The clinical and economic costs associated with regional disparities in varicella vaccine coverage in Italy over 50 years (2020-2070).

Italy implemented two-dose universal varicella vaccination (UVV) regionally from 2003 to 2013 and nationally from 2017 onwards. Our objective was to analyze regional disparities in varicella outcomes resulting from disparities in vaccine coverage rates (VCRs) projected over a 50-year time-horizon (2020-2070). A previously published dynamic transmission model was updated to quantify the potential public health impact of the UVV program in Italy at the national and regional levels. Four 2-dose vaccine strategies utilizing monovalent (V) and quadrivalent (MMRV) vaccines were evaluated for each region: (A) MMRV-MSD/MMRV-MSD, (B) MMRV-GSK/MMRV-GSK, (C) V-MSD/MMRV-MSD, and (D) V-GSK/MMRV-GSK. Costs were reported in 2022 Euros. Costs and quality-adjusted life-years (QALYs) were discounted 3% annually. Under strategy A, the three regions with the lowest first-dose VCR reported increased varicella cases (+ 34.3%), hospitalizations (+ 20.0%), QALYs lost (+ 5.9%), payer costs (+ 22.2%), and societal costs (+ 14.6%) over the 50-year time-horizon compared to the three regions with highest first-dose VCR. Regions with low first-dose VCR were more sensitive to changes in VCR than high first-dose VCR regions. Results with respect to second-dose VCR were qualitatively similar, although smaller in magnitude. Results were similar across all vaccine strategies.

Unraveling 5f-6d hybridization in uranium compounds via spin-resolved L-edge spectroscopy.

The multifaceted character of 5f electrons in actinide materials, from localized to itinerant and in between, together with their complex interactions with 6d and other conduction electron states, has thwarted efforts for fully understanding this class of compounds. While theoretical efforts abound, direct experimental probes of relevant electronic states and their hybridization are limited. Here we exploit the presence of sizable quadrupolar and dipolar contributions in the uranium L3-edge X-ray absorption cross section to provide unique information on the extent of spin-polarized hybridization between 5f and 6d electronic states by means of X-ray magnetic circular dichroism. As a result, we show how this 5f-6d hybridization regulates the magnetism of each sublattice in UCu2Si2 and UMn2Si2 compounds, demonstrating the potentiality of this methodology to investigate a plethora of magnetic actinide compounds.

A muscle-specific protein 'myoferlin' modulates IL-6/STAT3 signaling by chaperoning activated STAT3 to nucleus.

Myoferlin, a member of ferlin family of proteins, was first discovered as a candidate gene for muscular dystrophy and cardiomyopathy. Recently, myoferlin was shown to be also expressed in endothelial and cancer cells where it was shown to modulate vascular endothelial growth factor (VEGFR)-2 and epidermal growth factor receptor (EGFR) signaling by enhancing their stability and recycling. Based on these reports, we hypothesized that myoferlin might be regulating IL-6 signaling by modulating IL-6R stabilization and recycling. However, in our immunoprecipitation (IP) experiments, we did not observe myoferlin binding with IL-6R. Instead, we made a novel discovery that in resting cells myoferlin was bound to EHD2 protein and when cells were treated with IL-6, myoferlin dissociated from EHD2 and binds to activated STAT3. Interestingly, myoferlin depletion did not affect STAT3 phosphorylation, but completely blocked STAT3 translocation to nucleus. In addition, inhibition of STAT3 phosphorylation by phosphorylation-defective STAT3 mutants or JAK inhibitor blocked STAT3 binding to myoferlin and nuclear translocation. Myoferlin knockdown significantly decreased IL-6-mediated tumor cell migration, tumorsphere formation and ALDH-positive cancer stem cell population, in vitro. Furthermore, myoferlin knockdown significantly decreased IL-6-meditated tumor growth and tumor metastasis. Based on these results, we have proposed a novel model for the role of myoferlin in chaperoning phosphorylated STAT3 to the nucleus.

Crystallization of spin superlattices with pressure and field in the layered magnet SrCu2(BO3)2.

An exact mapping between quantum spins and boson gases provides fresh approaches to the creation of quantum condensates and crystals. Here we report on magnetization measurements on the dimerized quantum magnet SrCu2(BO3)2 at cryogenic temperatures and through a quantum-phase transition that demonstrate the emergence of fractionally filled bosonic crystals in mesoscopic patterns, specified by a sequence of magnetization plateaus. We apply tens of Teslas of magnetic field to tune the density of bosons and gigapascals of hydrostatic pressure to regulate the underlying interactions. Simulations help parse the balance between energy and geometry in the emergent spin superlattices. The magnetic crystallites are the end result of a progression from a direct product of singlet states in each short dimer at zero field to preferred filling fractions of spin-triplet bosons in each dimer at large magnetic field, enriching the known possibilities for collective states in both quantum spin and atomic systems.

Enhanced spin-phonon-electronic coupling in a 5d oxide.

Enhanced coupling of material properties offers new fundamental insights and routes to multifunctional devices. In this context 5d oxides provide new paradigms of cooperative interactions that drive novel emergent behaviour. This is exemplified in osmates that host metal-insulator transitions where magnetic order appears intimately entwined. Here we consider such a material, the 5d perovskite NaOsO3, and observe a coupling between spin and phonon manifested in a frequency shift of 40 cm(-1), the largest measured in any material. The anomalous modes are shown to involve solely Os-O interactions and magnetism is revealed as the driving microscopic mechanism for the phonon renormalization. The magnitude of the coupling in NaOsO3 is primarily due to a property common to all 5d materials: the large spatial extent of the ion. This allows magnetism to couple to phonons on an unprecedented scale and in general offers multiple new routes to enhanced coupled phenomena in 5d materials.

Itinerant ferromagnetism in the As 4p conduction band of Ba_{0.6}K_{0.4}Mn_{2}As_{2} identified by X-ray magnetic circular dichroism.

X-ray magnetic circular dichroism (XMCD) measurements on single-crystal and powder samples of Ba_{0.6}K_{0.4}Mn_{2}As_{2} show that the ferromagnetism below T_{C}≈100 K arises in the As 4p conduction band. No XMCD signal is observed at the Mn x-ray absorption edges. Below T_{C}, however, a clear XMCD signal is found at the As K edge which increases with decreasing temperature. The XMCD signal is absent in data taken with the beam directed parallel to the crystallographic c axis indicating that the orbital magnetic moment lies in the basal plane of the tetragonal lattice. These results show that the previously reported itinerant ferromagnetism is associated with the As 4p conduction band and that distinct local-moment antiferromagnetism and itinerant ferromagnetism with perpendicular easy axes coexist in this compound at low temperature.

Emergence of long-range order in sheets of magnetic dimers.

Quantum spins placed on the corners of a square lattice can dimerize and form singlets, which then can be transformed into a magnetic state as the interactions between dimers increase beyond threshold. This is a strictly 2D transition in theory, but real-world materials often need the third dimension to stabilize long-range order. We use high pressures to convert sheets of Cu(2+) spin 1/2 dimers from local singlets to global antiferromagnet in the model system SrCu2(BO3)2. Single-crystal neutron diffraction measurements at pressures above 5 GPa provide a direct signature of the antiferromagnetic ordered state, whereas high-resolution neutron powder and X-ray diffraction at commensurate pressures reveal a tilting of the Cu spins out of the plane with a critical exponent characteristic of 3D transitions. The addition of anisotropic, interplane, spin-orbit terms in the venerable Shastry-Sutherland Hamiltonian accounts for the influence of the third dimension.

Prevention of retinal light damage by zinc oxide combined with rosemary extract.

PURPOSE: Zinc oxide effectively reduces visual cell loss in rats exposed to intense visible light and is known to slow the rate of disease progression in advanced stages of age-related macular degeneration. Our goal was to determine the efficacy of zinc oxide in combination with novel and well-established antioxidants in an animal model of light-induced oxidative retinal damage. METHODS: One group of male Sprague-Dawley rats was pretreated with zinc oxide with or without a detergent extract of rosemary powder and then exposed to intense visible light for 4-24 h. Another group of animals received zinc oxide combined with rosemary oil diluted with a mixture of polyunsaturated fatty acids (ROPUFA) and a third group was given an antioxidant mineral mix containing zinc oxide, as recommended by the Age Related Eye Disease Study group's first clinical trial (AREDS1). Visual cell survival was determined 2 weeks after intense light treatment by measuring rhodopsin and photoreceptor cell DNA levels and confirmed by retinal histology and agarose gel electrophoresis of DNA. Western analysis was used to determine the effects of zinc and antioxidants on the oxidative stress markers, glial fibrillary acidic protein (GFAP), heme-oxygenase-1 (HO-1), and carboxyethylpyrrole (CEP). Rod and cone opsin and arrestin levels were used as markers of photoreceptor cell function. RESULTS: Dark-reared rats treated with 1.3 mg/kg zinc oxide and 17 mg/kg rosemary extract, or with one-half those doses, and exposed to moderate intensity green light retained 75%-85% of the rhodopsin and retinal DNA measured in unexposed rats. These levels were significantly higher than found for zinc oxide or rosemary treatment alone. Rosemary oil was also effective when combined with zinc oxide, but ROPUFA alone was no more effective than the detergent vehicle. Prolonged intense green light led to increases in retinal GFAP and HO-1 levels and to decreases in cone cell opsin and rod and cone arrestins. Rosemary plus zinc treatment reduced the expression of oxidative stress protein markers and enhanced visual cell survival, as shown by improved photoreceptor cell morphology and by decreased retinal DNA degradation. Using higher intensity white light for exposures in cyclic light-reared rats, treatment with an AREDS antioxidant/mineral mixture was found to be ineffective, whereas rosemary extract plus an equivalent dose of zinc oxide was significantly more effective in preserving visual cells. CEP protein adduct formation was reduced by all antioxidant treatments, but rosemary plus zinc oxide also prevented the loss of cone cell opsin and arrestin more effectively than AREDS. CONCLUSIONS: In the rat model of acute retinal light damage, zinc oxide combined with a detergent extract of rosemary powder or rosemary oil is more effective than treatment with either component alone and significantly more effective than an AREDS mixture containing a comparable dose of zinc oxide. Light-induced oxidative stress in animal models of retinal degeneration can be a useful preclinical paradigm for screening novel antioxidants and for testing potential therapeutics designed to slow the progression of age-related ocular disease.

Magnetically driven metal-insulator transition in NaOsO3.

The metal-insulator transition (MIT) is one of the most dramatic manifestations of electron correlations in materials. Various mechanisms producing MITs have been extensively considered, including the Mott (electron localization via Coulomb repulsion), Anderson (localization via disorder), and Peierls (localization via distortion of a periodic one-dimensional lattice) mechanisms. One additional route to a MIT proposed by Slater, in which long-range magnetic order in a three dimensional system drives the MIT, has received relatively little attention. Using neutron and x-ray scattering we show that the MIT in NaOsO(3) is coincident with the onset of long-range commensurate three dimensional magnetic order. While candidate materials have been suggested, our experimental methodology allows the first definitive demonstration of the long predicted Slater MIT.

A novel approach for x-ray scattering experiments in magnetic fields utilizing trapped flux in type-II superconductors.

We introduce a novel approach to x-ray scattering studies in applied magnetic fields by exploiting vortices in superconductors. This method is based on trapping magnetic flux in a small disk-shaped superconductor (known as a trapped field magnet, TFM) with a single-crystal sample mounted on or at close proximity to its surface. This opens an unrestricted optical access to the sample and allows magnetic fields to be applied precisely along the x-ray momentum transfer, facilitating polarization-sensitive experiments that have been impractical or impossible to perform to date. The TFMs used in our study remain stable and provide practically uniform magnetic fields for days, which are sufficient for comprehensive x-ray diffraction experiments, specifically x-ray resonance exchange scattering (XRES) to study field-induced phenomena at a modern synchrotron source. The TFM instrument has been used in a "proof-of-principle" XRES study of a meta-magnetic phase in a rare-earth compound, TbNi(2)Ge(2), in order to demonstrate its potential.

Continuous and discontinuous quantum phase transitions in a model two-dimensional magnet.

The Shasty-Sutherland model, which consists of a set of spin 1/2 dimers on a 2D square lattice, is simple and soluble but captures a central theme of condensed matter physics by sitting precariously on the quantum edge between isolated, gapped excitations and collective, ordered ground states. We compress the model Shastry-Sutherland material, SrCu(2)(BO(3))(2), in a diamond anvil cell at cryogenic temperatures to continuously tune the coupling energies and induce changes in state. High-resolution X-ray measurements exploit what emerges as a remarkably strong spin-lattice coupling to both monitor the magnetic behavior and the absence or presence of structural discontinuities. In the low-pressure spin-singlet regime, the onset of magnetism results in an expansion of the lattice with decreasing temperature, which permits a determination of the pressure-dependent energy gap and the almost isotropic spin-lattice coupling energies. The singlet-triplet gap energy is suppressed continuously with increasing pressure, vanishing completely by 2 GPa. This continuous quantum phase transition is followed by a structural distortion at higher pressure.

Interfacial magnetic coupling between Fe nanoparticles in Fe­Ag granular alloys.

The role of the interface in mediating interparticle magnetic interactions has been analysed in Fe50Ag50 and Fe55Ag45 granular thin films deposited by the pulsed laser deposition technique (PLD). These samples are composed of crystalline bcc Fe (2­4 nm) nanoparticles and fcc Ag (10­12 nm) nanoparticles, separated by an amorphous Fe50Ag50 interface, occupying around 20% of the sample volume, as determined by x-ray diffraction (XRD), x-ray absorption spectroscopy (XAS), and high resolution transmission electron microscopy (HRTEM). Interfacial magnetic coupling between Fe nanoparticles is studied by dc magnetization and x-ray magnetic circular dichroism (XMCD) measurements at the Fe K and Ag L2,3 edges. This paper reveals that these thin films present two magnetic transitions, at low and high temperatures, which are strongly related to the magnetic state of the amorphous interface, which acts as a barrier for interparticle magnetic coupling.

microRNA-107 functions as a candidate tumor-suppressor gene in head and neck squamous cell carcinoma by downregulation of protein kinase Cɛ.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent cancer worldwide with about 600 000 new cases diagnosed each year. Understanding the molecular pathways that lead to HNSCC is crucial to identify new targets for anti-cancer drug development. Protein kinase Cɛ (PKCɛ) is elevated in HNSCC and regulates the activation of Akt, Stat3 and Rho GTPases. To date, the molecular mechanism of PKCɛ dysregulation in HNSCC remains to be elucidated. In silico analysis identified three putative microRNA-107 (miR-107) binding sites in the 3'-untranslated region (UTR) of PKCɛ. An inverse relationship was revealed between miR-107 and PKCɛ in HNSCC cell lines. Delivery of miR-107 reduced PKCɛ levels in SCC15, SCC25 and CAL27, three HNSCC cell lines with high PKCɛ and low miR-107. The activity of a luciferase reporter construct containing the 3'-UTR of PKCɛ was downregulated by miR-107 and mutations in the three cognate miR-107 binding sites completely ablated the regulation by miR-107. Treatment with miR-107 significantly blocked cell proliferation, DNA replication, colony formation and invasion in SCC25 and CAL27 cells. Ectopic expression of miR-resistant PKCɛ was sufficient to partially rescue the loss-of-function phenotype in miR-107-overexpressing SCC25 cells. Tumor growth in nude mice was retarded by 93±7% in CAL27/miR-107 cells compared with CAL27/miR-control cells. Last, human primary HNSCC tumors with elevated PKCɛ had reduced miR-107 expression. Our results demonstrate that PKCɛ is directly regulated by miR-107 and, moreover, suggest that miR-107 may be a potential anti-cancer therapeutic for HNSCC.

Orbital magnetism and spin-orbit effects in the electronic structure of BaIrO3.

The electronic structure and magnetism of Ir 5d5 states in nonmetallic, weakly ferromagnetic BaIrO3 are probed with x-ray absorption techniques. Contrary to expectation, the Ir 5d orbital moment is found to be ~1.5 times larger than the spin moment. This unusual, atomiclike nature of the 5d moment is driven by a strong spin-orbit interaction in heavy Ir ions, as confirmed by the nonstatistical large branching ratio at Ir L(2,3) absorption edges. As a consequence, orbital interactions cannot be neglected when addressing the nature of magnetic ordering in BaIrO3. The local moment behavior persists even as the metallic-paramagnetic phase boundary is approached with Sr doping or applied pressure.

Breakdown of the Bardeen-Cooper-Schrieffer ground state at a quantum phase transition.

Advances in solid-state and atomic physics are exposing the hidden relationships between conventional and exotic states of quantum matter. Prominent examples include the discovery of exotic superconductivity proximate to conventional spin and charge order, and the crossover from long-range phase order to preformed pairs achieved in gases of cold fermions and inferred for copper oxide superconductors. The unifying theme is that incompatible ground states can be connected by quantum phase transitions. Quantum fluctuations about the transition are manifestations of the competition between qualitatively distinct organizing principles, such as a long-wavelength density wave and a short-coherence-length condensate. They may even give rise to 'protected' phases, like fluctuation-mediated superconductivity that survives only in the vicinity of an antiferromagnetic quantum critical point. However, few model systems that demonstrate continuous quantum phase transitions have been identified, and the complex nature of many systems of interest hinders efforts to more fully understand correlations and fluctuations near a zero-temperature instability. Here we report the suppression of magnetism by hydrostatic pressure in elemental chromium, a simple cubic metal that demonstrates a subtle form of itinerant antiferromagnetism formally equivalent to the Bardeen-Cooper-Schrieffer (BCS) state in conventional superconductors. By directly measuring the associated charge order in a diamond anvil cell at low temperatures, we find a phase transition at pressures of approximately 10 GPa driven by fluctuations that destroy the BCS-like state but preserve the strong magnetic interaction between itinerant electrons and holes. Chromium is unique among stoichiometric magnetic metals studied so far in that the quantum phase transition is continuous, allowing experimental access to the quantum singularity and a direct probe of the competition between conventional and exotic order in a theoretically tractable material.

Magnetic structure of RuSr2GdCu2O8 determined by resonant x-ray diffraction.

X-ray diffraction with photon energies near the Ru L2-absorption edge was used to detect resonant reflections characteristic of a G-type superstructure in RuSr2GdCu2O8 single crystals. A polarization analysis confirms that these reflections are due to magnetic order of Ru moments, and the azimuthal-angle dependence of the scattering amplitude reveals that the moments lie along a low-symmetry axis with substantial components parallel and perpendicular to the RuO2 layers. Complemented by susceptibility data and a symmetry analysis of the magnetic structure, these results reconcile many of the apparently contradictory findings reported in the literature.

Nature of Ho magnetism in multiferroic HoMnO3.

Using x-ray resonant magnetic scattering and x-ray magnetic circular dichroism, techniques that are element specific, we have elucidated the role of Ho3+ in multiferroic HoMnO3. In zero field, Ho3+ orders antiferromagnetically with moments aligned along the hexagonal c direction below 40 K, and undergoes a transition to another magnetic structure below 4.5 K. In applied electric fields of up to 1 x 10(7) V/m, the magnetic structure of Ho3+ remains unchanged.

Pressure-tuned spin and charge ordering in an itinerant antiferromagnet.

Elemental chromium orders antiferromagnetically near room temperature, but the ordering temperature can be driven to zero by applying large pressures. We combine diamond anvil cell and synchrotron x-ray diffraction techniques to measure directly the spin and charge order in the pure metal at the approach to its quantum critical point. Both spin and charge order are suppressed exponentially with pressure, well beyond the region where disorder cuts off such a simple evolution, and they maintain a harmonic scaling relationship over decades in scattering intensity. By comparing the development of the order parameter with that of the magnetic wave vector, it is possible to ascribe the destruction of antiferromagnetism to the growth in electron kinetic energy relative to the underlying magnetic exchange interaction.

Instrument for x-ray magnetic circular dichroism measurements at high pressures.

An instrument has been developed for x-ray magnetic circular dichroism (XMCD) measurements at high pressures and low temperatures. This instrument couples a nonmagnetic copper-beryllium diamond anvil cell featuring perforated diamonds with a helium flow cryostat and an electromagnet. The applied pressure can be controlled in situ using a gas membrane and calibrated using Cu K-edge x-ray absorption fine structure measurements. The performance of this instrument was tested by measuring the XMCD spectra of the Gd(5)Si(2)Ge(2) giant magnetocaloric material.