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Supplementary Figures 1-3 from Multipotent CD15+ Cancer Stem Cells in Patched-1–Deficient Mouse Medulloblastoma

Supplementary Figure 9 from Multipotent CD15+ Cancer Stem Cells in Patched-1–Deficient Mouse Medulloblastoma

Supplementary Figure 7 from Multipotent CD15+ Cancer Stem Cells in Patched-1–Deficient Mouse Medulloblastoma

Supplementary Figure 4 from Multipotent CD15+ Cancer Stem Cells in Patched-1–Deficient Mouse Medulloblastoma

Supplementary Figures 4-6 from Multipotent CD15+ Cancer Stem Cells in Patched-1–Deficient Mouse Medulloblastoma

Supplementary Figure 6 from Multipotent CD15+ Cancer Stem Cells in Patched-1–Deficient Mouse Medulloblastoma

Supplementary Figure 1 from Multipotent CD15+ Cancer Stem Cells in Patched-1–Deficient Mouse Medulloblastoma

Supplementary Figure 5 from Multipotent CD15+ Cancer Stem Cells in Patched-1–Deficient Mouse Medulloblastoma

Supplementary Figures 7-9 from Multipotent CD15+ Cancer Stem Cells in Patched-1–Deficient Mouse Medulloblastoma

Supplementary Figure 2 from Multipotent CD15+ Cancer Stem Cells in Patched-1–Deficient Mouse Medulloblastoma

Supplementary Figure 3 from Multipotent CD15+ Cancer Stem Cells in Patched-1–Deficient Mouse Medulloblastoma

Supplementary Figure 8 from Multipotent CD15+ Cancer Stem Cells in Patched-1–Deficient Mouse Medulloblastoma

Influenza, an acute viral respiratory disease that is currently causing severe financial and resource strains worldwide. With the recent COVID-19 pandemic exceeding 153 million cases worldwide, there is a need for a low-cost and contactless surveillance system to detect symptomatic individuals, more so in counties with limited healthcare resources. As with many diseases, there are bio-clinical signals relating to the physical symptoms. The main objective of this study was to develop FluNet, a novel, proof-of-concept, low-cost and contactless device for the detection of high-risk individuals. The system passively conducts face detection in the longwave infrared domain with a precision rating of 0.9798 and mean intersection over union of 0.7386 while sequentially taking the temperature trend of faces with a thermal accuracy of ± 1 K. While in parallel determining if someone in audible proximity is coughing by using a custom deep convolutional neural network with a precision rating of 0.9519. In addition to presenting FluNet, two datasets have been constructed, one for face detection in the longwave infrared domain consisting of 250 images of 20 participants’ faces at various rotations and coverings, including face masks. The other for the real-time detection of cough patterns comprised of a sizeable dataset of 40,482 cough / not cough sounds, coupled with a new lightweight artificial neural network architecture for the classification of cough spectrograms. These findings could be helpful for future low-cost edge computing applications for influenza-like monitoring.

The phenomenology of synaesthesia provides numerous cognitive benefits, which could be used towards augmenting interactive experiences with more refined multisensorial capabilities leading to more engaging and enriched experiences, better designs, and more transparent human-machine interfaces. In this study, we report a novel framework for the transformation of odours into the visual domain by applying the ideology from synaesthesia, to a low cost, portable, augmented reality/virtual reality system. The benefits of generating an artificial form of synesthesia are outlined and implemented using a custom made electronic nose to gather information about odour sources which is then sent to a mobile computing engine for characterisation, classification, and visualisation. The odours are visualised in the form of coloured 2D abstract shapes in real-time. Our results show that our affordable system has the potential to increase human odour discrimination comparable to that of natural syneasthesia highlighting the prospects for augmenting human-machine interfaces with an artificial form of this phenomenon.

Predicting olfactory perception with an electronic nose can aid in the design and evaluation of olfactory-based experiences. We investigate whether the human perception of odours can be predicted outside the bounds of perceived pleasantness and semantic descriptors. We tuned an electronic nose to predict an odour's colour in the CIELAB colour space using human judgements. This revealed that the crossmodal associations people have towards colours could be predicted. Our electronic nose system can predict an odour's colour with a 70 – 81% machine-human similarity rating. These findings suggest a systematic and predictable link exists between the chemical features of odours and the colour associated to them. These findings highlight the possibilities of predicting human olfactory perception using an electronic nose.

Mobile HMDs must sacrifice compute performance to achieve ergonomic and power requirements for extended use. Consequently, applications must either reduce rendering and simulation complexity - along with the richness of the experience - or offload complexity to a server. Within the context of edge-computing, a popular way to do this is through render streaming. Render streaming has been demonstrated for desktops and consoles. It has also been explored for HMDs. However, the latency requirements of head tracking make this application much more challenging. While mobile GPUs are not yet as capable as their desktop counterparts, we note that they are becoming more powerful and efficient. With the hard requirements of VR, it is worth continuing to investigate what schemes could optimally balance load, latency and quality. We propose an alternative we call edge-physics: streaming at the scene-graph level from a simulation running on edge-resources, analogous to cluster rendering. Scene streaming is not only straightforward, but compute and bandwidth efficient. The most demanding loops run locally. Jobs that hit the power-wall of mobile CPUs are off-loaded, while improving GPUs are leveraged, maximising compute utilisation. In this paper we create a prototypical implementation and evaluate its potential in terms of fidelity, bandwidth and performance. We show that an effective system which maintains high consistencies on typical edge-links can be easily built, but that some traditional concepts are not applicable, and a better understanding of the perception of motion is required to evaluate such a system comprehensively.

Distributed Virtual Environments (DVEs) are challenging to create as the goals of consistency and responsiveness become contradictory under increasing latency. DVEs have been considered as both distributed transactional databases and force-reflection systems. Both are good approaches, but they do have drawbacks. Transactional systems do not support Level 3 (L3) collaboration: manipulating the same degree-of-freedom at the same time. Force-reflection requires a client-server architecture and stabilisation techniques. With Consensus Based Networking (CBN), we suggest DVEs be considered as a distributed data-fusion problem. Many simulations run in parallel and exchange their states, with remote states integrated with continous authority. Over time the exchanges average out local differences, performing a distribued-average of a consistent, shared state. CBN aims to build simulations that are highly responsive, but consistent enough for use cases such as the piano-movers problem. CBN's support for heterogeneous nodes can transparently couple different input methods, avoid the requirement of determinism, and provide more options for personal control over the shared experience. Our work is early, however we demonstrate many successes, including L3 collaboration in room-scale VR, 1000's of interacting objects, complex configurations such as stacking, and transparent coupling of haptic devices. These have been shown before, but each with a different technique; CBN supports them all within a single, unified system.

A novel strategy for the direct analysis of non-conjugated steroids in water using paper spray mass spectrometry (PS-MS) has been developed. PS-MS was used in the identification and quantification of non-conjugated (free) steroids in fish tank water samples. Data shown herein indicates that individual amounts of free steroids can be detected in aqua as low as; 0.17 ng/µL, 0.039 ng/µL, 0.43 ng/µL, 0.0076 ng/µL for aldosterone, corticosterone, cortisol, and β-estrone, respectively, and with an average relative standard deviation of ca. in aqua.

Crossmodal correspondences are the associations between apparently distinct stimuli in different sensory modalities . These associations, albeit surprising, are generally shared in most of the population. Olfaction is ingrained in the fabric of our daily life and constitutes an integral part of our perceptual reality, with olfaction being more commonly used in the entertainment and analytical domains, it is crucial to uncover the robust correspondences underlying common aromatic compounds. Towards this end, we investigated an aggregate of crossmodal correspondences between ten olfactory stimuli and other modalities ( angularity of shapes, smoothness of texture, pleasantness, pitch, colours, musical genres and emotional dimensions ) using a large sample of 68 observers. We uncover the correspondences between these modalities and extent of these associations with respect to the explicit knowledge of the respective aromatic compound. The results revealed the robustness of prior studies, as well as, contributions towards olfactory integration between an aggregate of other dimensions. The knowledge of an odour's identity coupled with the multisensory perception of the odours indicates that these associations, for the most part, are relatively robust and do not rely on explicit knowledge of the odour. Through principal component analysis of the perceptual ratings, new cross-model mediations have been uncovered between odours and their intercorrelated sensory dimensions. Our results demonstrate a collective of associations between olfaction and other dimensions, potential cross modal mediations via exploratory factor analysis and the robustness of these correspondence with respect to the explicit knowledge of an odour. We anticipate the findings reported in this paper could be used as a psychophysical framework aiding in a collective of applications ranging from olfaction enhanced multimedia to marketing.

Developmental signal transduction pathways act diversely, with context-dependent roles across systems and disease types. Glioblastomas (GBMs), which are the poorest prognosis primary brain cancers, strongly resemble developmental systems, but these growth processes have not been exploited therapeutically, likely in part due to the extreme cellular and genetic heterogeneity observed in these tumors. The role of Wnt/βcatenin signaling in GBM stem cell (GSC) renewal and fate decisions remains controversial. Here, we report context-specific actions of Wnt/βcatenin signaling in directing cellular fate specification and renewal. A subset of primary GBM-derived stem cells requires Wnt proteins for self-renewal, and this subset specifically relies on Wnt/βcatenin signaling for enhanced tumor burden in xenograft models. In an orthotopic Wnt reporter model, Wnthi GBM cells (which exhibit high levels of βcatenin signaling) are a faster-cycling, highly self-renewing stem cell pool. In contrast, Wntlo cells (with low levels of signaling) are slower cycling and have decreased self-renewing potential. Dual inhibition of Wnt/βcatenin and Notch signaling in GSCs that express high levels of the proneural transcription factor ASCL1 leads to robust neuronal differentiation and inhibits clonogenic potential. Our work identifies new contexts for Wnt modulation for targeting stem cell differentiation and self-renewal in GBM heterogeneity, which deserve further exploration therapeutically.

Effective strategies to reverse or prevent chemotherapeutic resistance are required before cancer therapies can be curative. Telomerase is the ribonucleoprotein responsible for de novo synthesis and maintenance of telomeres, and its activity is predominantly observed in cancer cells. The telomerase enzyme has been successfully inhibited or inactivated to sensitize cells to cellular stresses; however, no studies have determined yet the effect of combining a pharmacological inhibitor of telomerase catalysis and traditional chemotherapeutics for the treatment of drug-sensitive or drug-resistant cancers. Here, we describe the effect of 2-[(E)-3-naphtalen-2-yl-but-2-enoylamino]-benzoic acid (BIBR1532), a small-molecule inhibitor of telomerase catalytic activity, on drug-resistant leukemia and breast cancer cells and their parental counterparts when treated in combination with chemotherapeutics. We observed that BIBR1532-treated cells show progressive telomere shortening, decreased proliferative capacity, and sensitization to chemotherapeutic treatment. These effects are telomere length-dependent, because cells insensitive to BIBR1532 or cells released from telomerase inhibition did not demonstrate changes in growth ability or drug sensitivity. Our novel observations suggest that pharmacological telomerase inhibition in combination therapy may be a valid strategy for the treatment of both drug-sensitive and drug-resistant cancers.

Subpopulations of tumorigenic cells have been identified in many human tumors, although these cells may not be very rare in some types of cancer. Here, we report that medulloblastomas arising from Patched-1–deficient mice contain a subpopulation of cells that show a neural precursor phenotype, clonogenic and multilineage differentiation capacity, activated Hedgehog signaling, wild-type Patched-1 expression, and the ability to initiate tumors following allogeneic orthotopic transplantation. The normal neural stem cell surface antigen CD15 enriches for the in vitro proliferative and in vivo tumorigenic potential from uncultured medulloblastomas, supporting the existence of a cancer stem cell hierarchy in this clinically relevant mouse model of cancer. [Cancer Res 2009;69(11):4682–90]

According to the cancer stem cell hypothesis, only a subpopulation of cells within a cancer has the capacity to sustain tumor growth. This subpopulation of cells is made up of cancer stem cells, which are defined simply as the population of cells within a tumor that can self-renew, differentiate, and regenerate a phenocopy of the cancer when injected in vivo. Cancer stem cells have now been prospectively isolated from human cancers of the blood, breast, and brain, and putative cancer stem cells have been identified from human skin, bone, and prostate tumors and from multiple established mammalian cancer cell lines. Furthermore, researchers are actively seeking cancer stem cells in every human cancer type. We present the current scientific evidence supporting the cancer stem cell hypothesis and discuss the experimental and therapeutic implications of the discovery of human cancer stem cells.

The identification of self-renewing and multipotent neural stem cells (NSCs) in the mammalian brain holds promise for the treatment of neurological diseases and has yielded new insight into brain cancer1,2,3. However, the complete repertoire of signaling pathways that governs the proliferation and self-renewal of NSCs, which we refer to as the 'ground state', remains largely uncharacterized. Although the candidate gene approach has uncovered vital pathways in NSC biology4,5,6,7,8, so far only a few highly studied pathways have been investigated. Based on the intimate relationship between NSC self-renewal and neurosphere proliferation8, we undertook a chemical genetic screen for inhibitors of neurosphere proliferation in order to probe the operational circuitry of the NSC. The screen recovered small molecules known to affect neurotransmission pathways previously thought to operate primarily in the mature central nervous system; these compounds also had potent inhibitory effects on cultures enriched for brain cancer stem cells. These results suggest that clinically approved neuromodulators may remodel the mature central nervous system and find application in the treatment of brain cancer.

Telomerase-mediated telomeric DNA synthesis is important for eukaryotic cell immortality. Telomerase adds tracts of short telomeric repeats to DNA substrates using a unique repeat addition form of processivity. It has been proposed that repeat addition processivity is partly regulated by a telomerase reverse transcriptase (TERT)-dependent anchor site; however, anchor site-mediating residues have not been identified in any TERT. We report the characterization of an N-terminal human TERT (hTERT) RNA interaction domain 1 (RID1) mutation that caused telomerase activity defects consistent with disruption of a template-proximal anchor site, including reduced processivity on short telomeric primers and reduced activity on substrates with nontelomeric 5′ sequences, but not on primers with nontelomeric G-rich 5′ sequences. This mutation was located within a subregion of RID1 previously implicated in biological telomerase functions unrelated to catalytic activity (N-DAT domain). Other N-DAT and C-terminal DAT (C-DAT) mutants and a C-terminally tagged hTERT-HA variant were defective in elongating short telomeric primers, and catalytic phenotypes of DAT variants were partially or completely rescued by increasing concentrations of DNA primers. These observations imply that RID1 and the hTERT C terminus contribute to telomerase's affinity for its substrate, and that RID1 may form part of the human telomerase anchor site.

Dyskeratosis congenita (DC) is a rare multi-system syndrome characterized by nail dystrophy, abnormal skin pigmentation and mucosal leukoplakia. The gene mutated in the X-linked form of human DC encodes for dyskerin, a nucleolar pseudourydilase that is involved in rRNA maturation. Dyskerin is also involved in telomerase function through its interaction with the telomerase RNA (hTR). Mutations in dyskerin result in low levels of hTR, decreased telomerase activity and telomere shortening. Autosomal dominant DC is characterized by mutations in hTR, supporting the hypothesis that the DC phenotype may be caused by impaired telomere maintenance. Several mutations have been identified in different regions of hTR in patients affected by autosomal dominant DC. Recent reports have shown that coexpression of wild-type hTR with hTR harboring mutations found in the pseudoknot domain does not affect telomerase activity in vitro. However, these studies did not assess the consequences of mutant hTR expression at the telomeres. Here we provide the first direct in vivo evidence that a mutant hTR carrying the GC to AG double substitution in the pseudoknot at nucleotides 107-108 found in patients affected by autosomal dominant DC does not behave as a dominant-negative for telomere maintenance. Rather it reconstitutes a weakly active telomerase enzyme, which is defective in telomere elongation.

Hedgehog (Hh) signaling is essential for embryonic development and adult homeostasis. Aberrant pathway activity can result in various developmental disorders and tumors. The Hh receptor Patched (PTCH1) is a negative regulator of the pathway and acts as a tumor suppressor. We and others have shown that suppressor of fused (SU(FU)) and KIF7 are two major negative regulators of the pathway downstream of PTCH1. Medulloblastoma (MB), the most common and aggressive pediatric brain tumor arising in the cerebellum, involves deregulation of Hh signaling. Similar to those observed in patients with PTCH1 mutations, Ptc1+/− mice spontaneously develop MB. In Ptc1+/− mice, the incidence of MB increases upon exposure to DNA damaging agents or a compounded loss of other tumor suppressor genes, such as p53. SU(FU) mutations have been found in MB, suggesting that SU(FU) is also a tumor suppressor in the cerebellum. However, we found that Su(fu)+/− mice do not develop any spontaneous MB, and that upon neonatal exposure to X-ray irradiation as well as a chemical carcinogen, these mice do not form any tumors. To examine the potential tumor suppressor function of Su(fu) in the brain, we performed conditional deletion of Su(fu) in neural progenitors. In mice, deletion of Su(fu) in neural progenitors using the Nestin-Cre line resulted in a disorganized cerebellum and motor defects. Unexpectedly, unlike Nestin-Cre;Ptc1f/- mice which developed MB, MB formation was not observed in Nestin-Cre;Su(fu)f/- mice. In contrast, similar to those reported previously, 100% of Su(fu)+/−;p53−/− mice developed MB between 2.5–4 months of age. Molecular analysis of primary tumor cell lines from these MBs revealed a loss of the wild type Su(fu) allele in the tumors. Together, these observations indicate that loss of Su(fu) alone is not sufficient for transformation into MB and suggest that other molecules, such as Kif7, may possess compensatory functions in the suppression of the tumor phenotype. Currently, we are examining the effects of Kif7 inactivation alone and in conjunction with Su(fu) inactivation on MB formation. Citation Information: Cancer Res 2009;69(23 Suppl):B29.

The identification of self-renewing and multipotent neural stem cells (NSCs) in the mammalian brain holds promise for the treatment of neurological diseases and has yielded newinsight into brain cancer. However, the complete repertoire of signaling pathways that governs the proliferation and self-renewal of NSCs, which we refer to as the ‘ground state’, remains largely uncharacterized. Although the candidate gene approach has uncovered vital pathways in NSC biology, so far only a few highly studied pathways have been investigated. Based on the intimate relationship between NSC self-renewal and neurosphere proliferation,we undertook a chemical genetic screen for inhibitors of neurosphere proliferation in order to probe the operational circuitry of the NSC. The screen recovered small molecules known to affect neurotransmission pathways previously thought to operate primarily in the mature central nervous system; these compounds also had potent inhibitory effects on cultures enriched for brain cancer stem cells. These results suggest that clinically approved neuromodulators may remodel the mature central nervous system and find application in the treatment of brain cancer. (colour figure available in PDF version)