We investigate whether the stationary solution of the Fokker-Planck equation of the complex Langevin algorithm reproduces the correct expectation values. When the complex Langevin algorithm for an ...action S(x) is convergent, it produces an equivalent complex probability distribution P(x) which ideally would coincide with e−S(x). We show that the projected Fokker-Planck equation fulfilled by P(x) may contain an anomalous term whose form is made explicit. Such a term spoils the relation P(x)=e−S(x), introducing a bias in the expectation values. Through the analysis of several periodic and nonperiodic one-dimensional problems, using either exact or numerical solutions of the Fokker-Planck equation on the complex plane, it is shown that the anomaly is present quite generally. In fact, an anomaly is expected whenever the Langevin walker needs only a finite time to go to infinity and come back, and this is the case for typical actions. We conjecture that the anomaly is the rule rather than the exception in the one-dimensional case; however, this could change as the number of variables involved increases.
A new technique is explored for the Monte Carlo sampling of complex-valued distributions. The method is based on a heat bath approach where the conditional probability is replaced by a positive ...representation of it on the complex plane. Efficient ways to construct such representations are also introduced. The performance of the algorithm is tested on small and large lattices with a λϕ4 theory with quadratic nearest-neighbor complex coupling. The method works for moderate complex couplings, reproducing reweighting and complex Langevin results and fulfilling various Schwinger-Dyson relations.
Using the method of covariant symbols we compute the divergent part of the effective action of the Proca field with non-minimal mass term. Specifically a quantum abelian vector field with a ...non-derivative coupling to an external tensor field in curved spacetime in four dimensions is considered. Relatively explicit expressions are obtained which are manifestly local but non polynomial in the external fields. Our result is shown to reproduce existing ones in all particular cases considered. Internal consistency with Weyl invariance is also verified.
The Global Coupled 3 (GC3) configuration of the Met Office Unified Model is presented. Among other applications, GC3 is the basis of the United Kingdom's submission to the Coupled Model ...Intercomparison Project 6 (CMIP6). This paper documents the model components that make up the configuration (although the scientific descriptions of these components are in companion papers) and details the coupling between them. The performance of GC3 is assessed in terms of mean biases and variability in long climate simulations using present‐day forcing. The suitability of the configuration for predictability on shorter time scales (weather and seasonal forecasting) is also briefly discussed. The performance of GC3 is compared against GC2, the previous Met Office coupled model configuration, and against an older configuration (HadGEM2‐AO) which was the submission to CMIP5. In many respects, the performance of GC3 is comparable with GC2, however, there is a notable improvement in the Southern Ocean warm sea surface temperature bias which has been reduced by 75%, and there are improvements in cloud amount and some aspects of tropical variability. Relative to HadGEM2‐AO, many aspects of the present‐day climate are improved in GC3 including tropospheric and stratospheric temperature structure, most aspects of tropical and extratropical variability and top‐of‐atmosphere and surface fluxes. A number of outstanding errors are identified including a residual asymmetric sea surface temperature bias (cool northern hemisphere, warm Southern Ocean), an overly strong global hydrological cycle and insufficient European blocking.
Key Points
Description of the Global Coupled 3 (GC3) configuration of the Met Office Unified Model
A cross‐time‐scale evaluation of the GC3 configuration is presented
Overall, GC3 is an improvement on previous configurations
Targeted delivery of therapeutics is an alternative approach for the selective treatment of infectious diseases. The surface of African trypanosomes, the causative agents of African trypanosomiasis, ...is covered by a surface coat consisting of a single variant surface glycoprotein, termed VSG. This coat is recycled by endocytosis at a very high speed, making the trypanosome surface an excellent target for the delivery of trypanocidal drugs. Here, we report the design of a drug nanocarrier based on poly ethylen glycol (PEG) covalently attached (PEGylated) to poly(D,L-lactide-co-glycolide acid) (PLGA) to generate PEGylated PLGA nanoparticles. This nanocarrier was coupled to a single domain heavy chain antibody fragment (nanobody) that specifically recognizes the surface of the protozoan pathogen Trypanosoma brucei. Nanoparticles were loaded with pentamidine, the first-line drug for T. b. gambiense acute infection. An in vitro effectiveness assay showed a 7-fold decrease in the half-inhibitory concentration (IC50) of the formulation relative to free drug. Furthermore, in vivo therapy using a murine model of African trypanosomiasis demonstrated that the formulation cured all infected mice at a 10-fold lower dose than the minimal full curative dose of free pentamidine and 60% of mice at a 100-fold lower dose. This nanocarrier has been designed with components approved for use in humans and loaded with a drug that is currently in use to treat the disease. Moreover, this flexible nanobody-based system can be adapted to load any compound, opening a range of new potential therapies with application to other diseases.
Objectives The primary aim of this systematic review is to objectively evaluate the test performance characteristics of three-dimensional echocardiography (3DE) in measuring left ventricular (LV) ...volumes and ejection fraction (EF). Background Despite its growing use in clinical laboratories, the accuracy of 3DE has not been studied on a large scale. It is unclear if this technology offers an advantage over traditional two-dimensional (2D) methods. Methods We searched for studies that compared LV volumes and EF measured by 3DE and cardiac magnetic resonance (CMR) imaging. A subset of those also compared standard 2D methods with CMR. We used meta-analyses to determine the overall bias and limits of agreement of LV end-diastolic volume (EDV), end-systolic volume (ESV), and EF measured by 3DE and 2D echocardiography (2DE). Results Twenty-three studies (1,638 echocardiograms) were included. The pooled biases ± 2 SDs for 3DE were −19.1 ± 34.2 ml, −10.1 ± 29.7 ml, and − 0.6 ± 11.8% for EDV, ESV, and EF, respectively. Nine studies also included data from 2DE, where the pooled biases were −48.2 ± 55.9 ml, −27.7 ± 45.7 ml, and 0.1 ± 13.9% for EDV, ESV, and EF, respectively. In this subset, the difference in bias between 3DE and 2D volumes was statistically significant (p = 0.01 for both EDV and ESV). The difference in variance was statistically significant (p < 0.001) for all 3 measurements. Conclusions Three-dimensional echocardiography underestimates volumes and has wide limits of agreement, but compared with traditional 2D methods in these carefully performed studies, 3DE is more accurate for volumes and more precise in all 3 measurements.
Silicon-substituted hydroxyapatite (SiHA) macroporous scaffolds have been prepared by robocasting. In order to optimize their bone regeneration properties, we have manufactured these scaffolds ...presenting different microstructures: nanocrystalline and crystalline. Moreover, their surfaces have been decorated with vascular endothelial growth factor (VEGF) to evaluate the potential coupling between vascularization and bone regeneration. In vitro cell culture tests evidence that nanocrystalline SiHA hinders pre-osteblast proliferation, whereas the presence of VEGF enhances the biological functions of both endothelial cells and pre-osteoblasts. The bone regeneration capability has been evaluated using an osteoporotic sheep model. In vivo observations strongly correlate with in vitro cell culture tests. Those scaffolds made of nanocrystalline SiHA were colonized by fibrous tissue, promoted inflammatory response and fostered osteoclast recruitment. These observations discard nanocystalline SiHA as a suitable material for bone regeneration purposes. On the contrary, those scaffolds made of crystalline SiHA and decorated with VEGF exhibited bone regeneration properties, with high ossification degree, thicker trabeculae and higher presence of osteoblasts and blood vessels. Considering these results, macroporous scaffolds made of SiHA and decorated with VEGF are suitable bone grafts for regeneration purposes, even in adverse pathological scenarios such as osteoporosis.
For the first time, the in vivo behavior of scaffolds made of silicon substituted hydroxyapatites (SiHA) has been evaluated under osteoporosis conditions. In order to optimize the bone regeneration properties of these bioceramics, 3D macroporous scaffolds have been manufactured by robocasting and implanted in osteoporotic sheep. Our experimental design shed light on the important issue of the biological response of nano-sized bioceramics vs highly crystalline bioceramics, as well as on the importance of coupling vascularization and bone growth processes by decorating SiHA scaffolds with vascular endothelial growth factor.
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Current climate models generally reflect too little solar radiation over the Southern Ocean, which may be the leading cause of the prevalent sea surface temperature biases in climate models. The ...authors study the role of clouds on the radiation biases in atmosphere-only simulations of the Cloud Feedback Model Intercomparison Project phase 2 (CFMIP2), as clouds have a leading role in controlling the solar radiation absorbed at those latitudes. The authors composite daily data around cyclone centers in the latitude band between 40° and 70°S during the summer. They use cloud property estimates from satellite to classify clouds into different regimes, which allow them to relate the cloud regimes and their associated radiative biases to the meteorological conditions in which they occur. The cloud regimes are defined using cloud properties retrieved using passive sensors and may suffer from the errors associated with this type of retrievals. The authors use information from theCloud–Aerosol Lidar and Infrared Pathfinder Satellite Observations (CALIPSO)lidar to investigate in more detail the properties of the “midlevel” cloud regime. Most of the model biases occur in the cold-air side of the cyclone composite, and the cyclone composite accounts formost of the climatological error in that latitudinal band. The midlevel regime is the main contributor to reflected shortwave radiation biases.CALIPSOdata show that the midlevel cloud regime is dominated by two main cloud types: cloud with tops actually at midlevel and low-level cloud. Improving the simulation of these cloud types should help reduce the biases in the simulation of the solar radiation budget in the Southern Ocean in climate models.
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