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Research and development of superconducting rotating machines has a history spanning greater than 30 years. Earlier, superconducting homo-polar DC machines that used low temperature superconductors may have found the first practical applications in superconducting rotating machines; however, it cannot be said with certainty, given their use in secretive war ships. Superconducting synchronous generators cooled by liquid helium are well developed, particularly by the Super-GM project in Japan. The paper discusses fundamental subjects in the design, manufacture, operation, control, and performance in power systems. The development of oxide superconducting wires and bulks, has found applications in superconducting electric motors (mainly synchronous ones), the structures of which are very similar to the generators. The paper also discusses the power system problems addressed by superconducting equipment, which have arisen due to the increase in the number of renewable sources of energy. The paper assesses the solutions offered by superconductivity to the above mentioned challenges.

Aminoglycoside use is limited by ototoxicity and nephrotoxicity. This study compared the incidences of toxicities associated with 2 recommended dosing regimens. Eighty-seven patients with tuberculosis or nontuberculous mycobacterial infections were prospectively randomized by drug to receive 15 mg/kg per day or 25 mg/kg 3 times per week of intravenous streptomycin, kanamycin, or amikacin. Doses were adjusted to achieve target serum concentrations. The size of the dosage and the frequency of administration were not associated with the incidences of ototoxicity (hearing loss determined by audiogram), vestibular toxicity (determined by the findings of a physical examination), or nephrotoxicity (determined by elevated serum creatinine levels). Risk of ototoxicity (found in 32 [37%] of the patients) was associated with older age and with a larger cumulative dose received. Vestibular toxicity (found in 8 [9%] of the patients) usually resolved, and nephrotoxicity (found in 13 [15%] of the patients) was mild and reversible in all cases. Subjective changes in hearing or balance did not correlate with objective findings. Streptomycin, kanamycin, and amikacin can be administered either daily or 3 times weekly without affecting the likelihood of toxicity.

Medulloblastoma is the most common malignant brain tumor of childhood. Group 3 medulloblastoma, the most aggressive molecular subtype, frequently disseminates through the leptomeningeal cerebral spinal fluid (CSF) spaces in the brain and spinal cord. The mechanism of dissemination through the CSF remains poorly understood, and the molecular pathways involved in medulloblastoma metastasis and self-renewal are largely unknown. Here we show that NOTCH1 signaling pathway regulates both the initiation of metastasis and the self-renewal of medulloblastoma. We identify a mechanism in which NOTCH1 activates BMI1 through the activation of TWIST1. NOTCH1 expression and activity are directly related to medulloblastoma metastasis and decreased survival rate of tumor-bearing mice. Finally, medulloblastoma-bearing mice intrathecally treated with anti-NRR1, a NOTCH1 blocking antibody, present lower frequency of spinal metastasis and higher survival rate. These findings identify NOTCH1 as a pivotal driver of Group 3 medulloblastoma metastasis and self-renewal, supporting the development of therapies targeting this pathway. Group 3 medulloblastoma is an aggressive pediatric brain tumour that disseminates through the leptomeningeal cerebral spinal fluid. Here, the authors show that in Group 3 medulloblastoma NOTCH1 activates BMI1 through the activation of TWIST1, driving metastasis and self-renewal, and in mouse models a NOTCH1 blocking antibody decreased spinal metastases.

Subgrid snow cover is one of the key parameters in global land models since snow cover has large impacts on the surface energy and moisture budgets, and hence the surface temperature. In this study, the Subgrid Snow Distribution (SSNOWD) snow cover parameterization was incorporated into the Minimal Advanced Treatments of Surface Interaction and Runoff (MATSIRO) land surface model. SSNOWD assumes that the subgrid snow water equivalent (SWE) distribution follows a lognormal distribution function, and its parameters are physically derived from geoclimatic information. Two 29-yr global offline simulations, with and without SSNOWD, were performed while forced with the Japanese 25-yr Reanalysis (JRA-25) dataset combined with an observed precipitation dataset. The simulated spatial patterns of mean monthly snow cover fraction were compared with satellite-based Moderate Resolution Imaging Spectroradiometer (MODIS) observations. The snow cover fraction was improved by the inclusion of SSNOWD, particularly for the accumulation season and/or regions with relatively small amounts of snowfall; snow cover fraction was typically underestimated in the simulation without SSNOWD. In the Northern Hemisphere, the daily snow-covered area was validated using Interactive Multisensor Snow and Ice Mapping System (IMS) snow analysis datasets. In the simulation with SSNOWD, snow-covered area largely agreed with the IMS snow analysis and the seasonal cycle in the Northern Hemisphere was improved. This was because SSNOWD formulates the snow cover fraction differently for the accumulation season and ablation season, and represents the hysteresis of the snow cover fraction between different seasons. The effects of including SSNOWD on hydrological properties and snow mass were also examined.

Glioblastoma (GBM) is the most common and fatal primary brain tumor in humans, and it is essential that new and better therapies are developed to treat this disease. Previous research suggests that casein kinase 2 (CK2) may be a promising therapeutic target for GBMs. CK2 has enhanced expression or activity in numerous cancers, including GBM, and it has been demonstrated that inhibitors of CK2 regressed tumor growth in GBM xenograft mouse models. Our studies demonstrate that the CK2 subunit, CK2α, is overexpressed in and has an important role in regulating brain tumor-initiating cells (BTIC) in GBM. Initial studies showed that two GBM cell lines (U87-MG and U138) transduced with CK2α had enhanced proliferation and anchorage-independent growth. Inhibition of CKα using siRNA or small-molecule inhibitors (TBBz, CX-4945) reduced cell growth, decreased tumor size, and increased survival rates in GBM xenograft mouse models. We also verified that inhibition of CK2α decreased the activity of a well-known GBM-initiating cell regulator, β-catenin. Loss of CK2α decreased two β-catenin-regulated genes that are involved in GBM-initiating cell growth, OCT4 and NANOG . To determine the importance of CK2α in GBM stem cell maintenance, we reduced CK2α activity in primary GBM samples and tumor spheres derived from GBM patients. We discovered that loss of CK2α activity reduced the sphere-forming capacity of BTIC and decreased numerous GBM stem cell markers, including CD133, CD90, CD49f and A2B5. Our study suggests that CK2α is involved in GBM tumorigenesis by maintaining BTIC through the regulation of β-catenin.

The retinoblastoma protein (pRB) is a critical regulator of cell proliferation and differentiation and an important tumor suppressor. In the G1phase of the cell cycle, pRB localizes to perinucleolar sites associated with lamin A/C intranuclear foci. Here, we examine pRB function in cells lacking lamin A/C, finding that pRB levels are dramatically decreased and that the remaining pRB is mislocalized. We demonstrate that A-type lamins protect pRB from proteasomal degradation. Both pRB levels and localization are restored upon reintroduction of lamin A. Lmna-/-cells resemble Rb-/-cells, exhibiting altered cell-cycle properties and reduced capacity to undergo cell-cycle arrest in response to DNA damage. These findings establish a functional link between a core nuclear structural component and an important cell-cycle regulator. They further raise the possibility that altered pRB function may be a contributing factor in dystrophic syndromes arising from LMNA mutation.

Background: Epithelial–mesenchymal transition (EMT) is characterised by the loss of cell-to-cell adhesion and gaining of mesenchymal phenotypes. Epithelial–mesenchymal transition is proposed to occur in various developmental processes and cancer progression. ‘Cadherin switch’, a process in which cells shift to express different isoforms of the cadherin transmembrane protein and usually refers to a switch from the expression of E-cadherin to N-cadherin, is one aspect of EMT and can have a profound effect on tumour invasion/metastasis. The aim of this study was to investigate the clinicopathological significance of EMT-related proteins and cadherin switch in extrahepatic cholangiocarcinoma (EHCC). Methods: We investigated the association between altered expression of 12 EMT-related proteins and clinical outcomes in patients with EHCC ( n =117) using immunohistochemistry on tissue microarrays. Results: Univariate and multivariate analyses revealed that, in addition to N classification ( P =0.0420), the expression of E-cadherin ( P =0.0208), N-cadherin ( P =0.0038) and S100A4 ( P =0.0157) was each an independent and a significant prognostic factor. We also demonstrated that cadherin switch was independently associated with poor prognosis ( P =0.0143) in patients with EHCC. Conclusions: These results may provide novel information for selection of patients with EHCC who require adjuvant therapy and strict surveillance.

We are developing a detector array for astronomical observations in the 100-GHz band using microwave kinetic inductance detectors (MKIDs) and a readout system for the array with frequency sweeping scheme, which uses a frequency sweeping probe signal instead of a fixed-frequency probe signal. This scheme enables us to simultaneously obtain the resonance spectra of MKIDs in an array and to derive the resonance frequencies corresponding to the power of incoming radiation. It has the advantage of the dynamic range being higher than the standard scheme and the derived resonance frequencies not being affected by changes of the gain or delay in the transmission line. The resonance profile measured, however, can be distorted by frequency sweeping, and hence, it is necessary to evaluate the effect of frequency sweeping on the resonance spectrum. We made measurements using the scheme with several frequency-sweep velocities and checked its effect on the resonance frequency and the quality factor. A slow frequency sweep causes only small differences in the resonance spectrum compared to an ideal profile, and hence suitable for astronomical applications.

A variety of drugs targeting monoamine receptors are routinely used in human pharmacology. We assessed the effect of these drugs on the viability of tumor‐initiating cells isolated from patients with glioblastoma. Among the drugs targeting monoamine receptors, we identified prazosin, an α1‐ and α2B‐adrenergic receptor antagonist, as the most potent inducer of patient‐derived glioblastoma‐initiating cell death. Prazosin triggered apoptosis of glioblastoma‐initiating cells and of their differentiated progeny, inhibited glioblastoma growth in orthotopic xenografts of patient‐derived glioblastoma‐initiating cells, and increased survival of glioblastoma‐bearing mice. We found that prazosin acted in glioblastoma‐initiating cells independently from adrenergic receptors. Its off‐target activity occurred via a PKCδ‐dependent inhibition of the AKT pathway, which resulted in caspase‐3 activation. Blockade of PKCδ activation prevented all molecular changes observed in prazosin‐treated glioblastoma‐initiating cells, as well as prazosin‐induced apoptosis. Based on these data, we conclude that prazosin, an FDA‐approved drug for the control of hypertension, inhibits glioblastoma growth through a PKCδ‐dependent mechanism. These findings open up promising prospects for the use of prazosin as an adjuvant therapy for glioblastoma patients. Synopsis Prazosin, an FDA‐approved drug for hypertension with a record of over 40 years of safe and effective clinical use, curbs intracranial glioblastoma growth in mice in a preclinical setting and is thus as a potential anti‐glioblastoma adjuvant drug. Prazosin induces glioblastoma cell apoptosis. PKCδ‐dependent inhibition of AKT pathway is identified as a possible mechanism for prazosin‐induced glioblastoma apoptosis, independently of adrenergic receptors. Glioblastoma growth in orthotopic xenograft mouse models was inhibited by prazosin and, as a consequence, mice survival increased. Graphical Abstract Prazosin, an FDA‐approved drug for hypertension with a record of over 40 years of safe and effective clinical use, curbs intracranial glioblastoma growth in mice in a preclinical setting and is thus as a potential anti‐glioblastoma adjuvant drug.

Despite numerous clinical trials over the past 2 decades, the overall survival for children diagnosed with diffuse intrinsic pontine glioma (DIPG) remains 9–10 months. Radiation therapy is the only treatment with proven effect and novel therapies are needed. Epidermal growth factor receptor variant III (EGFRvIII) is the most common variant of the epidermal growth factor receptor and is expressed in many tumor types but is rarely found in normal tissue. A peptide vaccine targeting EGFRvIII is currently undergoing investigation in phase 3 clinical trials for the treatment of newly diagnosed glioblastoma (GBM), the tumor in which this variant receptor was first discovered. In this study, we evaluated EGFRvIII expression in pediatric DIPG samples using immunohistochemistry with a double affinity purified antibody raised against the EGFRvIII peptide. Staining of pediatric DIPG histological samples revealed expression in 4 of 9 cases and the pattern of staining was consistent with what has been seen in EGFRvIII transfected cells as well as GBMs from adult trials. In addition, analysis of tumor samples collected immediately post mortem and of DIPG cells in culture by RT-PCR, western blot analysis, and flow cytometry confirmed EGFRvIII expression. We were therefore able to detect EGFRvIII expression in 6 of 11 DIPG cases. These data suggest that EGFRvIII warrants investigation as a target for these deadly pediatric tumors.