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Abstract We review the physics opportunities of the Future Circular Collider, covering its e+e-, pp, ep and heavy ion programmes. We describe the measurement capabilities of each FCC component, addressing the study of electroweak, Higgs and strong interactions, the top quark and flavour, as well as phenomena beyond the Standard Model. We highlight the synergy and complementarity of the different colliders, which will contribute to a uniquely coherent and ambitious research programme, providing an unmatchable combination of precision and sensitivity to new physics.

SuperKEKB is an asymmetric energy electron positrion collider currently under commissioning in Japan. It aims to achieve a record high luminosity of 8×10^{35} cm^{-2} s^{-1}, for which accurate control of β_{y}^{*} is needed. The advanced final focus system is also relevant for studies related to future linear colliders, which similarly need to achieve very small beam sizes. To work for SuperKEKB, the K modulation technique is generalized to allow known quadrupole fields between the modulated magnets and the interaction point. Initial measurements taken in HER agree with simulations, and show that K modulation is suitable for measuring the minimum of the β function at the interaction point within 1%, however it is too uncertain to be used for measuring the displacement of the beam waist away from the interaction point. In addition, tune shift equations for a modulated quadrupole are derived without assuming a thin lens perturbation, giving a simple method to calculate the tune shift to second order in the quadrupole strength modulation.

SuperKEKB is an electron-positron collider with asymmetric energies located at the High Energy Accelerator Research Organization (KEK) in Tsukuba, Japan. After more than five years of upgrading work on KEKB, phase-1 commissioning commenced in February 2016 and ended in June of the same year. Following a 20-month shutdown for the installation of a particle detector, BELLE II, phase-2 commissioning commenced in March 2018 and ended in July of the same year. This paper describes one major issue faced by SuperKEKB: the electron cloud effect (ECE) in the positron ring, which was observed during phase-1 commissioning. In the high-beam-current region, electron clouds, i.e., the source of the ECE, existed in the beam pipes at drift spaces of the ring, which had antechambers and a titanium nitride (TiN) film coating as countermeasures against the ECE. Permanent magnets and solenoids used to generate magnetic fields in the beam direction were attached to the beam pipes as additional countermeasures before the next commissioning phase commenced. Consequently, during phase-2 commissioning, experiments showed that the threshold of the current linear density for exciting the ECE increased by a factor of at least 2 compared to that during phase-1 commissioning. While the countermeasures were strengthened, the effectiveness of the antechambers and TiN film coating of the real beam pipe was reevaluated. Through various simulations and dedicated experiments during phase-2 commissioning, the antechambers were found to be less effective than anticipated with regard to reducing the number of photoelectrons in the beam channel. In contrast, the TiN film coating had a low secondary electron yield, as expected.

A beam optics scheme has been designed for the future circular collider-e^{+}e^{-} (FCC-ee). The main characteristics of the design are: beam energy 45 to 175 GeV, 100 km circumference with two interaction points (IPs) per ring, horizontal crossing angle of 30 mrad at the IP and the crab-waist scheme [P. Raimondi, D. Shatilov, and M. Zobov, arXiv:physics/0702033; P. Raimondi, M. Zobov, and D. Shatilov, in Proceedings of the 22nd Particle Accelerator Conference, PAC-2007, Albuquerque, NM (IEEE, New York, 2007), p. TUPAN037.] with local chromaticity correction. The crab-waist scheme is implemented within the local chromaticity correction system without additional sextupoles, by reducing the strength of one of the two sextupoles for vertical chromatic correction at each side of the IP. So-called “tapering” of the magnets is applied, which scales all fields of the magnets according to the local beam energy to compensate for the effect of synchrotron radiation (SR) loss along the ring. An asymmetric layout near the interaction region reduces the critical energy of SR photons on the incoming side of the IP to values below 100 keV, while matching the geometry to the beam line of the FCC proton collider (FCC-hh) [A. Chancé et al., Proceedings of IPAC’16, 9–13 May 2016, Busan, Korea, TUPMW020 (2016).] as closely as possible. Sufficient transverse/longitudinal dynamic aperture (DA) has been obtained, including major dynamical effects, to assure an adequate beam lifetime in the presence of beamstrahlung and top-up injection. In particular, a momentum acceptance larger than ±2% has been obtained, which is better than the momentum acceptance of typical collider rings by about a factor of 2. The effects of the detector solenoids including their compensation elements are taken into account as well as synchrotron radiation in all magnets. The optics presented in this paper is a step toward a full conceptual design for the collider. A number of issues have been identified for further study.

During 2008 and 2009 dedicated beam experiments with crab cavities were performed in the KEKB. The goal was to measure the impact of crab-cavity radio frequency (rf) noise on the beam quality. These experiments were performed as a validation of the crab-cavity beam dynamics models in view of the possible use of crab cavities in the upgrade of the CERN Large Hadron Collider (LHC). An unexpected strong beam-beam instability was observed during the course of the experiments as a kind of frequency response. Understanding this finding required extensive multiparticle and single particle simulations plus an extra experimental session to consolidate the observations.

Optics parameters such as betatron tunes, beta functions, and dispersions depend on momentum deviation. Such dependence is characterized by general chromaticity. General chromaticity can induce emittance growth and luminosity degradation in colliders. To investigate the influence of general chromaticity on beam dynamics, a symplectic map for chromaticity was implemented in the beam-beam codes and used in simulations at KEKB. A systematic investigation revealed that chromatic X-Y couplings can deteriorate the machine luminosity in the order of 10% with head-on colliding beams. The results of this study triggered the installation of skew sextupoles to KEKB rings for the purpose of correcting the chromatic X-Y couplings. Beam commissioning with skew-sextupole tuning knobs at KEKB has proved to be very successful; a new world’s record luminosity of 2.1×10^{34} cm^{-2} s^{-1} was achieved with Belle taking data in June, 2009. In this paper, we discuss the approach of general chromaticity and present the results of simulations at KEKB.

We have measured and corrected chromatic X-Y coupling at an interaction point to improve the luminosity of KEKB. We have measured the beam position of betatron oscillations induced by the kicker using turn-by-turn beam position monitors. A phase space structure reconstructed by the beam position provides us not only the Twiss parameters but also information regarding X-Y coupling. We have also determined chromatic X-Y coupling using the measured X-Y coupling at each momentum deviation from the designed beam energy. Skew sextupole magnets are used to correct the chromatic X-Y coupling.

Microwave instability in the low energy ring of KEKB was studied using a broadband impedance model. The model gave excellent descriptions of longitudinal dynamics for both positive and negative momentum compactions. Moreover, it predicted that the threshold of microwave instability was a factor of 2 lower than the machine nominal operating bunch current. The prediction was confirmed by a measurement using the Belle detector. Furthermore, we integrated the longitudinal wakefield into the beam-beam simulation and applied it to study the combined effects in KEKB. As a result, the beam-beam simulation became truly three dimensional with emittance growth in all three dimensions simultaneously as the beam currents increase. In addition, an observed mystery of asymmetry in the horizontal scan could also be explained by our simulations.

An orbit feedback system around the interaction point (IP) has been developed and successfully employed at KEKB for more than 6 years. The purpose of the system is to maintain an optimum geometrical relationship of orbits of two beams at the IP and to prevent a luminosity degradation due to orbit drifts. The feedback system is based on orbit measurements around the IP rather than a direct measurement of the luminosity. Owing to the system, the luminosity degradation due to the orbit drifts is suppressed to around or less than 1%.

Incoherent emittance growth caused by a strong nonlinear interaction between beam and electron cloud is discussed. This emittance growth arises from nonlinear diffusion related to chaos and resonances, and strongly depends on the number of degrees of freedom of the interacting system. A simple model, in which beam particles interact with a fixed round charge distribution, is used to study the mechanism of the emittance growth. The same discussion can be applied to the emittance growth due to beam-beam interactions in colliders and space charge effects in low energy proton rings.

A coupled-bunch instability caused by an electron cloud has been observed in the KEKB LER. The time evolution of the instabilities just after the turning-off the transverse bunch feedback was recorded with several weak solenoid-field conditions, which are used to suppress the vertical blowup of the beam size due to the electron cloud. The mode spectra and their growth rates of the coupled-bunch instabilities were compared with simulations of electrons moving in drift space, a weak solenoid field, and a strong bending field. Mode spectra without a solenoid field support the model where the instability is dominated by the electron clouds in the drift space with a lower secondary yield of photoelectron δ_{2,max}=1.0 rather than 1.5. With the solenoid field, the behavior of unstable modes and the growth rate with the strength of solenoid field also support the simulation with lower secondary emission yield.

An electron cloud induces a wake force on a charged particle beam which creates correlations between bunches—i.e., a small displacement of a bunch creates a perturbation of the electron cloud, which affects the motions of the following bunches, with the result that a coupled-bunch instability is caused. The coupling mode of the instability is determined by the motion of the electrons in the cloud—that is, it depends on which electrons, moving in a drift space, a weak solenoid field or a strong bending field, are dominant for the instability. We discuss the coupled-bunch instability focusing on the relation between the mode spectrum and the electron motion.

In recent high luminosity colliders, the finite crossing angle scheme becomes popular to gain the luminosity with multibunch or long bunch operation. Success of the KEKB factory showed that the finite crossing angle scheme has no problem achieving beam-beam parameters up to 0.05. We have studied the beam-beam interactions with and without crossing angle toward higher luminosity. We discuss how the crossing angle affects the beam-beam parameter and luminosity in the present KEKB using computer simulations. The simulations showed that crab cavities, which realize the head-on collision effectively, can be expected to double the luminosity.

A vertical coupled-bunch instability was observed for a positron beam at the Beijing Electron Positron Collider (BEPC). The experimental results show that the instability has similar characteristics as that observed in the Photon Factory of KEK several years ago. The instability at BEPC can be explained by the effect of an electron cloud which is produced in the beam chamber by synchrotron light hitting the wall.

A three-dimensional particle in cell simulation code has been developed to study the photoelectron cloud instabilities in KEKB LER. In this report, the program is described in detail. In particular, typical simulation results are presented for the photoelectron motion in various kinds of magnetic fields. The simulation shows that a solenoid is very effective in confining the photoelectrons to the vicinity of the vacuum chamber wall and in creating a region free of photoelectrons at the vacuum pipe center. The more uniform the solenoid field is, the more effectively does it suppress the electron-cloud buildup. Multipacting can occur both in a drift region and in a dipole magnet, and the heat load deposited on the chamber wall due to the lost electrons is important in these two cases. Electron trapping by the beam field as well as by various magnetic fields is an important phenomenon, especially inside quadrupole and sextupole magnets. Our numerical results qualitatively agree with the experimental studies.

An e^{-}p instability has been observed in some proton rings. The instability, which causes beam loss, limits the performance of the ring. The instability may be serious for 3 and 50 GeV proton storage rings in the Japan Proton Accelerator Research Complex (J-PARC). We study the e^{-}p instability in several high intensity proton storage rings operated in the world. This work informs J-PARC of the necessity to cure the instability, for example, by applying a TiN coating on the chamber surface.

In recent years the "crab-waist collision" scheme [P. Raimondi, Proceedings of 2nd SuperB Workshop, Frascati, 2006.; M. Zobov et al., Phys. Rev. Lett. 104, 174801 (2010)PRLTAO0031-900710.1103/PhysRevLett.104.174801] has become popular for circular e^{+} e^{-} colliders. The designs of several future colliders are based on this scheme. So far the beam-beam effects for collisions under a large crossing angle with or without crab waist were mostly studied using weak-strong simulations. We present here strong-strong simulations showing a novel strong coherent head-tail instability, which can limit the performance of proposed future colliders. We explain the underlying instability mechanism starting from the "cross-wake force" induced by the beam-beam interaction. Using this beam-beam wake, the beam-beam head tail modes are studied by an eigenmode analysis. The instability may affect all collider designs based on the crab-waist scheme. We suggest an experimental verification at SuperKEKB during its commissioning phase II.

We theoretically demonstrate for the first time that a single free electron in circular or spiral motion emits twisted photons carrying well-defined orbital angular momentum along the axis of the electron circulation, in adding to spin angular momentum. We show that, when the electron velocity is relativistic, the radiation field contains harmonic components and the photons of lth harmonic carry lℏ total angular momentum for each. This work indicates that twisted photons are naturally emitted by free electrons and are more ubiquitous in laboratories and in nature than ever thought.

We examined the change in the self-recognition about the accuracy of data on Okinawa in the Mizushima Prefectural Life Table, and discussed:its relationship to the "Okinawa Is a Traditional Longevity Prefecture" theory. In the Prefectural Life Table made before WWII, Mizushima had suspended his judgment as to the reliability of infant mortality data in Okinawa. However, after the production of the "Proto-'1921-25' Life Table" in 1952-1954, Mizushima asserted that infant mortality data in Okinawa was incomplete and unreliable, and excluded Okinawa in his analysis in two times of the life table. On the other hand, the "Pre-publication of the 1921-25 Prefectural Life Table" was, in a way that ignores Mizushima's own interpretation, used as the basis of the "Okinawa Is a Traditional Longevity Prefecture" thesis used by the Ryukyu government in its occupation era, and in recent years by other commentators.

Aquaporin-2 (AQP2) is essential to maintain body water homeostasis. AQP2 traffics from intracellular vesicles to the apical membrane of kidney collecting duct principal cells in response to vasopressin [arginine vasopressin (AVP)], a hormone released with low intravascular volume, which causes decreased kidney perfusion. Decreased kidney perfusion activates AMP-activated kinase (AMPK), a metabolic sensor that inhibits the activity of several transport proteins. We hypothesized that AMPK activation also inhibits AQP2 function. These putative AMPK effects could protect interstitial ionic gradients required for urinary concentration during metabolic stress when low intravascular volume induces AVP release. Here we found that short-term AMPK activation by treatment with 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR; 75 min) in kidney tissue prevented baseline AQP2 apical accumulation in principal cells, but did not prevent AQP2 apical accumulation in response to the AVP analog desmopressin (dDAVP). Prolonged AMPK activation prevented AQP2 cell membrane accumulation in response to forskolin in mouse collecting duct mpkCCD c14 cells. Moreover, AMPK inhibition accelerated hypotonic lysis of Xenopus oocytes expressing AQP2. We performed phosphorylation assays to elucidate the mechanism by which AMPK regulates AQP2. Although AMPK weakly phosphorylated immunoprecipitated AQP2 in vitro, no direct AMPK phosphorylation of the AQP2 COOH-terminus was detected by mass spectrometry. AMPK promoted Ser-261 phosphorylation and antagonized dDAVP-dependent phosphorylation of other AQP2 COOH-terminal sites in cells. Our findings suggest an increasing, time-dependent antagonism of AMPK on AQP2 regulation with AICAR-dependent inhibition of cAMP-dependent apical accumulation and AVP-dependent phosphorylation of AQP2. This inhibition likely occurs via a mechanism that does not involve direct AQP2 phosphorylation by AMPK., (Copyright © 2016 the American Physiological Society.)

We examined the first appearing papers of a series of the Mizushima Prefectural Life Table and checked its publication history and the transition of manufacturing methods as a first step in order to examine the theory that life expectancy in Okinawa has been long from a long time ago. However, the Prefectural Life Table of 1921-25 was first published in 1960, and its original form (as the "Pre-publication of the 1921-25 Prefectural Life Table") was estimated to have been started after WWII and completed in 1952-1954, based on the publication history and the transition of the manufacturing methods. In our next publication we will examine the change in the self-recognition about the accuracy of data from Okinawa in the Mizushima Prefectural Life Table, and discuss its relationship to the "Okinawa Is a Traditional Longevity Prefecture" theory.

A high intensity bluish-white emitting Ba2TiP2O9 phosphor was synthesized by a conventional solid-state reaction method and the precise crystal structure was investigated for the first time by Rietveld refinement analysis. Ba2TiP2O9 has a monoclinic crystal structure with a space group C2/c (no. 15), which is built out of PO4 tetrahedra and TiO5 pyramidal polyhedra connected to form a chain structure along the c-axis. The emission of Ba2TiP2O9 is due to a charge transfer transition between Ti(4+)-O(2-) in the pyramidal TiO5. The obtained Ba2TiP2O9 was excited efficiently by UV and VUV and displayed a bright bluish-white luminescence.

Extracellular proton-secreting transport systems that contribute to extracellular pH include the vacuolar H(+)-ATPase (V-ATPase). This pump, which mediates ATP-driven transport of H(+) across membranes, is involved in metastasis. We previously showed (Alzamora R, Thali RF, Gong F, Smolak C, Li H, Baty CJ, Bertrand CA, Auchli Y, Brunisholz RA, Neumann D, Hallows KR, Pastor-Soler NM. J Biol Chem 285: 24676-24685, 2010) that V-ATPase A subunit phosphorylation at Ser-175 is important for PKA-induced V-ATPase activity at the membrane of kidney intercalated cells. However, Ser-175 is also located within a larger phosphorylation consensus sequence for Aurora kinases, which are known to phosphorylate proteins that contribute to the pathogenesis of metastatic carcinomas. We thus hypothesized that Aurora kinase A (AURKA), overexpressed in aggressive carcinomas, regulates the V-ATPase in human kidney carcinoma cells (Caki-2) via Ser-175 phosphorylation. We found that AURKA is abnormally expressed in Caki-2 cells, where it binds the V-ATPase A subunit in an AURKA phosphorylation-dependent manner. Treatment with the AURKA activator anacardic acid increased V-ATPase expression and activity at the plasma membrane of Caki-2 cells. In addition, AURKA phosphorylates the V-ATPase A subunit at Ser-175 in vitro and in Caki-2 cells. Immunolabeling revealed that anacardic acid induced marked membrane accumulation of the V-ATPase A subunit in transfected Caki-2 cells. However, anacardic acid failed to induce membrane accumulation of a phosphorylation-deficient Ser-175-to-Ala (S175A) A subunit mutant. Finally, S175A-expressing cells had decreased migration in a wound-healing assay compared with cells expressing wild-type or a phospho-mimetic Ser-175-to-Asp (S175D) mutant A subunit. We conclude that AURKA activates the V-ATPase in kidney carcinoma cells via phosphorylation of Ser-175 in the V-ATPase A subunit. This regulation contributes to kidney carcinoma V-ATPase-mediated extracellular acidification and cell migration., (Copyright © 2016 the American Physiological Society.)

Severe progressive neurological paediatric disease mucopolysaccharidosis III type C is caused by mutations in the HGSNAT gene leading to deficiency of acetyl-CoA: α-glucosaminide N-acetyltransferase involved in the lysosomal catabolism of heparan sulphate. To understand the pathophysiology of the disease we generated a mouse model of mucopolysaccharidosis III type C by germline inactivation of the Hgsnat gene. At 6-8 months mice showed hyperactivity, and reduced anxiety. Cognitive memory decline was detected at 10 months and at 12-13 months mice showed signs of unbalanced hesitant walk and urinary retention. Lysosomal accumulation of heparan sulphate was observed in hepatocytes, splenic sinus endothelium, cerebral microglia, liver Kupffer cells, fibroblasts and pericytes. Starting from 5 months, brain neurons showed enlarged, structurally abnormal mitochondria, impaired mitochondrial energy metabolism, and storage of densely packed autofluorescent material, gangliosides, lysozyme, phosphorylated tau, and amyloid-β. Taken together, our data demonstrate for the first time that deficiency of acetyl-CoA: α-glucosaminide N-acetyltransferase causes lysosomal accumulation of heparan sulphate in microglial cells followed by their activation and cytokine release. They also show mitochondrial dysfunction in the neurons and neuronal loss explaining why mucopolysaccharidosis III type C manifests primarily as a neurodegenerative disease., (© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Mucopolysaccharidosis type IIIB (MPS IIIB, Sanfilippo syndrome type B) is a lysosomal storage disease characterized by profound intellectual disability, dementia, and a lifespan of about two decades. The cause is mutation in the gene encoding α-N-acetylglucosaminidase (NAGLU), deficiency of NAGLU, and accumulation of heparan sulfate. Impediments to enzyme replacement therapy are the absence of mannose 6-phosphate on recombinant human NAGLU and the blood-brain barrier. To overcome the first impediment, a fusion protein of recombinant NAGLU and a fragment of insulin-like growth factor II (IGFII) was prepared for endocytosis by the mannose 6-phosphate/IGFII receptor. To bypass the blood-brain barrier, the fusion protein ("enzyme") in artificial cerebrospinal fluid ("vehicle") was administered intracerebroventricularly to the brain of adult MPS IIIB mice, four times over 2 wk. The brains were analyzed 1-28 d later and compared with brains of MPS IIIB mice that received vehicle alone or control (heterozygous) mice that received vehicle. There was marked uptake of the administered enzyme in many parts of the brain, where it persisted with a half-life of approximately 10 d. Heparan sulfate, and especially disease-specific heparan sulfate, was reduced to control level. A number of secondary accumulations in neurons [β-hexosaminidase, LAMP1(lysosome-associated membrane protein 1), SCMAS (subunit c of mitochondrial ATP synthase), glypican 5, β-amyloid, P-tau] were reduced almost to control level. CD68, a microglial protein, was reduced halfway. A large amount of enzyme also appeared in liver cells, where it reduced heparan sulfate and β-hexosaminidase accumulation to control levels. These results suggest the feasibility of enzyme replacement therapy for MPS IIIB.

Objectives: To estimate the excess death associated with influenza pandemics and epidemics in Japan after World War II, and to reexamine the relationship between the excess death and the vaccination system in Japan., Methods: Using the Japanese national vital statistics data for 1952-2009, we specified months with influenza epidemics, monthly mortality rates and the seasonal index for 1952-74 and for 1975-2009. Then we calculated excess deaths of each month from the observed number of deaths and the 95% range of expected deaths. Lastly we calculated age-adjusted excess death rates using the 1985 model population of Japan., Results: The total number of excess deaths for 1952-2009 was 687,279 (95% range, 384,149-970,468), 12,058 (95% range, 6,739-17,026) per year. The total number of excess deaths in 6 pandemic years of 1957-58, 58-59, 1968-69, 69-70, 77-78 and 78-79, was 95,904, while that in 51 'non-pandemic' years was 591,376, 6.17 fold larger than pandemic years. The average number of excess deaths for pandemic years was 23,976, nearly equal to that for 'non-pandemic' years, 23,655. At the beginning of pandemics, 1957-58, 1968-69, 1969-70, the proportion of those aged <65 years in excess deaths rose compared with 'non-pandemic' years. In the 1970s and 1980s, when the vaccination program for schoolchildren was mandatory in Japan on the basis of the "Fukumi thesis", age-adjusted average excess mortality rates were relatively low, with an average of 6.17 per hundred thousand. In the 1990s, when group vaccination was discontinued, age-adjusted excess mortality rose up to 9.42, only to drop again to 2.04 when influenza vaccination was made available to the elderly in the 2000s, suggesting that the vaccination of Japanese children prevented excess deaths from influenza pandemics and epidemics. Moreover, in the age group under 65, average excess mortality rates were low in the 1970s and 1980s rather than in the 2000s, which shows that the "Social Defensive" schoolchildren vaccination program in the 1970s and 1980s was more effective than the "Individual Defensive" vaccination program in the 2000s., Conclusion: Excess deaths were observed continually, and not limited to pandemic years. We must not slight public health interventions for 'non-pandemic' influenza as well as pandemic influenza. We should also re-examine the importance of "Social Defenses", including preventative vaccination, for public health policy.

Sanfilippo syndrome type B (MPS IIIB) is characterized by profound mental retardation in childhood, dementia and death in late adolescence; it is caused by deficiency of α-N-acetylglucosaminidase and resulting lysosomal storage of heparan sulfate. A mouse model, generated by homologous recombination of the Naglu gene, was used to study pathological changes in the brain. We found earlier that neurons in the medial entorhinal cortex (MEC) and the dentate gyrus showed a number of secondary defects, including the presence of hyperphosphorylated tau (Ptau) detected with antibodies raised against Ptau in Alzheimer disease brain. By further use of immunohistochemistry, we now show staining in neurons of the same area for beta amyloid, extending the resemblance to Alzheimer disease. Ptau inclusions in the dentate gyrus of MPS IIIB mice were reduced in number when the mice were administered LiCl, a specific inhibitor of Gsk3β. Additional proteins found elevated in MEC include proteins involved in autophagy and the heparan sulfate proteoglycans, glypicans 1 and 5, the latter closely related to the primary defect. The level of secondary accumulations was associated with elevation of glypican, as seen by comparing brains of mice at different ages or with different mucopolysaccharide storage diseases. The MEC of an MPS IIIA mouse had the same intense immunostaining for glypican 1 and other markers as MPS IIIB, while MEC of MPS I and MPS II mice had weak staining, and MEC of an MPS VI mouse had no staining at all for the same proteins. A considerable amount of glypican was found in MEC of MPS IIIB mice outside of lysosomes. We propose that it is the extralysosomal glypican that would be harmful to neurons, because its heparan sulfate branches could potentiate the formation of Ptau and beta amyloid aggregates, which would be toxic as well as difficult to degrade.

The electron-positron collider DAPhiNE, the Italian Phi factory, has been recently upgraded in order to implement an innovative collision scheme based on large crossing angle, small beam sizes at the crossing point, and compensation of beam-beam interaction by means of sextupole pairs creating a "crab-waist" configuration in the interaction region. Experimental tests of the novel scheme exhibited an increase by a factor of 3 in the peak luminosity of the collider with respect to the performances reached before the upgrade. In this Letter we present the new collision scheme, discuss its advantages, describe the hardware modifications realized for the upgrade, and report the results of the experimental tests carried out during commissioning of the machine in the new configuration and standard operation for the users.

Sanfilippo syndrome type B (mucopolysaccharidosis III B, MPS III B) is an autosomal recessive, neurodegenerative disease of children, characterized by profound mental retardation and dementia. The primary cause is mutation in the NAGLU gene, resulting in deficiency of alpha-N-acetylglucosaminidase and lysosomal accumulation of heparan sulfate. In the mouse model of MPS III B, neurons and microglia display the characteristic vacuolation of lysosomal storage of undegraded substrate, but neurons in the medial entorhinal cortex (MEC) display accumulation of several additional substances. We used whole genome microarray analysis to examine differential gene expression in MEC neurons isolated by laser capture microdissection from Naglu(-/-) and Naglu(+/-) mice. Neurons from the lateral entorhinal cortex (LEC) were used as tissue controls. The highest increase in gene expression (6- to 7-fold between mutant and control) in MEC and LEC neurons was that of Lyzs, which encodes lysozyme, but accumulation of lysozyme protein was seen in MEC neurons only. Because of a report that lysozyme induced the formation of hyperphosphorylated tau (P-tau) in cultured neurons, we searched for P-tau by immunohistochemistry. P-tau was found in MEC of Naglu(-/-) mice, in the same neurons as lysozyme. In older mutant mice, it was also seen in the dentate gyrus, an area important for memory. Electron microscopy of dentate gyrus neurons showed cytoplasmic inclusions of paired helical filaments, P-tau aggregates characteristic of tauopathies-a group of age-related dementias that include Alzheimer disease. Our findings indicate that the Sanfilippo syndrome type B should also be considered a tauopathy.

Despite the clinical fact that endosseous titanium implants directly contacts periosteum, the behavior and response of the periosteum-derived cells to surface topography of titanium have rarely been studied. This study examines the effect of titanium surface microtopography on osteoblastic and possibly-modulated chondroblastic phenotypes of femoral periosteum-derived cells. Rat femoral periosteum-derived cells were cultured on either relatively smooth, machined titanium surface or acid-etched, micro-roughened titanium surface. The osteoblastic gene expressions, including collagen I, osteopontin and osteocalcin, were downregulated on the acid-etched surface, compared with the machined surface. Alkaline phosphatase and mineralization activities on the acid-etched surface were approximately 20% of those on the machined surface. Instead, chondroblastic specific genes, including collagen II and IX, and sox 9, were exclusively expressed or highly upregulated on the acid-etched surface. Alcian blue stain revealed an extensive deposition of glycosaminoglycan on the acid-etched surface. The cultured matrix on the acid-etched surface lacked the submicron globular structures that were extensively seen on the machined surface, and contained a remarkably increased percentage of sulfur relative to calcium compared with the culture on the machined surface. These results indicated that titanium microroughness suppresses the osteoblastic phenotype and induces or at least considerably enhances the chondroblastic phenotype of the periosteal cells, suggesting the unique role of titanium surface topography in regulating the periosteal cell differentiation. The suppressive effect of titanium microroughness on the periosteal cells toward the osteoblastic linage was contrasted to the known promotive effect on the bone marrow-derived osteoblasts.

Natural immunological tolerance can be induced in certain types of allogeneic liver transplantation in rats. To screen for genes associated with the induction of tolerance, suppression subtractive hybridization was performed in the rat liver transplantation model between a DA donor and PVG recipient combination where spontaneous immunological tolerance is known to occur without any immunosuppressive treatment. As a result, 112 genes were cloned from a DA liver graft that survived for 20 days in the fully allogeneic PVG recipient. After confirmation of the expression intensity using an in-house manufactured DNA array with cDNAs from the DA graft, 36 genes were classified in the highly expressed group and 26 moderately expressed group. In the first group, there were 8 immunoglobulin-related genes and 6 MHC class II-related genes, suggesting the existence of an underlying rejection response. Among those genes, an antiapoptotic gene in the p38 MAP kinase pathway, heme oxygenase gene (HO-1), and a ras cascade gene, IQ motif containing GTPase activating protein 1 (Iqgapl), retained biological significance. The results suggested that the molecular response to a liver graft tends to be antiapoptotic and to terminate the rejection response. Unfortunately, there was no gene identified that qualified as a putative immunosuppressive protein, liver suppressor factor-1 (LSF-1). The panel of genes identified in the present work will be a useful panel of candidate genes to investigate the induction of spontaneous tolerance.

Rationale: The dopamine transporter (DAT) and the vesicular monoamine transporter 2 (VMAT2) play pivotal roles in the action of methamphetamine (MAP), including acute locomotor effects and behavioral sensitization. However, the relative impact of heterozygous DAT and VMAT2 knockouts (KOs) on the behavioral effects of MAP remains unknown., Objectives: To evaluate the roles of DAT and VMAT2 in MAP-induced locomotor behavior, we examined locomotor activity and sensitization in heterozygous DAT KO (DAT+/-), heterozygous VMAT2 KO (VMAT2+/-), double heterozygous DAT/VMAT2 KO (DAT+/-VMAT2+/-), and wild-type (WT) mice., Results: Acute 1 mg/kg MAP injection induced significant locomotor increases in WT and VMAT2+/- mice but not in DAT+/- and DAT+/-VMAT2+/- mice. Acute 2 mg/kg MAP significantly increased locomotor activity in all genotypes. Repeated 1 mg/kg MAP injections revealed a delayed and attenuated development of sensitization in DAT+/- and DAT+/-VMAT2+/- mice compared to WT mice and delayed development in VMAT2+/- mice. In repeated 2 mg/kg MAP injections, DAT+/- and DAT+/-VMAT2+/- mice showed delayed but not attenuated development of sensitization, while there was no difference in the onset of sensitization between VMAT2+/- and WT mice. In DAT+/-VMAT2+/- mice, all of MAP-induced behavioral responses were similar to those in DAT+/- but not VMAT2+/- mice., Conclusions: Heterozygous deletion of DAT attenuates the locomotor effects of MAP and may play larger role in behavioral responses to MAP compared to heterozygous deletion of VMAT2.

The neurodegenerative disease MPS III B (Sanfilippo syndrome type B) is caused by mutations in the gene encoding the lysosomal enzyme alpha-N-acetylglucosaminidase, with a resulting block in heparan sulfate degradation. A mouse model with disruption of the Naglu gene allows detailed study of brain pathology. In contrast to somatic cells, which accumulate primarily heparan sulfate, neurons accumulate a number of apparently unrelated metabolites, including subunit c of mitochondrial ATP synthase (SCMAS). SCMAS accumulated from 1 month of age, primarily in the medial entorhinal cortex and layer V of the somatosensory cortex. Its accumulation was not due to the absence of specific proteases. Light microscopy of brain sections of 6-months-old mice showed SCMAS to accumulate in the same areas as glycosaminoglycan and unesterified cholesterol, in the same cells as ubiquitin and GM3 ganglioside, and in the same organelles as Lamp 1 and Lamp 2. Cryo-immuno electron microscopy showed SCMAS to be present in Lamp positive vesicles bounded by a single membrane (lysosomes), in fingerprint-like layered arrays. GM3 ganglioside was found in the same lysosomes, but was not associated with the SCMAS arrays. GM3 ganglioside was also seen in lysosomes of microglia, suggesting phagocytosis of neuronal membranes. Samples used for cryo-EM and further processed by standard EM procedures (osmium tetroxide fixation and plastic embedding) showed the disappearance of the SCMAS fingerprint arrays and appearance in the same location of "zebra bodies", well known but little understood inclusions in the brain of patients with mucopolysaccharidoses.

We present the first evidence of the decay B- --> tau- nu(tau), using 414 fb(-1) of data collected at the Upsilon(4S) resonance with the Belle detector at the KEKB asymmetric-energy e+ e- collider. Events are tagged by fully reconstructing one of the B mesons in hadronic modes. We detect the signal with a significance of 3.5 standard deviations including systematics and measure the branching fraction to be B(B- --> tau- nu(tau)) = (1.79(-0.49) +0.56(stat)(-0.51) +0.46(syst)) x 10(-4). This implies that fB = 0.229(-0.031) +0.036(stat)(-0.037) +0.034(syst) GeV and is the first direct measurement of this quantity.

We investigated the effect of fluoridation and its discontinuation on fluoride content in the alveolar portion of the mandible in rats. Drinking water with three different fluoride contents (0, 50, 100 ppmF) was given to rats for three different periods (4, 13 and 25 weeks). Fluoride concentrations were measured in the crest, the middle, and the apical parts of the alveolar bone and in the body of the mandible. Furthermore, after fluoridated drinking water was given to rats for 4 or 13 weeks, distilled water was given to them for 21 or 12 weeks respectively; and the effect of the discontinuation on fluoride profiles was investigated. Layer samples were analyzed by abrasive microsampling. Fluoride and phosphorus concentrations were determined by ion-specific electrode and colorimetric procedures, respectively. There was an increase in fluoride concentrations in the mandible in proportion to the fluoride content in the drinking water and the duration of fluoridation. After fluoridation was discontinued, fluoride concentrations in the surface layers of the mandible presented a decrease. Among the four different parts of the mandible, the upper part of the alveolar bone and the alveolar crest part presented the highest rates of reduction. The relative reduction rate of fluoride concentration was closely related to the duration of discontinuation. The alveolar crest was affected most by the discontinuation of fluoridation, presenting the greatest reduction.

We report the observation of the decay B0-->pi(0)pi(0), using a 253 fb(-1) data sample collected at the Upsilon(4S) resonance with the Belle detector at the KEKB e(+)e(-) collider. The measured branching fraction is B(B0-->pi(0)pi(0))=(2.3(+0.4+0.2)(-0.5-0.3))x10(-6), with a significance of 5.8 standard deviations including systematic uncertainties. We also make a measurement of the direct CP violating asymmetry in this mode.

The effects of electron clouds on positively charged beams have been an active area of research in recent years at particle accelerators around the world. Transverse beam-size blowup due to electron clouds has been observed in some machines and is considered to be a major limiting factor in the development of higher-current, higher-luminosity electron-positron colliders. The leading proposed mechanism for beam blowup is the excitation of a fast head-tail instability due to short-range wakes within the electron cloud. We present here observations of betatron oscillation sidebands in bunch-by-bunch spectra that may provide direct evidence of such head-tail motion in a positron beam.

We report evidence for direct CP violation in the decay B0-->K+pi(-) with 253 fb(-1) of data collected with the Belle detector at the KEKB e(+)e(-) collider. Using 275x10(6) BB pairs we observe a B-->K+/-pi(-/+) signal with 2140+/-53 events. The measured CP violating asymmetry is A(CP)(K+pi(-))=-0.101+/-0.025(stat)+/-0.005(syst), corresponding to a significance of 3.9sigma including systematics. We also search for CP violation in the decays B+-->K+pi(0) and B+-->pi(+)pi(0). The measured CP violating asymmetries are A(CP)(K+pi(0))=0.04+/-0.05(stat)+/-0.02(syst) and A(CP)(pi(+)pi(0))=-0.02+/-0.10(stat)+/-0.01(syst), corresponding to the intervals -0.05

The cell cycle inhibitor p21 plays an important role in monocytic cell differentiation, during which it translocates from the nucleus to cytoplasm. This process involves the negative regulation of the p21 nuclear localization signal (NLS). Here, we sought to determine the relationship between the cytoplasmic translocation of p21 and another molecule, Brap2, a cytoplasmic protein which binds the NLS of BRCA1 and was recently reported to inactivate KSR in the Ras-activating signal pathway under the name of IMP. We report that p21 and Brap2 directly interact, both in vitro and in vivo, in a manner requiring the NLS of p21 and the C-terminal portion of Brap2. When it is cotransfected with Brap2, p21 is expressed in the cytoplasm. Monocytic differentiation of the promyelomonocytic cell lines U937 and HL60 is associated with the upregulation of Brap2 expression concomitantly with the upregulation and cytoplasmic relocalization of p21. Our results underscore the role played by Brap2 in the process of cytoplasmic translocation of p21 during monocyte differentiation.

The energy gain and motion of electrons can quantitatively describe the mechanism of electron multipacting in a long-bunched proton machine. Strong multipacting usually happens around the bunches' tails due to the high energy of electrons when they hit the chamber surface. We investigated several important parameters of electron multipacting, proving that it is sensitive to the beam's intensity, the shape of its longitudinal profile, its transverse size, the secondary emission yield, and the energy at peak secondary emission yield. Our analyses, simulations, and experiments are all in agreement.

Mucopolysaccharidosis IIIB (MPS IIIB) is a lysosomal storage disorder caused by mutations in NAGLU, the gene encoding alpha-N-acetylglucosaminidase. The disease is characterized by profound mental retardation and eventual neurodegeneration, but relatively mild somatic manifestations. There is no available therapy. We have used a mouse knockout model of the disease to test therapy by genetically modified bone marrow. Bone marrow from Naglu -/- male mice was transduced with human NAGLU cDNA in an MND-MFG vector, and transplanted into 6- to 8-week-old lethally irradiated female -/- mice. Sham-treated mice received bone marrow transduced with eGFP cDNA in an MND vector. alpha-N-Acetylglucosaminidase activity in plasma and leukocytes, measured 3 and 6 months after transplantation, varied from marginal to nearly 30 times wild-type. A low level of alpha-N-acetylglucosaminidase activity, as little as provided by transplantation of unmodified Naglu +/+ bone marrow, could normalize biochemical defects (glycosaminoglycan storage and beta-hexosaminidase elevation) in liver and spleen, but a very high level was required for an effect on kidney. Effects on the brain were best seen by examination of cellular morphology using light and electron microcopy. Mice that expressed very high levels of alpha-N-acetylglucosaminidase in blood had an increased number of normal-appearing neurons in the cortex and other parts of the brain, while microglia with engorged lysosomes had almost completely disappeared. Immunohistochemistry showed a marked decrease of staining for subunit c of mitochondrial ATP synthase and for Lamp1, markers of neuronal and microglial pathology, respectively, as well as a decrease in staining for glial fibrillary acid protein, a marker of activated astrocytes. These results show that genetically modified cells of hematopoietic origin can reduce the pathologic manifestations of MPS IIIB in the Naglu -/- mouse brain.

We report the first observation of CP violation in B0-->pi(+)pi(-) decays based on 152x10(6) gamma (4S)-->BB decays collected with the Belle detector at the KEKB asymmetric-energy e(+)e(-) collider. We reconstruct a B0-->pi(+)pi(-) CP eigenstate and identify the flavor of the accompanying B meson from its decay products. From the distribution of the time intervals between the two B meson decay points, we obtain A(pipi)=+0.58+/-0.15(stat)+/-0.07(syst) and S(pipi)=-1.00+/-0.21(stat)+/-0.07(syst). We rule out the CP-conserving case, A(pipi)=S(pipi)=0, at a level of 5.2 standard deviations. We also find evidence for direct CP violation with a significance at or greater than 3.2 standard deviations for any S(pipi) value.

Serous, mucinous, endometrioid, and clear cell adenocarcinomas arise from reproductive organs of mullerian origin. Although the mutation of PTEN, a tumor suppressor, is known to be involved in tumorigenesis of endometrioid adenocarcinomas of the endometrium and ovary, the role of PTEN alteration in endometrioid adenocarcinoma of the cervix remains to be investigated. To elucidate the molecular pathogenesis of cervical adenocarcinoma and adenosquamous carcinoma, and in particular to examine the potential role of PTEN mutation in endometrioid-type cancer of the cervix, we analyzed 32 cervical adeno- or adenosquamous carcinomas (8 endometrioid adenocarcinomas, 14 mucinous adenocarcinomas and 10 adenosquamous carcinomas) for PTEN mutations and HPV infections. PTEN mutation was detected in 2 of 8 (25.0%) endometrioid cases, 2 of 14 (14.3%) mucinous cases, and none of 10 (0%) adenosquamous cases. HPV DNA was detected in 11 out of 18 (61.1%) PTEN wild-type adenocarcinomas and 8 out of 10 (80.0%) adenosquamous carcinomas. Among 11 HPV-negative adenocarcinomas, 40.0% (2/5) endometrioid cases and 33.3% (2/6) mucinous cases were shown to be PTEN mutated, while no cases (0/21) were PTEN-mutant in the remainder (i.e. adenosquamous carcinomas and HPV-positive adenocarcinomas). The current observations suggest that PTEN mutation is frequently detected in HPV-negative adenocarcinomas of the cervix and the most prevalent occurrence of PTEN mutation in endometrioid subtype is keeping with endometrial and ovarian carcinomas., (Copyright 2004 Elsevier Ireland Ltd.)

Beam-beam effects limit the luminosity of circular colliders. Once the bunch population exceeds a threshold, the luminosity increases at a slower rate. This phenomenon is called the beam-beam limit. Onset of the beam-beam limit has been analyzed with various simulation methods based on the weak-strong and strong-strong models. We have observed that an incoherent phenomenon is mainly concerned in the beam-beam limit. The simulation have shown that equilibrium distributions of the two colliding beams are distorted from Gaussians when the luminosity is limited. The beam-beam limit is estimated to be xi approximately 0.1 for a B factory with damping time of several thousand turns.

We have performed a search for the lepton-flavor-violating decay tau-->microgamma using a data sample of 86.3 fb(-1) accumulated by the Belle detector at KEK. No evidence for a signal is seen, and we set an upper limit for the branching fraction of B(tau-->microgamma)<3.1 x 10(-7) at the 90% confidence level.