assessed by reliability, reproducibility, and repeatability. RESULTS: CGM was reliable with a Bland-Altman agreement between CGM and OGTT of 0.81 mmol/l (95% CI for bias +/- 2.90 mmol/l) and good correlation between the two (r = 0.74-0.9; P < 0.01). CGM was reproducible with no significant differences in the coefficient of variation of the CGM assessment between visits and repeatable with a mean difference between CGM1 and CGM2 of 0.09 mmol/l (95% CI for difference +/- 0.46 mmol/l) and a discriminant ratio of 13.0 and 15.1, respectively. CONCLUSIONS: In this cohort of children and adolescents with cystic fibrosis, CGM performed on two occasions over a 12-month period was reliable, reproducible, and repeatable

Usefulness of Current Patient-Reported Outcome Scales for ACL Injury: A Mixed-Methods Evaluation of Stakeholder-Perceived Utility of Specific Constructs and Items Across the Rehabilitation Timeline

BACKGROUND: Numerous patient-reported outcome measures (PROMs) have been used in patients with anterior cruciate ligament reconstruction (ACLR), often with overlapping constructs of interest and limited content validity. Inefficient scale application increases burden and diminishes overall usefulness for both the patient and practitioner. PURPOSE: To isolate specific PROM items across a diverse set of constructs that patients and practitioners perceive as having the greatest value at various stages of recovery and return to sport (RTS) in patients after ACLR. STUDY DESIGN: Cross-sectional study. METHODS: A combined 77 stakeholders participated in this 2-phase mixed-methods investigation. In phase 1, a total of 27 patients and 21 practitioners selected individual PROM items from various constructs that had the greatest utility or importance. In phase 2, the highest rated items were further tested in a head-to-head comparison with 29 stakeholders who attended the 2022 ACL Injury Research Retreat. In addition to the utility assessment, practitioners answered other questions related to importance and timing of PROM assessments. RESULTS: In phase 1, both patients and practitioners shared the same top item in 6 of the 8 (75%) constructs assessed. In phase 2, the construct of psychological burden was rated as extremely important by 59% of respondents, followed by physical function (54%), symptoms (35%), and donor site issues (10%). The PROM items of confidence, perceived likelihood of reinjury, and difficulty stopping quickly were rated by a respective 93%, 89%, and 86% of the sample as either very useful or extremely useful. All constructs except donor site issues were rated by most stakeholders to be absolutely necessary to evaluate treatment progress and RTS readiness at the 6-month postoperative time and at RTS. CONCLUSION: Overall, psychological burden, with specific items related to confidence and reinjury likelihood, were rated as most important and useful by both patients and practitioners. The second most important and useful PROM item was related to higher intensity function (eg, decelerating or jumping/landing activities during sports)