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The large-scale expansion dynamics of quantum gases is a central tool for ultracold gas experiments and poses a significant challenge for theory. In this work we provide an exact reformulation of the Gross-Pitaevskii equation for the ultracold Bose gas in a coordinate frame that adaptively scales with the system size during evolution, enabling simulations of long evolution times during expansion or similar large-scale manipulation. Our approach makes no hydrodynamic approximations, is not restricted to a scaling ansatz, harmonic potentials, or energy eigenstates, and can be generalized readily to non-contact interactions via the appropriate stress tensor of the quantum fluid. As applications, we simulate the expansion of the ideal gas, a cigar-shaped condensate in the Thomas-Fermi regime, and a linear superposition of counter propagating Gaussian wavepackets. We recover known scaling for the ideal gas and Thomas-Fermi regimes, and identify a linear regime of aspect-ratio preserving free expansion; analysis of the scaling dynamics equations shows that an exact, aspect-ratio invariant, free expansion does not exist for nonlinear evolution. Our treatment enables exploration of nonlinear effects in matter-wave dynamics over large scale-changing evolution., 12 pages, 3 figures, 2 appendices

Cell embedment into a solid support matrix is considered essential for the culture of intestinal epithelial organoids and tumoroids, but this technique presents challenges that impede scalable culture expansion, experimental manipulation, high-throughput screening and diagnostic applications. We have developed a low-viscosity matrix (LVM) suspension culture method that enables efficient establishment and propagation of organoids and tumoroids from the human large intestine. Organoids and tumoroids cultured in LVM suspension recapitulate the morphological development observed in solid matrices, with tumoroids reflecting the histological features and genetic heterogeneity of primary colorectal cancers. We demonstrate the utility of LVM suspension culture for organoid and tumoroid bioreactor applications and biobanking, as well as tumoroid high-throughput drug sensitivity testing. These methods provide opportunities for the study and use of patient-derived organoids and tumoroids from the large intestine., Given the practical limitations of solid matrix-based protocols in organoid culture, Yumiko Hirokawa et al. assess the ability of low-concentration Matrigel conditions to promote intestinal organoid growth. Their results suggest that a low-viscosity culture system can improve live cell yield compared to the existing dome method, while maintaining similar morphology, and represents a useful approach for high-throughput applications of organoids.

e15571 Background: Many patients with metastatic colorectal cancer (mCRC) that have failed standard first- and second-line therapies remain fit and eager for further treatment. Therapeutic options include two agents with proven but modest survival benefit, a clinical trial of an investigational agent, rechallenge with agents successfully used in earlier lines of treatment, or agents that have shown some activity in non-randomised phase II studies. Patient derived tumouroid (PDT) are self-organizing three-dimensional in vitro models cultured from a fresh tumour biopsy. They potentially represent a robust personalized model for real-time drug sensitivity testing to determine optimal anti-cancer therapies for individual patients. Methods: FORECAST-1 is an observational, non-randomized study to determine the feasibility of PDT based drug sensitivity screening for patients with mCRC that have failed at least two lines of therapy. Once established, PDTs undergo drug sensitivity screening including agents regorafenib, trifluridine/tipiracil (TAS102), oxaliplatin, irinotecan, 5-fluorouracil (5FU), erlotinib (a surrogate EGFR-inhibitor), gemcitabine, pemetrexed and temozolomide. Patients are treated at clinician discretion, with clinical response to be correlated with PDT response. Results: Since September 2020 we have enrolled 18 of a planned 30 patients, median age 55 years (range 44 – 81). 17 patients were ECOG 0-1. Four patients had received prior TAS102 treatment. Biopsies were obtained from liver (n = 6), soft tissue/peritoneal metastases (5), lung (2), lymph node (2), primary (1), brain (1) and bone (1). Drug sensitivity testing has been performed on seven PDTs at a median of 62 days from biopsy (range 42 – 128), one PDT culture has failed. A standardised reporting template has been developed. Treatments received by patients to date include TAS102 (n = 5), regorafenib (2), FOLFOX (3), FOLFIRI (1) FOLFIRI plus EGFR-inhibitor (1), capecitabine plus bevacizumab (1) and an immunotherapy-based clinical trial (1). Four patients did not receive further anti-cancer therapy post enrolment, and one patient is yet to commence further systemic therapy. Conclusions: Enrolment to this feasibility study has been rapid demonstrating this to be an area of clinical need. PDTs have been successfully established from a high proportion of patients, but with variable growth rates. Methods to accelerate PDT culture and drug testing are being pursued to increase the feasibility of a planned prospective study of PDT sensitivity informing patient management. Clinical trial information: ACTRN12620001353987.

Nicotine exposure during the fetal and neonatal periods (Developmental nicotine exposure, DNE) is associated with ineffective upper airway protective reflexes in infants. This could be explained by desensitized chemoreceptors and/or mechanoreceptors, diminished neuromuscular transmission or altered synaptic transmission among central neurons, as each of these systems depend in part on cholinergic signaling through nicotinic acetylcholine receptors (nAChRs). Here we showed that DNE blunts the response of the genioglossus muscle to nasal airway occlusion in lightly anesthetized rat pups. The genioglossus muscle helps keep the upper airway open and is innervated by hypoglossal motoneurons (XIIMNs). Experiments using the phrenic nerve-diaphragm preparation showed that DNE does not alter transmission across the neuromuscular junction. Accordingly, we used whole cell recordings from XIIMNs in brainstem slices to examine the influence of DNE on glutamatergic synaptic transmission under baseline conditions and in response to an acute nicotine challenge. DNE did not alter excitatory transmission under baseline conditions. Analysis of cumulative probability distributions revealed that acute nicotine challenge of P1-P2 preparations resulted in an increase in the frequency of nicotine-induced glutamatergic inputs to XIIMNs in both control and DNE. By contrast, P3-P5 DNE pups showed a decrease, rather than an increase in frequency. We suggest that this, together with previous studies showing that DNE is associated with a compensatory increase in inhibitory synaptic input to XIIMNs, leads to an excitatory-inhibitory imbalance. This imbalance may contribute to the blunting of airway protective reflexes observed in nicotine exposed animals and human infants. Significance statement The number one risk factor for sudden infant death (SIDS) is maternal smoking. While the use of nicotine delivery devices such as e-cigarettes is increasing among women of childbearing age, reflecting the belief that the use of nicotine alone is safer than tobacco, SIDS deaths are not decreasing, suggesting that nicotine is the link between maternal smoking and SIDS. Here we show that perinatal nicotine exposure alters a major motor pathway responsible for upper airway patency during sleep. We also introduce an animal model that is well suited to probing the mechanisms underlying the link between maternal nicotine consumption and SIDS, and a phenotype that nicely models key aspects of the events believed to give rise to SIDS.

The benefits of adult stem cells for repair of the heart have been attributed to the repertoire of salutary paracrine activities they appear to exert. We previously isolated human W8B2+ cardiac stem cells (CSCs) and found they powerfully influence cardiomyocytes and endothelial cells to collectively promote cardiac repair and regeneration. Here, the complexity of the W8B2+ CSC secretomes was characterised and examined in more detail. Using ion exchange chromatography to separate soluble proteins based on their net surface charge, the secreted factors responsible for the pro-survival activity of W8B2+ CSCs were found within the low and medium cation fractions. In addition to the soluble proteins, extracellular vesicles generated from W8B2+ CSCs not only exhibited pro-survival and pro-angiogenic activities, but also promoted proliferation of neonatal cardiomyocytes. These extracellular vesicles contain a cargo of proteins, mRNA and primary microRNA precursors that are enriched in exosomes and are capable of modulating collectively many of the cellular pathways involved in protein metabolism, cell growth, as well as cellular responses to stress and organisation of the extracellular matrix. Thus the W8B2+ CSC secretome contains a multitude of bioactive paracrine factors we have now characterised, that might well be harnessed for therapeutic application for cardiac repair and regeneration.

The benefits of adult stem cells for repair of the heart have been attributed to the repertoire of salutary paracrine activities they appear to exert. We previously isolated human W8B2+ cardiac stem cells (CSCs) and found they powerfully influence cardiomyocytes and endothelial cells to collectively promote cardiac repair and regeneration. Here, the complexity of the W8B2+ CSC secretomes was characterised and examined in more detail. Using ion exchange chromatography to separate soluble proteins based on their net surface charge, the secreted factors responsible for the pro-survival activity of W8B2+ CSCs were found within the low and medium cation fractions. In addition to the soluble proteins, extracellular vesicles generated from W8B2+ CSCs not only exhibited pro-survival and pro-angiogenic activities, but also promoted proliferation of neonatal cardiomyocytes. These extracellular vesicles contain a cargo of proteins, mRNA and primary microRNA precursors that are enriched in exosomes and are capable of modulating collectively many of the cellular pathways involved in protein metabolism, cell growth, as well as cellular responses to stress and organisation of the extracellular matrix. Thus the W8B2+ CSC secretome contains a multitude of bioactive paracrine factors we have now characterised, that might well be harnessed for therapeutic application for cardiac repair and regeneration.