A beam with an angular-dependant phase Φ = ℓϕ about the beam axis carries an orbital angular momentum of ℓℏ per photon. Such beams are exploited to provide superresolution in microscopy. Creating ...extreme ultraviolet or soft-x-ray beams with controllable orbital angular momentum is a critical step towards extending superresolution to much higher spatial resolution. We show that orbital angular momentum is conserved during high-harmonic generation. Experimentally, we use a fundamental beam with |ℓ| = 1 and interferometrically determine that the harmonics each have orbital angular momentum equal to their harmonic number. Theoretically, we show how any small value of orbital angular momentum can be coupled to any harmonic in a controlled manner. Our results open a route to microscopy on the molecular, or even submolecular, scale.
Sepsis, a systemic inflammatory response to infection, is often accompanied by abnormalities of blood coagulation. Prior work with a mouse model of sepsis induced by cecal ligation and puncture (CLP) ...suggested that the protease factor XIa contributed to disseminated intravascular coagulation (DIC) and to the cytokine response during sepsis. We investigated the importance of factor XI to cytokine and coagulation responses during the first 24 hours after CLP. Compared to wild type littermates, factor XI-deficient (FXI-/-) mice had a survival advantage after CLP, with smaller increases in plasma levels of TNF-α and IL-10 and delayed IL-1β and IL-6 responses. Plasma levels of serum amyloid P, an acute phase protein, were increased in wild type mice 24 hours post-CLP, but not in FXI-/- mice, supporting the impression of a reduced inflammatory response in the absence of factor XI. Surprisingly, there was little evidence of DIC in mice of either genotype. Plasma levels of the contact factors factor XII and prekallikrein were reduced in WT mice after CLP, consistent with induction of contact activation. However, factor XII and PK levels were not reduced in FXI-/- animals, indicating factor XI deficiency blunted contact activation. Intravenous infusion of polyphosphate into WT mice also induced changes in factor XII, but had much less effect in FXI deficient mice. In vitro analysis revealed that factor XIa activates factor XII, and that this reaction is enhanced by polyanions such polyphosphate and nucleic acids. These data suggest that factor XI deficiency confers a survival advantage in the CLP sepsis model by altering the cytokine response to infection and blunting activation of the contact (kallikrein-kinin) system. The findings support the hypothesis that factor XI functions as a bidirectional interface between contact activation and thrombin generation, allowing the two processes to influence each other.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Optical vortices, which carry orbital angular momentum (OAM), can be flexibly produced and measured with infrared and visible light. Their application is an important research topic for ...super-resolution imaging, optical communications and quantum optics. However, only a few methods can produce OAM beams in the extreme ultraviolet (XUV) or X-ray, and controlling the OAM on these beams remains challenging. Here we apply wave mixing to a tabletop high-harmonic source, as proposed in our previous work, and control the topological charge (OAM value) of XUV beams. Our technique enables us to produce first-order OAM beams with the smallest possible central intensity null at XUV wavelengths. This work opens a route for carrier-injected laser machining and lithography, which may reach nanometre or even angstrom resolution. Such a light source is also ideal for space communications, both in the classical and quantum regimes.
Adeno-associated virus (AAV) vector-based gene therapy is a promising treatment strategy for delivery of neurotrophic transgenes to retinal ganglion cells (RGCs) in glaucoma patients. Retinal ...distribution of transgene expression following intravitreal injection (IVT) of AAV is variable in animal models and the vitreous humor may represent a barrier to initial vector penetration. The primary goal of our study was to investigate the effect of prior core vitrectomy with posterior hyaloid membrane peeling on pattern and efficiency of transduction of a capsid amino acid substituted AAV2 vector, carrying the green fluorescent protein (GFP) reporter transgene following IVT in dogs. When progressive intraocular inflammation developed starting 4 weeks post IVT, the study plan was modified to allow detailed characterization of the etiology as a secondary goal. Unexpectedly, surgical vitrectomy was found to significantly limit transduction, whereas in non-vitrectomized eyes transduction efficiency reached upwards to 37.3% of RGC layer cells. The developing retinitis was characterized by mononuclear cell infiltrates resulting from a delayed-type hypersensitivity reaction, which we suspect was directed at the GFP transgene. Our results, in a canine large animal model, support caution when considering surgical vitrectomy before IVT for retinal gene therapy in patients, as prior vitrectomy appears to significantly reduce transduction efficiency and may predispose the patient to development of vector-induced immune reactions.
In a joint NRL/Manila Observatory mission, as part of the Seven SouthEast Asian Studies program (7-SEAS), a 2-week, late September 2011 research cruise in the northern Palawan archipelago was ...undertaken to observe the nature of southwest monsoonal aerosol particles in the South China Sea/East Sea (SCS/ES) and Sulu Sea region. Previous analyses suggested this region as a receptor for biomass burning from Borneo and Sumatra for boundary layer air entering the monsoonal trough. Anthropogenic pollution and biofuel emissions are also ubiquitous, as is heavy shipping traffic. Here, we provide an overview of the regional environment during the cruise, a time series of key aerosol and meteorological parameters, and their interrelationships. Overall, this cruise provides a narrative of the processes that control regional aerosol loadings and their possible feedbacks with clouds and precipitation. While 2011 was a moderate El Nino-Southern Oscillation (ENSO) La Nina year, higher burning activity and lower precipitation was more typical of neutral conditions. The large-scale aerosol environment was modulated by the Madden-Julian Oscillation (MJO) and its associated tropical cyclone (TC) activity in a manner consistent with the conceptual analysis performed by Reid et al. (2012). Advancement of the MJO from phase 3 to 6 with accompanying cyclogenesis during the cruise period strengthened flow patterns in the SCS/ES that modulated aerosol life cycle. TC inflow arms of significant convection sometimes span from Sumatra to Luzon, resulting in very low particle concentrations (minimum condensation nuclei CN < 150 cm-3, non-sea-salt PM2.5 < 1 mu g m-3). However, elevated carbon monoxide levels were occasionally observed suggesting passage of polluted air masses whose aerosol particles had been rained out. Conversely, two drier periods occurred with higher aerosol particle concentrations originating from Borneo and Southern Sumatra (CN > 3000 cm-3 and non-sea-salt PM2.5 10-25 mu g m-3). These cases corresponded with two different mechanisms of convection suppression: lower free-tropospheric dry-air intrusion from the Indian Ocean, and large-scale TC-induced subsidence. Veering vertical wind shear also resulted in aerosol transport into this region being mainly in the marine boundary layer (MBL), although lower free troposphere transport was possible on the western sides of Sumatra and Borneo. At the hourly time scale, particle concentrations were observed to be modulated by integer factors through convection and associated cold pools. Geostationary satellite observations suggest that convection often takes the form of squall lines, which are bowed up to 500 km across the monsoonal flow and 50 km wide. These squall lines, initiated by cold pools from large thunderstorms and likely sustained by a veering vertical wind shear and aforementioned mid-troposphere dry layers, propagated over 1500 km across the entirety of the SCS/ES, effectively cutting large swaths of MBL aerosol particles out of the region. Our conclusion is that while large-scale flow patterns are very important in modulating convection, and hence in allowing long-range transport of smoke and pollution, more short-lived phenomena can modulate cloud condensation nuclei (CCN) concentrations in the region, resulting in pockets of clean and polluted MBL air. This will no doubt complicate large scale comparisons of aerosol-cloud interaction.
Abstract
A high-resolution primitive equation model simulation is used to form an energy budget for the principal semidiurnal tide (M2) over a region of the Hawaiian Ridge from Niihau to Maui. This ...region includes the Kaena Ridge, one of the three main internal tide generation sites along the Hawaiian Ridge and the main study site of the Hawaii Ocean Mixing Experiment. The 0.01°–horizontal resolution simulation has a high level of skill when compared to satellite and in situ sea level observations, moored ADCP currents, and notably reasonable agreement with microstructure data. Barotropic and baroclinic energy equations are derived from the model’s sigma coordinate governing equations and are evaluated from the model simulation to form an energy budget. The M2 barotropic tide loses 2.7 GW of energy over the study region. Of this, 163 MW (6%) is dissipated by bottom friction and 2.3 GW (85%) is converted into internal tides. Internal tide generation primarily occurs along the flanks of the Kaena Ridge and south of Niihau and Kauai. The majority of the baroclinic energy (1.7 GW) is radiated out of the model domain, while 0.45 GW is dissipated close to the generation regions. The modeled baroclinic dissipation within the 1000-m isobath for the Kaena Ridge agrees to within a factor of 2 with the area-weighted dissipation from 313 microstructure profiles. Topographic resolution is important, with the present 0.01° resolution model resulting in 20% more barotropic-to-baroclinic conversion compared to when the same analysis is performed on a 4-km resolution simulation. A simple extrapolation of these results to the entire Hawaiian Ridge is in qualitative agreement with recent estimates based on satellite altimetry data.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The condition of information asymmetry between current owners and potential IPO investors creates a context wherein the legitimacy of the top management team (TMT) may serve as a valid signal of ...value to potential investors. The results confirm our hypotheses that TMT legitimacy is negatively correlated with post-IPO stock value run-up. Our results support a previously unexplored view of the TMT as an important signal of value in IPOs, and suggest that dual benefits accrue to the TMT selection process in IPO firms.
Delivery of therapeutic transgenes to retinal photoreceptors using adeno-associated virus (AAV) vectors has traditionally required subretinal injection. Recently, photoreceptor transduction ...efficiency following intravitreal injection (IVT) has improved in rodent models through use of capsid-mutant AAV vectors; but remains limited in large animal models. Thickness of the inner limiting membrane (ILM) in large animals is thought to impair retinal penetration by AAV. Our study compared two newly developed AAV vectors containing multiple capsid amino acid substitutions following IVT in dogs. The ability of two promoter constructs to restrict reporter transgene expression to photoreceptors was also evaluated. AAV vectors containing the interphotoreceptor-binding protein (IRBP) promoter drove expression exclusively in rod and cone photoreceptors, with transduction efficiencies of ~4% of cones and 2% of rods. Notably, in the central region containing the cone-rich visual streak, 15.6% of cones were transduced. Significant regional variation existed, with lower transduction efficiencies in the temporal regions of all eyes. This variation did not correlate with ILM thickness. Vectors carrying a cone-specific promoter failed to transduce a quantifiable percentage of cone photoreceptors. The newly developed AAV vectors containing the IRBP promoter were capable of producing photoreceptor-specific transgene expression following IVT in the dog.
An acquired V617F mutation in JAK2 occurs in most patients with polycythaemia vera, but is seen in only half those with essential thrombocythaemia and idiopathic myelofibrosis. We aimed to assess ...whether patients with the mutation are biologically distinct from those without, and why the same mutation is associated with different disease phenotypes.
Two sensitive PCR-based methods were used to assess the JAK2 mutation status of 806 patients with essential thrombocythaemia, including 776 from the Medical Research Council's Primary Thrombocythaemia trial (MRC PT-1) and two other prospective studies. Laboratory and clinical features, response to treatment, and clinical events were compared for V617F-positive and V617F-negative patients with essential thrombocythaemia.
Mutation-positive patients had multiple features resembling polycythaemia vera, with significantly increased haemoglobin (mean increase 9·6 g/L, 95% CI 7·6–11·6 g/L; p<0·0001), neutrophil counts (1·1×109/L, 0·7–1·5×109/L; p<0·0001), bone marrow erythropoiesis and granulopoiesis, more venous thromboses, and a higher rate of polycythaemic transformation than those without the mutation. Mutation-positive patients had lower serum erythropoietin (mean decrease 13·8 U/L; 95% CI, 10·8–16·9 U/L; p<0·0001) and ferritin (n=182; median 58 vs 91 μg/L; p=0·01) concentrations than did mutation-negative patients. Mutation-negative patients did, nonetheless, show many clinical and laboratory features that were characteristic of a myeloproliferative disorder. V617F-positive individuals were more sensitive to therapy with hydroxyurea, but not anagrelide, than those without the JAK2 mutation.
Our results suggest that JAK2 V617F-positive essential thrombocythaemia and polycythaemia vera form a biological continuum, with the degree of erythrocytosis determined by physiological or genetic modifiers.
Abstract In the current study, we used an estrogen-deficient mouse model of osteoporosis to test the efficacy of a cell-generated bone tissue construct for bone augmentation of an impaired healing ...fracture. A reduction in new bone formation at the defect site was observed in ovariectomized fractures compared to the control group using repeated measures in vivo micro-computed tomography (μCT) imaging over 4 weeks. A significant increase in the bone mineral density (BMD), trabecular bone volume ratio, and trabecular number, thickness and connectivity were associated with fracture repair in the control group, whereas the fractured bones of the ovariectomized mice exhibited a loss in all of these parameters ( p < 0.001). In a separate group, ovariectomized fractures were treated with murine embryonic stem (ES) cell-derived osteoblasts loaded in a three-dimensional collagen I gel and recovery of the bone at the defect site was observed. A significant increase in the trabecular bone volume ratio ( p < 0.001) and trabecular number ( p < 0.01) was observed by 4 weeks in the fractures treated with cell-loaded collagen matrix compared to those treated with collagen I alone. The stem cell-derived osteoblasts were identified at the fracture site at 4 weeks post-implantation through in situ hybridization histochemistry. Although this cell tracking method was effective, the formation of an ectopic cellular nodule adjacent to the knee joints of two mice suggested that alternative in vivo cell tracking methods should be employed in order to definitively assess migration of the implanted cells. To our knowledge, this study is the first of its kind to examine the efficacy of stem cell therapy for fracture repair in an osteoporosis-related fracture model in vivo. The findings presented provide novel insight into the use of stem cell therapies for bone injuries.
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