Quantifying the microstructural and biomechanical changes in the porcine ventricles during growth and remodelling

Cardiac tissue growth and remodelling (G & R) occur in response to the changing physiological demands of the heart after birth. The early shift to pulmonary circulation produces an immediate increase in ventricular workload, causing microstructural and biomechanical changes that serve to maintain overall physiological homoeostasis. Such cardiac G & R continues throughout life. Quantifying the tissue's mechanical and microstructural changes because of G & R is of increasing interest, dovetailing with the emerging fields of personalised and precision solutions. This study aimed to determine equibiaxial, and non-equibiaxial extension, stress-relaxation, and the underlying microstructure of the passive porcine ventricles tissue at four time points spanning from neonatal to adulthood. The three-dimensional microstructure was investigated via two-photon excited fluorescence and second-harmonic generation microscopy on optically cleared tissues, describing the 3D orientation, rotation and dispersion of the cardiomyocytes and collagen fibrils. The results revealed that during biomechanical testing, myocardial ventricular tissue possessed non-linear, anisotropic, and viscoelastic behaviour. An increase in stiffness and viscoelasticity was noted for the left and right ventricular free walls from neonatal to adulthood. Microstructural analyses revealed concomitant increases in cardiomyocyte rotation and dispersion. This study provides baseline data, describing the biomechanical and microstructural changes in the left and right ventricular myocardial tissue during G & R, which should prove valuable to researchers in developing age-specific, constitutive models for more accurate computational simulations

Design of experiment (DoE)-driven in vitro and in vivo uptake studies of exosomes for pancreatic cancer delivery enabled by copper-free click chemistry-based labelling

Exosomes (Exo)-based therapy holds promise for treatment of lethal pancreatic cancer (PC). Limited understanding of key factors affecting Exo uptake in PC cells restricts better design of Exo-based therapy. This work aims to study the uptake properties of different Exo by PC cells. Exo from pancreatic carcinoma, melanoma and non-cancer cell lines were isolated and characterised for yield, size, morphology and exosomal marker expression. Isolated Exo were fluorescently labelled using a novel in-house developed method based on copper-free click chemistry to enable intracellular tracking and uptake quantification in cells. Important factors influencing Exo uptake were initially predicted by Design of Experiments (DoE) approach to facilitate subsequent actual experimental investigations. Uptake of all Exo types by PC cells (PANC-1) showed time- and dose-dependence as predicted by the DoE model. PANC-1 cell-derived exosomes (PANC-1 Exo) showed significantly higher uptake in PANC-1 cells than that of other Exo types at the longest incubation time and highest Exo dose. In vivo biodistribution studies in subcutaneous tumour-bearing mice similarly showed favoured accumulation of PANC-1 Exo in self-tissue (i.e. PANC-1 tumour mass) over the more vascularised melanoma (B16-F10) tumours, suggesting intrinsic tropism of PC-derived Exo for their parent cells. This study provides a simple, universal and reliable surface modification approach via click chemistry for in vitro and in vivo exosome uptake studies and can serve as a basis for a rationalised design approach for pre-clinical Exo cancer therapies

Spontaneous fractures during 13-cis retinoic acid therapy for neuroblastoma.

peer reviewe

Pharmacokinetics and Safety of a Novel Oral Liquid Formulation of 13-cis Retinoic Acid in Children with Neuroblastoma: A Randomized Crossover Clinical Trial.

(1) Background: 13-cis-retinoic acid (13-CRA) is a key component of neuroblastoma treatment protocols. This randomized crossover study compares the pharmacokinetics (PK), safety and palatability of a novel oral liquid formulation to the current method of extracting 13-CRA from capsules. (2) Methods: Pharmacokinetics was evaluated in two consecutive treatment cycles. Patients were randomized to receive either liquid or capsule formulation on cycle 1 and then crossed over to the alternative formulation on cycle 2. The daily dose was 200 mg/m2, reduced to 160 mg/m2 in patients with weight ≤ 12 kg. (3) Results: A total of 20 children, median (range) age 4.3 (1-11.6) y were recruited. Pharmacokinetic data were pooled and a population model describing the disposition of 13-CRA and 4-oxo-13-CRA was developed. Bioavailability of the liquid formulation was estimated to be 65% higher (95% CI; 51-79%) than the extracted capsule. CmaxSS and AUC(0-12)SS estimates were also significantly higher; mean (95% CI) differences were 489 (144-835) ng/mL and 3933 (2020-5846) ng/mL·h, respectively (p < 0.01). There were no significant differences in reported adverse effects. Parents found dosing considerably easier with liquid formulation. (4) Conclusions: The pharmacokinetics, safety and palatability of a new liquid formulation of 13-CRA compares favorably to 13-CRA extracted from capsules. Clinical Trial Registration: clinicaltrial.gov NCT03291080

Rapid urbanisation and security: Holistic approach to enhancing security of urban spaces

Rapid urbanisation, particularly driven by rural-urban migration, can pose a wide range of security challenges in the global south and global north. The management of such a transition, in terms of the provision of social goods and quality of life raises significant challenges. Security of contemporary urban environments has become more complex due to a greater range of risk drivers, many of which can be exacerbated by the observed and portended impacts of climate change. This chapter outlines the phenomena underlying the transition to urbanisation - and the security challenges that have been exacerbated by these transitions. In doing so this work a holistic approach to security and highlights a gradual trend in the increased securitisation of issues (such as climate change) that in the past were not considered part of typical ‘security’ dialogues. It also introduces a decision support framework that can aid a broad range of stakeholders in making decisions about the enhancement of security of urban spaces in a context of multiple threats exacerbated by these new security challenges

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Germination and ex situ storage of Hakea dohertyi (Proteaceae) seed

Fresh seeds of the endangered Hakea dohertyi Haegi (Proteaceae) germinated at 15°C (with 12 hour light) within 14 days. At higher temperatures (20°, 25°C) seeds were slower to germinate. After 28 days only 5% of seeds germinated at 30°C, but when moved to 15°C, close to 100% of seeds germinated within 14 days. Having established optimum germination conditions, the effects of ex situ storage conditions and duration were examined. Storage at low moisture content appeared to have little effect on the germinability of Hakea dohertyi seeds and this species can be considered orthodox in that respect. Seeds stored at 4.5 or 9% moisture content, 5 or -20°C and tested after 1 and 7 years of storage achieved close to 100% germination. Issues relating to the in situ and ex situ conservation of Hakea dohertyi are discussed