There is a growing awareness that complex 3-dimensional (3D) organs are not well represented by monolayers of a single cell type - the standard format for many drug screens. To address this ...deficiency, and with the goal of improving screens so that drugs with good efficacy and low toxicity can be identified, microphysiological systems (MPS) are being developed that better capture the complexity of in vivo physiology. We have previously described an organ-on-a-chip platform that incorporates perfused microvessels, such that survival of the surrounding tissue is entirely dependent on delivery of nutrients through the vessels. Here we describe an arrayed version of the platform that incorporates multiple vascularized micro-organs (VMOs) on a 96-well plate. Each VMO is independently-addressable and flow through the micro-organ is driven by hydrostatic pressure. The platform is easy to use, requires no external pumps or valves, and is highly reproducible. As a proof-of-concept we have created arrayed vascularized micro tumors (VMTs) and used these in a blinded screen to assay a small library of compounds, including FDA-approved anti-cancer drugs, and successfully identified both anti-angiogenic and anti-tumor drugs. This 3D platform is suitable for efficacy/toxicity screening against multiple tissues in a more physiological environment than previously possible.
Epiphytic bromeliads represent a major component of Neotropical forests, but the potential effect of climate change on these plants is unclear. We investigated whether and how bromeliads are affected ...by the predicted 3°C temperature rise by the end of the century.
We conducted growth experiments with 17 epiphytic bromeliad species at different temperatures to determine their fundamental thermal niches. By comparing those with niches for germination, we tested whether ontogenetic niche shift or niche contraction occurs in Bromeliaceae. Applying a classical growth analysis, we assessed the relative importance of the underlying growth components on interspecific variations in growth.
Members of two bromeliad subfamilies differed in their response to elevated temperatures: Tillandsioideae may be negatively affected, whereas Bromelioideae moved closer to their thermal optimum. Across different ontogenetic stages, thermal niche characteristics revealed both niche shift and niche contraction. Interspecific variation in growth was driven almost exclusively by net assimilation rate at all temperatures.
We conclude that the vulnerability of tropical plants to a future increase in temperature may be more variable than suggested by previous studies. We emphasize the importance of assessing niche breadth over multiple life stages and the need for better microclimatic data to link laboratory data with field conditions.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NMLJ, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Genome size is known to vary widely across plants. Yet, the evolutionary drivers and consequences of genome size variation across organisms are far from understood. We investigated genome size ...variation and evolution in two major subfamilies of the Neotropical family Bromeliaceae by determining new genome size values for 83 species, testing phylogenetic signal in genome size variation, and assessing the fit to different evolutionary models. For a subset of epiphytic bromeliad species, we also evaluated the relationship of genome size with thermal traits and relative growth rate (RGR), respectively. Genome size variation in Bromelioideae appears to be evolutionary conserved, while genome size among Tillandsioideae varies considerably, not just due to polyploidy but arguably also due to environmental factors. The subfamilies show fundamental differences in genome size and RGR: Bromelioideae have, on average, lower genome sizes than Tillandsioideae and at the same time exhibit higher RGR. We attribute this to different resource use strategies in the subfamilies. Analyses among subfamilies, however, revealed unexpected positive relationships between RGR and genome size, which might be explained by the nutrient regime during cultivation. Future research should test whether there is indeed a trade-off between genome size and growth efficiency as a function of nutrient supply.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
1. By the end of this century, temperature is predicted to increase by about 6 °C at higher latitudes and about 3 °C in the tropics. Although values predicted for tropical latitudes are lower, rising ...temperatures in the tropics are likely to have more severe consequences for tropical species that are generally assumed to have narrower climatic niches due to a higher degree of climatic stability and higher niche specialization. 2. Even though temperature affects all ontogenetic stages, the regeneration niche of a species is fundamental for overall niche breadth and hence represents a potential major bottleneck for its distribution. 3. We conducted germination experiments along a range of temperatures with 41 epiphytic bromeliad species to determine thermal germination traits (thermal niche breadth, lower and upper thermal limit, thermal optimum). Based on these traits, we asked whether the thermal germination niche breadth of these species is wide enough to cope with the predicted increase in temperature. Furthermore, we conducted phylogenetic comparative analyses to detect possible niche conservatism of these traits in Bromeliaceae. 4. For 93% of all tested bromeliad species, the predicted mean annual temperature range does not exceed the thermal niche breadth. Moreover, for 85% of all tested species, the current mean annual temperature across the distribution range is well below our estimates of their thermal optima. Furthermore, we found evidence for phylogenetic niche conservatism in most assessed traits. 5. Synthesis. Our report represents an important first step to understand and predict present and future responses of epiphytic bromeliads to global warming. At least with regard to seed germination, epiphytic bromeliads should not be negatively affected by the predicted temperature rise of 3 °C. To the contrary, future temperatures are closer to the thermal optima of most species, potentially leading to an increase in performance. However, since niche conservatism in Bromeliaceae may limit their adaptability to novel climatic conditions, a negative effect of increasing temperatures cannot be completely rejected when considering ontogenetic niche shifts.
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BFBNIB, FZAB, GIS, IJS, INZLJ, KILJ, NLZOH, NMLJ, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZRSKP
Glioblastomas (GBM) grow in a rich neurochemical milieu, but the impact of neurochemicals on GBM growth is largely unexplored. We interrogated 680 neurochemical compounds in patient-derived GBM ...neural stem cells (GNS) to determine the effects on proliferation and survival. Compounds that modulate dopaminergic, serotonergic, and cholinergic signaling pathways selectively affected GNS growth. In particular, dopamine receptor D4 (DRD4) antagonists selectively inhibited GNS growth and promoted differentiation of normal neural stem cells. DRD4 antagonists inhibited the downstream effectors PDGFRβ, ERK1/2, and mTOR and disrupted the autophagy-lysosomal pathway, leading to accumulation of autophagic vacuoles followed by G0/G1 arrest and apoptosis. These results demonstrate a role for neurochemical pathways in governing GBM stem cell proliferation and suggest therapeutic approaches for GBM.
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•Dopaminergic, serotonergic, and cholinergic pathways affect GNS survival•GBM tumors and patient-derived GNS express functional DRD4 receptor•DRD4 antagonism selectively targets GNS growth in vitro and in vivo•GNS are vulnerable to DRD4-mediated disruption of autophagy-lysosomal pathway
Dolma et al. show that compounds that modulate dopaminergic, serotonergic, and cholinergic signaling pathways selectively affected glioblastoma neural stem cells (GNS). In particular, dopamine receptor D4 antagonists disrupt the autophagy-lysosomal pathway of GNS, leading to growth arrest and apoptosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
To ensure diversity, a partnership was established with the Institute for Population and Precision Health (IPPH) at the University of Chicago (UOC), which also participates in the Precision Medicine ...Initiative, All of Us Research Program, and Chicago Multiethnic Prevention and Surveillance Study. ...clear commitment and careful planning, which begins by involving clinical sites located in traditionally difficult-to-reach populations and implementing focused approaches that facilitate easier trial participation, are crucial for inclusivity. Baseline Participants’ Demographic and Sociodemographic Information Enrolled Participants Count % Total enrollment 269 Female 175 65.1% Male 94 34.9% Age 58.8 ± 8.3 BMI 31.4 ± 7.3 Race Black or African American 183 68.0% White 67 24.9% Asian 6 2.2% American Indian or Alaska Native 1 0.4% Mix 5 1.9% Other 5 1.9% Unknown 2 0.7% Ethnicity Hispanic or Latino 22 8.2% Not Hispanic or Latino 239 88.8% Refuse to answer 3 1.1% Unknown 4 1.5% Not Reported 1 0.4% Insurance Payers Private Payer Insurance 134 63.2% Public Payer: Medicaid 50 23.6% Public Payer: Medicare/Medicare Advantage 64 30.2% Unknown 21 9.9% Marital Status Married 113 42.0% Single 97 36.1% Divorced 25 9.3% Widowed 12 4.5% Author Notes *Presenter
Introduction
Spinal muscular atrophy is a congenital condition associated with mutations in the SMN1 gene. Patients have normal intellectual development, but the natural history is progressive ...respiratory failure resulting in premature death.
Case
Diagnosed with spinal muscular atrophy type 2 in early primary school, the wheelchair‐bound girl developed severe pneumonia on one occasion, when she became critically ill and was admitted to the paediatric intensive care unit with multiorgan dysfunction, requiring mechanical ventilation and high inotropic support. Parents and the patient expressed strong desire for full respiratory and intensive care support to be given. Survived the episode, she is wheelchair ambulatory and continues to pursue a creative artistic career.
Discussion
Children with SMA and their families need to be supported by a comprehensive multi‐disciplinary team to manage this illness. Pediatricians and healthcare givers must provide up‐to‐date health advice on COVID‐19 prophylaxis and management to special groups of patients with respiratory and neurological risks.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Glioblastomas exhibit a hierarchical cellular organization, suggesting that they are driven by neoplastic stem cells that retain partial yet abnormal differentiation potential. Here, we show that a ...large subset of patient-derived glioblastoma stem cells (GSCs) express high levels of Achaete-scute homolog 1 (ASCL1), a proneural transcription factor involved in normal neurogenesis. ASCL1hi GSCs exhibit a latent capacity for terminal neuronal differentiation in response to inhibition of Notch signaling, whereas ASCL1lo GSCs do not. Increasing ASCL1 levels in ASCL1lo GSCs restores neuronal lineage potential, promotes terminal differentiation, and attenuates tumorigenicity. ASCL1 mediates these effects by functioning as a pioneer factor at closed chromatin, opening new sites to activate a neurogenic gene expression program. Directing GSCs toward terminal differentiation may provide therapeutic applications for a subset of GBM patients and strongly supports efforts to restore differentiation potential in GBM and other cancers.
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•GSCs can be classified into two subgroups based on ASCL1 expression•ASCL1 is required for GSCs to undergo neuronal lineage differentiation•ASCL1hi GSCs are responsive to Notch pathway inhibitors•ASCL1 binds closed chromatin to activate target genes that drive neuronal fate
Glioblastoma is characterized by a block in cellular differentiation. Park et al. identify a subset of glioblastoma stem cells (GSCs) that express high levels of the proneural transcription factor ASCL1 and differentiate in response to Notch inhibition, effectively abrogating their stemness properties and tumorigenic potential.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
3D Printing of a BAHA Protective Cap Siu, Alice K. Y.; Lee, Lilian P. Y.; Leung, Samantha M. L.
Ear, nose, & throat journal,
06/2021, Volume:
100, Issue:
3_suppl
Journal Article
Peer reviewed
Open access
Mechanical feedback is one of the most common difficulties encountered when fitting hearing aids for toddlers and young children. We described the use of 3D printing to tailor a protective cap for a ...toddler with bilateral microtia/canal atresia to facilitate bone-anchoring hearing aid use.
The nondetection of dark matter (DM) particles in increasingly stringent laboratory searches has encouraged alternative gravity theories where gravity is sourced only from visible matter. Here, we ...consider whether such theories can pass a two-dimensional test posed by gravitational lensing-to reproduce a particularly detailed Einstein ring in the core of the galaxy cluster A3827. We find that when we require the lensing mass distribution to strictly follow the shape (ellipticity and position angle) of the light distribution of cluster member galaxies, intracluster stars, and the X-ray emitting intracluster medium, we cannot reproduce the Einstein ring, despite allowing the mass-to-light ratios of these visible components to freely vary with radius to mimic alternative gravity theories. Alternatively, we show that the detailed features of the Einstein ring are accurately reproduced by allowing a smooth, freely oriented DM halo in the lens model, with relatively small contributions from the visible components at a level consistent with their observed brightnesses. This dominant DM component is constrained to have the same orientation as the light from the intracluster stars, indicating that the intracluster stars trace the gravitational potential of this component. The Einstein ring of A3827 therefore presents a new challenge for alternative gravity theories: not only must such theories find agreement between the total lensing mass and visible mass, but they must also find agreement between the projected sky distribution of the lensing mass and that of the visible matter, a more stringent test than has hitherto been posed by lensing data.
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