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P53 is frequently mutated in most human cancers, including glioblastoma (GBM). Many p53 mutants acquire gain-of-function oncogenic effects through only partially understood mechanisms. To investigate the role of gain-of-function mutant p53 (MUT-p53) in GBM, we performed ChIP-seq of wildtype p53 (WT-p53) and MUT-p53 GBM cell lines. Among 2834 unique peaks reads in MUT-p53 cells, we found 242 long non-coding RNAs (lncRNAs) with up to 145 fold enrichment relative to WT-p53. LncRNAs regulate many molecular and cellular functions, including gene expression, cell proliferation, death, cancer stem cell renewal and differentiation. We selected lncRNAs SOX21-AS1 and LINC00643 with highly enriched binding by MUT-p53 and investigated their expressions and functions in the p53 pathway. We performed ChIP confirmation of MUT-p53 binding to the promoters of these lncRNAs. We found that these lncRNAs are deregulated in GBM and correlated with GBM patient survival in the TCGA database. To investigate the functions of these LncRNAs, we knocked down their expressions by siRNA, and found significant cell death induced by si-SOX21-AS1, but not by si-LINC00643. Overexpression of LINC00643 in GBM cells led to inhibition of GBM cell proliferation, migration, invasion and in vivo xenograft growth. LINC00643 mediated the effects of MUT-p53. Co-expression of human LINC00643 and its mouse homologous in a RCAS transgenic mouse model of GBM reduced tumor growth and improved animal survival. To elucidate the mechanisms of action of the lncRNA, we performed Chromatin Isolation by RNA purification high-throughput sequencing (CHIRP-seq) to identify its binding targets. We found that LINC00643 binds to HIF1a 5’ promoter/enhancer region. Overexpression of LINC00643 in GBM cells at hypoxia growth condition reduced HIF1a mRNA and protein expression. Our study shows for the first time that gain-of-function mutant p53 regulates a subset of lncRNAs and that the lncRNAs mediate the oncogenic effects of the MUT-p53 in GBM.

YAP1 is a transcriptional co-activator and oncogene under the control of the Hippo Signaling Pathway. Functional inactivation of Hippo Pathway tumor suppressors, including NF2, are frequent events in human cancers. Meningiomas are the most common primary brain tumors, and a large percentage exhibit heterozygous loss of chromosome 22 (harboring the NF2 gene) and functional inactivation of the remaining NF2 gene copy, implicating oncogenic YAP activity in the pathobiology of almost half of these tumors. An alternate type of activating YAP1 mutation are YAP1 gene fusions that have been identified in several cancer subtypes. Recently, fusions between YAP1 and MAML2 have been identified in a subset of pediatric NF2-wild type meningiomas. Here, we show that the expression profile of human YAP1-MAML2-positive pediatric meningiomas resembles that of the common NF2-mutant meningiomas based on global and YAP-related gene expression signatures. We then use the RCAS/tv-a system for postnatal gene transfer and show that the intracranial expression of YAP1-MAML2 in neonatal mice results in the formation of meningioma-like tumors that exert a similar gene expression pattern as seen in human YAP1 fusion-positive and NF2-mutant meningiomas and regulate classical YAP1 target genes. We demonstrate that YAP1-MAML2 exerts oncogenic YAP activity that is resistant to inhibitory Hippo pathway signaling and relies on the interaction with TEAD transcription factors. Pharmacological disruption of this interaction is sufficient to inhibit the viability of YAP1-MAML2-expressing mouse tumors ex vivo. Finally, we show that constitutively active YAP1 (S127/397A-YAP1) is also sufficient to cause the formation of similar meningioma-like tumors suggesting that the YAP component of the gene fusion is the critical driver of these tumors. In summary, our results implicate YAP1-MAML2 as a sufficient oncogenic driver in YAP1-MAML2 fusion-positive meningiomas, which mimic NF2-mutant meningiomas, and highlight TEAD-dependent YAP activity as a potential therapeutic target in these tumors.

BACKGROUND Oligodendroglioma, IDH-mutant and 1p/19q-codeleted has variable outcomes that are strongly influenced by patient age. This study aimed to discover novel molecular biomarkers that may characterize an aggressive subgroup of oligodendroglioma that is associated with, but independently prognostic of patient age. METHODS Differential gene expression analysis, gene ontology analysis, and gene set enrichment analysis were conducted on TCGA RNA-seq data (N=169) to identify genes and pathways that differ significantly between older and younger patients. Genes whose expression was associated with age and survival in multivariate analyses were further studied using DNA methylation (N=171). The prognostic value of their expression and methylation profiles was then compared to known genomic biomarkers, radiographic features, and histopathologic features. RNA-seq and DNA methylation validation data were obtained from the CGGA (N=44) and a cohort published by Capper et al. (N=144), respectively. RESULTS Highly activated pathways in older oligodendrogliomas were linked to developmental transcription factors. Overexpression of HOXD12 was associated with patient age and survival in the TCGA (FDR< 0.01, FDR=1e-5) and the CGGA (p=0.03, p< 1e-3). Hypermethylation of HOXD12 was associated with age, tumor grade, and survival in the TCGA (p< 1e-5, p< 0.001, p< 1e-3) and with age and tumor grade in Capper et al. (p< 0.02, p=0.001). In the TCGA, HOXD12 hypermethylation and overexpression were independently prognostic of NOTCH1 and PIK3CA mutations, loss of 15q, and MYC activation as well as mitotic figures, Ki-67 index, microvascular proliferation, and necrosis. HOXD12 overexpression was also independently prognostic of T1-post contrast enhancement, whole tumor volume, and peritumoral edema volume. We developed a risk-stratification nomogram predicting 5- and 10-year overall survival using patient age, HOXD12 methylation, and WHO grade. CONCLUSIONS HOXD12 overexpression and hypermethylation are associated with an aggressive subtype of oligodendroglioma and may serve as superior prognostic biomarkers than previously reported genomic, radiographic, and histopathologic features.

As larger, higher-quality quantum devices are built and demonstrated in quantum information applications, such as quantum computation and quantum communication, the need for high-quality quantum memories to store quantum states becomes ever more pressing. Future quantum devices likely will use a variety of physical hardware, some being used primarily for processing of quantum information and others for storage. Here, we study the correlation of the structure of quantum information with physical noise models of various possible quantum memory implementations. Through numerical simulation of different noise models and approximate analytical formulas applied to a variety of interesting quantum states, we provide comparisons between quantum hardware with different structure, including both qubit- and qudit-based quantum memories. Our findings point to simple, experimentally relevant formulas for the relative lifetimes of quantum information in different quantum memories and have relevance to the design of hybrid quantum devices., Comment: 12 pages, 7 figures

Myeloid cells and macrophages have been shown to promote immunosuppression in high-grade gliomas (HGG), however their roles in malignant progression of low-grade glioma (LGG) are poorly understood. Here, we investigated the heterogeneity of the immune microenvironment during glioma progression using a murine model that recapitulates the malignant progression of low to high-grade glioma. To that end, we performed single-cell RNA sequencing on CD45+ immune cells isolated from animals bearing no tumor (NT), LGG, and HGG. We observed an increased infiltration of CD4+ T cells, CD8+ T cells, B cells, and natural killer cells in the tumor microenvironment of LGG, whereas this infiltration was abrogated in HGG. Our study identified two distinct macrophage clusters across all 3 samples, with signatures of bone marrow derived and resident macrophages, respectively. These macrophages showed an immune-activated phenotype (Stat1, Tnf, Cxcl9 and Cxcl10) in LGG, but then evolved to a more immunosuppressive state (Lgals3, Apoc1 and Id2) in HGG, restricting T cell recruitment and activation. In addition, we identified CD74 and macrophage migration inhibition factor (MIF) as potential targets for both these distinct macrophage populations, based on their increased expression in LGG and HGG compared to NT. Targeting these factors during the LGG therapeutic window may inhibit myeloid cells and intra-tumoral macrophages and attenuate their immunosuppressive properties and impair malignant progression.

We propose a method for enacting the unitary time propagation of two interacting neutrons at leading order of chiral effective-field theory by efficiently encoding the nuclear dynamics into a single multilevel quantum device. The emulated output of the quantum simulation shows that, by applying a single gate that draws on the underlying characteristics of the device, it is possible to observe multiple cycles of the nuclear dynamics before the onset of decoherence. Owing to the signal's longevity, we can then extract spectroscopic properties of the simulated nuclear system. This allows us to validate the encoding of the nuclear Hamiltonian and the robustness of the simulation in the presence of quantum-hardware noise by comparing the extracted spectroscopic information to exact calculations. This work paves the way for transformative calculations of the dynamical properties of nuclei on near-term quantum devices.

For quantum computing to become fault tolerant, the underlying quantum bits must be effectively isolated from the noisy environment. It is well known that including an electromagnetic bandgap around the qubit operating frequency improves coherence for superconducting circuits. However, investigations of bandgaps to other environmental coupling mechanisms remain largely unexplored. Here we present a method to enhance the coherence of superconducting circuits by introducing a phononic bandgap around the device operating frequency. The phononic bandgaps block resonant decay of defect states within the gapped frequency range, removing the electromagnetic coupling to phonons at the gap frequencies. We construct a multi-scale model that derives the decrease in the density of states due to the bandgap and the resulting increase in defect state $T_1$ times. We demonstrate that emission rates from in-plane defect states can be suppressed by up to two orders of magnitude. We combine these simulations with theory for resonators operated in the continuous-wave regime and show that improvements in quality factors are expected by up to the enhancement in defect $T_1$ times. Furthermore, we use full master equation simulation to demonstrate the suppression of qubit energy relaxation even when interacting with 200 defects states. We conclude with an exploration of device implementation including tradeoffs between fabrication complexity and qubit performance., The following article has been submitted to Applied Physics Letters

Qubit information processors are increasing in footprint but currently rely on e-beam lithography for patterning the required Josephson junctions (JJs). Advanced optical lithography is an alternative patterning method, and we report on the development of transmon qubits patterned solely with optical lithography. The lithography uses 193 nm wavelength exposure and 300-mm large silicon wafers. Qubits and arrays of evaluation JJs were patterned with process control which resulted in narrow feature distributions: a standard deviation of 0:78% for a 220 nm linewidth pattern realized across over half the width of the wafers. Room temperature evaluation found a 2.8-3.6% standard deviation in JJ resistance in completed chips. The qubits used aluminum and titanium nitride films on silicon substrates without substantial silicon etching. T1 times of the qubits were extracted at 26 - 27 microseconds, indicating a low level of material-based qubit defects. This study shows that large wafer optical lithography on silicon is adequate for high-quality transmon qubits, and shows a promising path for improving many-qubit processors., 7 pages, 4 figures, submitted to Quantum Science and Technology

Superconducting circuit testing and materials loss characterization requires robust and reliable methods for the extraction of internal and coupling quality factors of microwave resonators. A common method, imposed by limitations on the device design or experimental configuration, is the single-port reflection geometry, i.e. reflection-mode. However, impedance mismatches in cryogenic systems must be accounted for through calibration of the measurement chain while it is at low temperatures. In this paper, we demonstrate a data-based, single-port calibration using commercial microwave standards and a vector network analyzer (VNA) with samples at millikelvin temperature in a dilution refrigerator, making this method useful for measurements of quantum phenomena. Finally, we cross reference our data-based, single-port calibration and reflection measurement with over-coupled 2D- and 3D-resonators against well established two-port techniques corroborating the validity of our method.

Lesson on what it means for biological processes to be Poissonian, published in CourseSource

It has been suggested that there is a need to deepen the understanding of fluid dynamics in the introductory physics course and to offer interesting experiments to do so.1 To address this need we have developed a laboratory experiment and the supporting analysis to demonstrate the role of viscosity and the interestingly mysterious use of dimensionless parameters in fluid dynamics.2 Since viscosity indicates the frictional dependence between the layers of a flowing fluid, a thoughtful student may ask why or when viscosity can be neglected. The laboratory experiment presented here uses common fluids to provide a concrete answer to this question and an easily understandable example of the role of dimensionless parameters in fluid dynamics.

The large available Hilbert space and high coherence of cavity resonators makes these systems an interesting resource for storing encoded quantum bits. To perform a quantum gate on this encoded information, however, complex nonlinear operations must be applied to the many levels of the oscillator simultaneously. In this work, we introduce the Selective Number-dependent Arbitrary Phase (SNAP) gate, which imparts a different phase to each Fock state component using an off-resonantly coupled qubit. We show that the SNAP gate allows control over the quantum phases by correcting the unwanted phase evolution due to the Kerr effect. Furthermore, by combining the SNAP gate with oscillator displacements, we create a one-photon Fock state with high fidelity. Using just these two controls, one can construct arbitrary unitary operations, offering a scalable route to performing logical manipulations on oscillator-encoded qubits., Comment: 9 pages

We examined the acute effect of cold-water temperature on post-exercise energy intake (EI) for 1 h. In a randomized, crossover design, 11 men (25.6 ± 5 y) exercised for 45 min on a submersed cycle ergometer at 60 ± 2% VO2max in 33°C (neutral) and 20° (cold) water temperatures, and also rested for 45 min (control). Energy expenditure (EE) was determined using indirect calorimetry before, during, and after each condition. Following exercise or rest, subjects had free access to a standard assortment of food items of known caloric value. EE was similar for the cold and neutral water conditions, averaging 505 ± 22 (± standard deviation) and 517 ± 42 kcal, respectively (P = NS). EI after the cold condition averaged 877 ± 457 kcal, 44% and 41% higher (P < 0.05) than for the neutral and resting conditions, respectively. Cold-water temperature thus stimulated post-exercise EI. Water temperature warrants consideration in aquatic programs designed for weight loss.

Significant advances in coherence render superconducting quantum circuits a viable platform for fault-tolerant quantum computing. To further extend capabilities, highly coherent quantum systems could act as quantum memories for these circuits. A useful quantum memory must be rapidly addressable by Josephson-junction-based artificial atoms, while maintaining superior coherence. We demonstrate a superconducting microwave cavity architecture that is highly robust against major sources of loss that are encountered in the engineering of circuit QED systems. The architecture allows for storage of quantum superpositions in a resonator on the millisecond scale, while strong coupling between the resonator and a transmon qubit enables control, encoding, and readout at MHz rates. This extends the maximum available coherence time attainable in superconducting circuits by almost an order of magnitude compared to earlier hardware. Our design is an ideal platform for studying coherent quantum optics and marks an important step towards hardware-efficient quantum computing in Josephson-junction-based quantum circuits.

The Mouse Models of Cancer Consortium of the NCI sponsored a meeting of neuropathologists and veterinary pathologists in New York City in November of 2000. A rapidly growing number of genetically engineered mice (GEM) predisposed to tumors of the nervous system have led to a concomitant need for neuropathological evaluation and validation of these models. A panel of 13 pathologists reviewed material representing most of the available published and unpublished GEM models of medulloblastoma, primitive neuroectodermal tumor, astrocytoma, oligodendroglioma, mixed glioma, and tumors of the peripheral nerve. The GEM tumors were found to have many similarities and some distinct differences with respect to human disease. After review of the biology and pathology for all models presented, participants were split into groups reflective of clinical expertise in human pathology, tumor biology, neuroimaging, or treatment/intervention. Recommendations were made detailing an extensive and complete neuropathological characterization of animals. Importance was placed on including information on strains, tumor clonality, and examination for genetic mutation or altered gene expression characteristics of the corresponding human malignancy. Specific proposals were made to incorporate GEM models in emerging neuroradiological modalities. Recommendations were also made for preclinical validation of these models in cancer therapeutics, and for incorporation of surrogate markers of tumor burden to facilitate preclinical evaluation of new therapies.

The Tennessee Department of Environment and Conservation (TDEC) will soon establish a total maximum daily load (TMDL) for the mass of hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) that can be discharged into the Holston River. Holston Army Ammunition Plant (HSAAP), a manufacturer of military explosives in Kingsport, TN, will need additional wastewater treatment in order to comply with this revised regulation. The objective of this effort was to demonstrate two technologies, alkaline hydrolysis and direct electrochemical reduction, as potential pretreatment systems. Three laboratory scale pilot reactors were constructed and tested: a 115-L semibatch alkaline hydrolysis system, a 106-L rotating electrode batch electrochemical treatment system, and a 300-mL/min packed electrode continuous flow electrochemical treatment system. All three laboratory scale pilot reactors were effective in removing RDX from HSAAP process wastewater. A 10,000 gallon per day (gpd) alkaline treatment system may be built for $439,200 with a corresponding estimated annual operating cost of $296,737. Based on the laboratory results, a 10,000-gpd rotating electrode system may be built for $687,520, with an annual operating cost of $184,599. A packed electrode continuous flow reactor may be built for $1,774,000, with an annual operating cost of $82,308. The present costs of the evaluated treatment systems are $2.81M, $2.16M, and $2.43M for an alkaline system, a rotating electrode system, and a packed electrode system, respectively. Given the potential of electrochemical treatment systems to operate at much lower costs, continued development and demonstration of electrochemical treatment systems is warranted.

Three-dimensional microwave cavities have recently been combined with superconducting qubits in the circuit quantum electrodynamics (cQED) architecture. These cavities should have less sensitivity to dielectric and conductor losses at surfaces and interfaces, which currently limit the performance of planar resonators. We expect that significantly (>10^3) higher quality factors and longer lifetimes should be achievable for 3D structures. Motivated by this principle, we have reached internal quality factors greater than 0.5x10^9 and intrinsic lifetimes of 0.01 seconds for multiple aluminum superconducting cavity resonators at single photon energies and millikelvin temperatures. These improvements could enable long lived quantum memories with submicrosecond access times when strongly coupled to superconducting qubits., 4 pages, 2 figures

The g-Plunger technique has been introduced, which allows for the simultaneous measurement of lifetimes and absolute values of g-factors using a plunger device in inverse kinematics. Experiments on the 104,106,108Pd isotopes using Coulomb excitation resulted in g-factors in agreement with literature data. Lifetimes of 2 1 + states have in part significantly changed in this work.