Background
Dorsal root ganglion neuron-derived immortal cell lines including ND7/23 and F-11 cells have been used extensively as in vitro model systems of native peripheral sensory neurons. However, ...while it is clear that some sensory neuron-specific receptors and ion channels are present in these cell lines, a systematic comparison of the molecular targets expressed by these cell lines with those expressed in intact peripheral neurons is lacking.
Results
In this study, we examined the expression of RNA transcripts in the human neuroblastoma-derived cell line, SH-SY5Y, and two dorsal root ganglion hybridoma cell lines, F-11 and ND7/23, using Illumina next-generation sequencing, and compared the results with native whole murine dorsal root ganglions. The gene expression profiles of these three cell lines did not resemble any specific defined dorsal root ganglion subclass. The cell lines lacked many markers for nociceptive sensory neurons, such as the Transient receptor potential V1 gene, but expressed markers for both myelinated and unmyelinated neurons. Global gene ontology analysis on whole dorsal root ganglions and cell lines showed similar enrichment of biological process terms across all samples.
Conclusions
This paper provides insights into the receptor repertoire expressed in common dorsal root ganglion neuron-derived cell lines compared with whole murine dorsal root ganglions, and illustrates the limits and potentials of these cell lines as tools for neuropharmacological exploration.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The human kidney contains up to 2 million epithelial nephrons responsible for blood filtration. Regenerating the kidney requires the induction of the more than 20 distinct cell types required for ...excretion and the regulation of pH, and electrolyte and fluid balance. We have previously described the simultaneous induction of progenitors for both collecting duct and nephrons via the directed differentiation of human pluripotent stem cells. Paradoxically, although both are of intermediate mesoderm in origin, collecting duct and nephrons have distinct temporospatial origins. Here we identify the developmental mechanism regulating the preferential induction of collecting duct versus kidney mesenchyme progenitors. Using this knowledge, we have generated kidney organoids that contain nephrons associated with a collecting duct network surrounded by renal interstitium and endothelial cells. Within these organoids, individual nephrons segment into distal and proximal tubules, early loops of Henle, and glomeruli containing podocytes elaborating foot processes and undergoing vascularization. When transcription profiles of kidney organoids were compared to human fetal tissues, they showed highest congruence with first trimester human kidney. Furthermore, the proximal tubules endocytose dextran and differentially apoptose in response to cisplatin, a nephrotoxicant. Such kidney organoids represent powerful models of the human organ for future applications, including nephrotoxicity screening, disease modelling and as a source of cells for therapy.
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DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
The remodeling of specific calcium-permeable ion channels is a feature of some breast cancer subtypes. ORAI1 is a protein that forms a calcium-permeable ion channel responsible for store-operated ...calcium entry (SOCE) in a variety of cell types. ORAI3, a related isoform, is not a regulator of SOCE in most cell types. However, ORAI3 does control SOCE in many estrogen receptor-positive breast cancer cell lines, where it also controls proliferation. ORAI1 is a well-characterized regulator of the proliferation and migration of many basal breast cancer cells; however, the role of ORAI3 in these types of breast cancer cells remains unclear. Here, we sought to define
and
expression in breast cancer cell lines of different molecular subtypes and assess the potential role and regulation of ORAI3 in basal breast cancer cells. Our study demonstrates that elevated
is a feature of basal-like breast cancers, while elevated
is a feature of luminal breast cancers. Intriguingly, we found that
is over-expressed in the mesenchymal subtype of triple-negative breast cancer. Given this, we assessed
levels in the presence of two inducers of the mesenchymal phenotype, hypoxia and epidermal growth factor (EGF). Hypoxia induced
levels in basal breast cancer cell lines through a pathway involving hypoxia-inducible factor-1 alpha (HIF1α. The silencing of ORAI3 attenuated hypoxia-associated phosphorylation of the EGF receptor (EGFR) and the expression of genes associated with cell migration and inflammatory/immune responses in the MDA-MB-468 model of basal breast cancer. Although elevated
levels were not associated with survival; basal, estrogen receptor-negative and triple-negative breast cancers with high
and low
levels were associated with poorer clinical outcomes. This study defines ORAI3 as a potential fine-tuner for processes relevant to the progression of basal breast cancers.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Temple-Baraitser syndrome (TBS) is a multisystem developmental disorder characterized by intellectual disability, epilepsy, and hypoplasia or aplasia of the nails of the thumb and great toe. Here we ...report damaging de novo mutations in KCNH1 (encoding a protein called ether à go-go, EAG1 or KV10.1), a voltage-gated potassium channel that is predominantly expressed in the central nervous system (CNS), in six individuals with TBS. Characterization of the mutant channels in both Xenopus laevis oocytes and human HEK293T cells showed a decreased threshold of activation and delayed deactivation, demonstrating that TBS-associated KCNH1 mutations lead to deleterious gain of function. Consistent with this result, we find that two mothers of children with TBS, who have epilepsy but are otherwise healthy, are low-level (10% and 27%) mosaic carriers of pathogenic KCNH1 mutations. Consistent with recent reports, this finding demonstrates that the etiology of many unresolved CNS disorders, including epilepsies, might be explained by pathogenic mosaic mutations.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
The drastic reduction in launch and manufacturing costs of space hardware has facilitated the emergence of "commercial" space. Radiation‐hard organometal halide perovskite solar cells (PSCs) with ...low‐cost and high‐efficiency potentials are promising for space applications.High‐efficiency PSCs are tested with different hole transport materials (HTMs) and dopants on 175µm sapphire substrates under 7MeV‐proton‐irradiation‐tests at accumulated fluences of 1011, 1012, and 1013 protons cm−2. While all cells retain >90% of their initial power conversion efficiencies (PCEs) after 1011 protons cm−2 irradiation, PSCs that have tris(pentafluorophenyl)borane (TPFB) as the HTM dopant and polybis(4‐phenyl)(2,5,6‐trimethylphenyl) amine (PTAA) or PTAA:C8BTBT (C8BTBT = 2,7‐Dioctyl1benzothieno3,2‐b1benzothiophene) as the HTM are more tolerant to higher‐fluence radiation than their counterparts with the lithium bis(trifluoromethanesulfonyl)imide (LiTFSI) dopant and the 2,2′,7,7′‐TetrakisN,N‐di(4‐methoxyphenyl)amino‐9,9′‐spirobifluorene (Spiro‐OMeTAD) HTM. Radiation induces fluorine diffusion from the LiTFSI dopant toward the perovskite absorber (confirmed by depth‐resolved X‐ray photoelectron spectroscopy) introducing defects. Radiation‐induced defects in cells with the TPFB dopant instead are different and can be “annealed out” by thermal vacuum resulting in PCE recovery. This is the first report using thermal admittance spectroscopy and deep‐level transient spectroscopy for defect analyses on proton‐irradiated and thermal‐vacuum‐recovered PSCs. The insights generated are expected to contribute to efforts in developing low‐cost light‐weight solar cells for space applications.
High‐efficiency perovskite solar cells are tested with different hole transport materials and dopants on 175‐µm sapphire under 7‐MeV proton radiation. Thermal vacuum recovers the radiation‐induced damage for cells free of 2,2′,7,7′‐TetrakisN,N‐di(4‐methoxyphenyl)amino‐9,9′‐spirobifluorene (Spiro‐OMeTAD) and lithium bis(trifluoromethanesulfonyl)imide (LiTFSI) as evidenced by thermal admittance spectroscopy and deep‐level transient spectroscopy, making them suitable for space.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The lymphatic vasculature plays roles in tissue fluid balance, immune cell trafficking, fatty acid absorption, cancer metastasis, and cardiovascular disease. Lymphatic vessels form by ...lymphangiogenesis, the sprouting of new lymphatics from pre-existing vessels, in both development and disease contexts. The apical signaling pathway in lymphangiogenesis is the VEGFC/VEGFR3 pathway, yet how signaling controls cellular transcriptional output remains unknown. We used a forward genetic screen in zebrafish to identify the transcription factor mafba as essential for lymphatic vessel development. We found that mafba is required for the migration of lymphatic precursors after their initial sprouting from the posterior cardinal vein. mafba expression is enriched in sprouts emerging from veins, and we show that mafba functions cell-autonomously during lymphatic vessel development. Mechanistically, Vegfc signaling increases mafba expression to control downstream transcription, and this regulatory relationship is dependent on the activity of SoxF transcription factors, which are essential for mafba expression in venous endothelium. Here we identify an indispensable Vegfc-SoxF-Mafba pathway in lymphatic development.
Perovskite materials have generated significant interest from academia and industry as a potential component in next-generation, high-efficiency, low-cost, photovoltaic (PV) devices. The record ...efficiency reported for perovskite solar cells has risen rapidly, and is now more than 22%. However, due to their complex dynamic behaviour, the process of measuring the efficiency of perovskite solar cells appears to be much more complicated than for other technologies. It has long been acknowledged that this is likely to greatly reduce the reliability of reported efficiency measurements, but the quantitative extent to which this occurs has not been determined. To investigate this, we conduct the first major inter-comparison of this PV technology. The participants included two labs accredited for PV performance measurement (CSIRO and NREL) and eight PV research laboratories. We find that the inter-laboratory measurement variability can be almost ten times larger for a slowly responding perovskite cell than for a control silicon cell. We show that for such a cell, the choice of measurement method, far more so than measurement hardware, is the single-greatest cause for this undesirably large variability. We provide recommendations for identifying the most appropriate method for a given cell, depending on its stabilisation and degradation behaviour. The results of this study suggest that identifying a consensus technique for accurate and meaningful efficiency measurements of perovskite solar cells will lead to an immediate improvement in reliability. This, in turn, should assist device researchers to correctly evaluate promising new materials and fabrication methods, and further boost the development of this technology.
The ability of influenza A viruses (IAVs) to cross species barriers and evade host immunity is a major public health concern. Studies on the phylodynamics of IAVs across different scales - from the ...individual to the population - are essential for devising effective measures to predict, prevent or contain influenza emergence. Understanding how IAVs spread and evolve during outbreaks is critical for the management of epidemics. Reconstructing the transmission network during a single outbreak by sampling viral genetic data in time and space can generate insights about these processes. Here, we obtained intra-host viral sequence data from horses infected with equine influenza virus (EIV) to reconstruct the spread of EIV during a large outbreak. To this end, we analyzed within-host viral populations from sequences covering 90% of the infected yards. By combining gene sequence analyses with epidemiological data, we inferred a plausible transmission network, in turn enabling the comparison of transmission patterns during the course of the outbreak and revealing important epidemiological features that were not apparent using either approach alone. The EIV populations displayed high levels of genetic diversity, and in many cases we observed distinct viral populations containing a dominant variant and a number of related minor variants that were transmitted between infectious horses. In addition, we found evidence of frequent mixed infections and loose transmission bottlenecks in these naturally occurring populations. These frequent mixed infections likely influence the size of epidemics.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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