Solving the degeneracy of the lepton-flavor mixing angle theta_atm by the T2KK two detector neutrino oscillation experiment

If the atmospheric neutrino oscillation amplitude, sin^2 2theta_atm is not maximal, there is a two fold ambiguity in the neutrino parameter space: sin^2 theta_atm>0.5 or sin^2 theta_atm<0.5. In this article, we study the impact of this degeneracy, the so-called octant degeneracy, on the T2KK experiment, which is a proposed extension of the T2K (Tokai-to-Kaimoka) neutrino oscillation experiment with an additional water cherenkov detector placed in Korea. We find that the degeneracy between sin^2 theta_atm= 0.40 and 0.60 can be resolved at the 3sigma level for sin^2 2theta_rct>0.12 (0.08) for the optimal combination of a 3.0^circ off-axis beam (OAB) at SK (L=295km) and a 0.5^circ OAB at L=1000km with a far detector of 100kton volume, after 5 years of exposure with 1.0(5.0) time 10^21 POT/year, if the hierarchy is normal. We also study the influence of the octant degeneracy on the capability of T2KK experiment to determine the mass hierarchy and the leptonic CP phase. The capability of rejecting the wrong mass hierarchy grows with increasing sin^2 theta_atm when the hierarchy is normal, whereas it is rather insensitive to sin^2 theta_atm for the inverted hierarchy. We also find that the 1sigma allowed region of the CP phase is not affected significantly even when the octant degeneracy is not resolved. All our results are obtained for the 22.5 kton Super-Kamiokande as a near detector and without an anti-neutrino beam.Comment: 23 pages, 9 figure

Asymptotic Regge Trajectories of Non-strange Mesons

We analyze the asymptotic behavior of Regge trajectories of non-strange mesons. In contrast to an existing belief, it is demonstrated that for the asymptotically linear Regge trajectories the width of heavy hadrons cannot linearly depend on their mass. Using the data on masses and widths of rho_J, omega_J, a_J and f_J mesons for the spin values J \leq 6, we extract the parameters of the asymptotically linear Regge trajectory predicted by the finite width model of quark gluon bags. As it is shown the obtained parameters for the data set B correspond to the cross-over temperature lying in the interval 170.9-175.3 MeV which is consistent with the kinetic freeze-out temperature of early hadronizing particles found in relativistic heavy ion collisions at and above the highest SPS energy.Comment: 14 pages, 3 figure

Activity and high-order effective connectivity alterations in Sanfilippo C patient-specific neuronal networks

Induced pluripotent stem cell (iPSC) technology has been successfully used to recapitulate phenotypic traits of several human diseases in vitro. Patient-specific iPSC-based disease models are also expected to reveal early functional phenotypes, although this remains to be proved. Here, we generated iPSC lines from two patients with Sanfilippo type C syndrome, a lysosomal storage disorder with inheritable progressive neurodegeneration. Mature neurons obtained from patient-specific iPSC lines recapitulated the main known phenotypes of the disease, not present in genetically corrected patient-specific iPSC-derived cultures. Moreover, neuronal networks organized in vitro from mature patient-derived neurons showed early defects in neuronal activity, network-wide degradation, and altered effective connectivity. Our findings establish the importance of iPSC-based technology to identify early functional phenotypes, which can in turn shed light on the pathological mechanisms occurring in Sanfilippo syndrome. This technology also has the potential to provide valuable readouts to screen compounds, which can prevent the onset of neurodegeneration

Multimodal action of KRP203 on phosphoinositide kinases in vitro and in cells

Increased phosphoinositide signaling is commonly associated with cancers. While "one-drug one-target" has been a major drug discovery strategy for cancer therapy, a "one-drug multi-targets" approach for phosphoinositide enzymes has the potential to offer a new therapeutic approach. In this study, we sought a new way to target phosphoinositides metabolism. Using a high-throughput phosphatidylinositol 5-phosphate 4-kinase-alpha (PI5P4Kα) assay, we have identified that the immunosuppressor KRP203/Mocravimod induces a significant perturbation in phosphoinositide metabolism in U87MG glioblastoma cells. Despite high sequence similarity of PI5P4K and PI4K isozymes, in vitro kinase assays showed that KRP203 activates some (e.g., PI5P4Kα, PI4KIIβ) while inhibiting other phosphoinositide kinases (e.g., PI5P4Kβ, γ, PI4KIIα, class I PI3K-p110α, δ, γ). Furthermore, KRP203 enhances PI3P5K/PIKFYVE's substrate selectivity for phosphatidylinositol (PI) while preserving its selectivity for PI(3)P. At cellular levels, 3 h of KRP203 treatment induces a prominent increase of PI(3)P and moderate increase of PI(5)P, PI(3, 5)P₂, and PI(3, 4, 5)P₃ levels in U87MG cells. Collectively, the finding of multimodal activity of KRP203 towards multi-phosphoinositide kinases may open a novel basis to modulate cellular processes, potentially leading to more effective treatments for diseases associated with phosphoinositide signaling pathways

Engineered Macroscale Cardiac Constructs Elicit Human Myocardial Tissue-like Functionality

In vitro surrogate models of human cardiac tissue hold great promise in disease modeling, cardiotoxicity testing, and future applications in regenerative medicine. However, the generation of engineered human cardiac constructs with tissue-like functionality is currently thwarted by difficulties in achieving efficient maturation at the cellular and/or tissular level. Here, we report on the design and implementation of a platform for the production of engineered cardiac macrotissues from human pluripotent stem cells (PSCs), which we term "CardioSlice." PSC-derived cardiomyocytes, together with human fibroblasts, are seeded into large 3D porous scaffolds and cultured using a parallelized perfusion bioreactor with custom-made culture chambers. Continuous electrical stimulation for 2 weeks promotes cardiomyocyte alignment and synchronization, and the emergence of cardiac tissue-like properties. These include electrocardiogram-like signals that can be readily measured on the surface of CardioSlice constructs, and a response to proarrhythmic drugs that is predictive of their effect in human patients

Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson's disease

Induced pluripotent stem cells (iPSC) offer an unprecedented opportunity to model human disease in relevant cell types, but it is unclear whether they could successfully model age-related diseases such as Parkinson's disease (PD). Here, we generated iPSC lines from seven patients with idiopathic PD (ID-PD), four patients with familial PD associated to the G2019S mutation in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene (LRRK2-PD) and four age- and sex-matched healthy individuals (Ctrl). Over long-time culture, dopaminergic neurons (DAn) differentiated from either ID-PD- or LRRK2-PD-iPSC showed morphological alterations, including reduced numbers of neurites and neurite arborization, as well as accumulation of autophagic vacuoles, which were not evident in DAn differentiated from Ctrl-iPSC. Further induction of autophagy and/or inhibition of lysosomal proteolysis greatly exacerbated the DAn morphological alterations, indicating autophagic compromise in DAn from ID-PD- and LRRK2-PD-iPSC, which we demonstrate occurs at the level of autophagosome clearance. Our study provides an iPSC-based in vitro model that captures the patients' genetic complexity and allows investigation of the pathogenesis of both sporadic and familial PD cases in a disease-relevant cell type

Analysis of a panel of antibodies to APC reveals consistent activity towards an unidentified protein

Acquisition of truncating mutations in the adenomatous polyposis coli (APC) protein underlies the progression of the majority of sporadic and familial colorectal cancers. As such, the localisation patterns and interacting partners of APC have been extensively studied in a range of systems, relying on the use of a broad panel of antibodies. Until recently, antibodies to APC have been used largely unchecked. However, several recent reports have been invaluable in clarifying the use of a number of antibodies commonly used to detect APC. Here, we analyse the specificity of a further subset of antibodies to APC. We used a panel of six commercially available antibodies (directed to the amino and carboxy termini of APC) and confirm the detection of full-length APC by immunoblotting. We demonstrate that a 150 kDa protein, also reproducibly detected by this panel of antibodies, is unlikely to be APC. We present data for the immunological staining patterns of the APC antibodies and validate the results through RNAi. Using this approach, we confirm that the apical staining pattern, observed by immunofluorescence and previously reported in cell systems, is unlikely to be APC. Finally, we present our data as a summary of APC-antibody specificities for APC

Characterization of Pseudomonas aeruginosa isolates: Occurrence rates, antimicrobial susceptibility patterns, and molecular typing in the global SENTRY Antimicrobial Surveillance Program, 1997-1999

During 1997–1999, a total of 70,067 isolates (6631 Pseudomonas aeruginosa isolates) were analyzed in the SENTRY program by geographic region and body site of infection. The respiratory tract was the most common source of P. aeruginosa. P. aeruginosa isolation rates increased during the study interval. Europe was the only region to show a significant decline in β-lactam and aminoglycoside susceptibility rates. There was a reduction in the rates of susceptibility of Canadian isolates to imipenem and of Latin American isolates to meropenem. A total of 218 multidrug-resistant P. aeruginosa isolates (MDR-PSA; resistant to piperacillin, ceftazidime, imipenem, and gentamicin) were observed; MDR-PSA occurrence rates (percentages of all isolates) ranged from 8.2% (Latin America) to 0.9% (Canada). No antimicrobial inhibited >50% of MDR-PSA strains. Molecular characterization of selected, generally resistant strains was performed. Isolates showing unique ribogroups were found in Europe, Latin America, and the United States, but clonal spread was documented in several medical centers.A. C. Gales, R. N. Jones, J. Turnidge, R. Rennie, and R. Rampha

Stable Field Emitters for a Miniature X-ray Tube Using Carbon Nanotube Drop Drying on a Flat Metal Tip

Stable carbon nanotube (CNT) field emitters for a vacuum-sealed miniature X-ray tube have been fabricated. The field emitters with a uniform CNT coating are prepared by a simple drop drying of a CNT mixture solution that is composed of chemically modified multi-walled CNTs, silver nanoparticles, and isopropyl alcohol on flat tungsten tips. A highly thermal- and electrical-conductive silver layer strongly attaches CNTs to the tungsten tips. Consequently, the field emitters exhibit good electron emission stability: continuous electron emission of around 100 μA at 2.3 V/μm has stably lasted over 40 h even at non-high vacuum ambient (~10−3 Pa)