Ferrochelatase regulates retinal neovascularization

Ferrochelatase (FECH) is the terminal enzyme in heme biosynthesis. We previously showed that FECH is required for endothelial cell growth in vitro and choroidal neovascularization in vivo. But FECH has not been explored in retinal neovascularization, which underlies diseases like proliferative diabetic retinopathy and retinopathy of prematurity. Here, we investigated the inhibition of FECH using genetic and chemical approaches in the oxygen-induced retinopathy (OIR) mouse model. In OIR mice, FECH expression is upregulated and co-localized with neovascular tufts. Partial loss-of-function Fechm1Pas mutant mice showed reduced retinal neovascularization and endothelial cell proliferation in OIR. An intravitreal injection of the FECH inhibitor N-methyl protoporphyrin had similar effects. Griseofulvin is an antifungal drug that inhibits FECH as an off-target effect. Strikingly, intravitreal griseofulvin decreased both pathological tuft formation and areas of vasoobliteration compared to vehicle, suggesting potential as a FECH-targeting therapy. Ocular toxicity studies revealed that intravitreal injection of griseofulvin in adult mice does not disrupt retinal vasculature, function, or morphology. In sum, mutation and chemical inhibition of Fech reduces retinal neovascularization and promotes physiological angiogenesis, suggesting a dual effect on vascular repair upon FECH inhibition, without ocular toxicity. These findings suggest that FECH inhibitors could be repurposed to treat retinal neovascularization

Many-body Theory vs Simulations for the pseudogap in the Hubbard model

The opening of a critical-fluctuation induced pseudogap (or precursor pseudogap) in the one-particle spectral weight of the half-filled two-dimensional Hubbard model is discussed. This pseudogap, appearing in our Monte Carlo simulations, may be obtained from many-body techniques that use Green functions and vertex corrections that are at the same level of approximation. Self-consistent theories of the Eliashberg type (such as the Fluctuation Exchange Approximation) use renormalized Green functions and bare vertices in a context where there is no Migdal theorem. They do not find the pseudogap, in quantitative and qualitative disagreement with simulations, suggesting these methods are inadequate for this problem. Differences between precursor pseudogaps and strong-coupling pseudogaps are also discussed.Comment: Accepted, Phys. Rev. B15 15Mar00. Expanded version of original submission, Latex, 8 pages, epsfig, 5 eps figures (Last one new). Discussion on fluctuation and strong coupling induced pseudogaps expande

Role of symmetry and dimension on pseudogap phenomena

The attractive Hubbard model in d=2 is studied through Monte Carlo simulations at intermediate coupling. There is a crossover temperature $T_X$ where a pseudogap appears with concomitant precursors of Bogoliubov quasiparticles that are not local pairs. The pseudogap in $A(k,\omega)$ occurs in the renormalized classical regime when the correlation length is larger than the direction-dependent thermal de Broglie wave length, $\xi_{th}=\hbar v_{F}(k)/k_{B}T.$ The ratio $T_{X}/T_{c}$ for the pseudogap may be made arbitrarily large when the system is close to a point where the order parameter has SO(n) symmetry with n>2. This is relevant in the context of SO(5) theories of high $T_c$ but has more general applicability.Comment: 4 pages, LaTeX, 4 epsf figures included. Corrected to agree with published version. Main change, one new figur

Discovery of the Isotopes with 11 <= Z <= 19

A total of 194 isotopes with 11 $\le$ Z $\le$ 19 have been identified to date. The discovery of these isotopes which includes the observation of unbound nuclei, is discussed. For each isotope a brief summary of the first refereed publication, including the production and identification method, is presented.Comment: to be pubslihed in At. Data Nucl. Data Table

Pinned Balseiro-Falicov Model of Tunneling and Photoemission in the Cuprates

The smooth evolution of the tunneling gap of Bi_2Sr_2CaCu_2O_8 with doping from a pseudogap state in the underdoped cuprates to a superconducting state at optimal and overdoping, has been interpreted as evidence that the pseudogap must be due to precursor pairing. We suggest an alternative explanation, that the smoothness reflects a hidden SO(N) symmetry near the (pi,0) points of the Brillouin zone (with N = 3, 4, 5, or 6). Because of this symmetry, the pseudogap could actually be due to any of a number of nesting instabilities, including charge or spin density waves or more exotic phases. We present a detailed analysis of this competition for one particular model: the pinned Balseiro-Falicov model of competing charge density wave and (s-wave) superconductivity. We show that most of the anomalous features of both tunneling and photoemission follow naturally from the model, including the smooth crossover, the general shape of the pseudogap phase diagram, the shrinking Fermi surface of the pseudogap phase, and the asymmetry of the tunneling gap away from optimal doping. Below T_c, the sharp peak at Delta_1 and the dip seen in the tunneling and photoemission near 2Delta_1 cannot be described in detail by this model, but we suggest a simple generalization to account for inhomogeneity, which does provide an adequate description. We show that it should be possible, with a combination of photoemission and tunneling, to demonstrate the extent of pinning of the Fermi level to the Van Hove singularity. A preliminary analysis of the data suggests pinning in the underdoped, but not in the overdoped regime.Comment: 18 pages LaTeX, 26 ps. figure

Pairing fluctuations and pseudogaps in the attractive Hubbard model

The two-dimensional attractive Hubbard model is studied in the weak to intermediate coupling regime by employing a non-perturbative approach. It is first shown that this approach is in quantitative agreement with Monte Carlo calculations for both single-particle and two-particle quantities. Both the density of states and the single-particle spectral weight show a pseudogap at the Fermi energy below some characteristic temperature T*, also in good agreement with quantum Monte Carlo calculations. The pseudogap is caused by critical pairing fluctuations in the low-temperature renormalized classical regime $\omega < T$ of the two-dimensional system. With increasing temperature the spectral weight fills in the pseudogap instead of closing it and the pseudogap appears earlier in the density of states than in the spectral function. Small temperature changes around T* can modify the spectral weight over frequency scales much larger than temperature. Several qualitative results for the s-wave case should remain true for d-wave superconductors.Comment: 20 pages, 12 figure

Treatment of Hepatitis C as Prevention: A Modeling Case Study in Vietnam

Background: Treatment of hepatitis C (HCV) is very effective, achieving a cure in 50–90 % of patients. Besides its own good for individuals, this most likely translates in reduced transmission, but this phenomenon has yet to be fully explored. Methods and Findings: In this mathematical modeling study done in the context of Vietnam, we estimated the public health benefit that HCV therapy for injecting drug users (IDUs) may achieve. Treatment coverage of 25, 50 and 75 % of chronically HCV-infected IDUs (4 years into infection) is predicted to reduce the chronic HCV viremia prevalence respectively by 21, 37 and 50%, 11 years after full scale up to the intended coverage. At a constant 50 % coverage level, earlier treatment, 3, 2, and 1 year into infection is predicted to reduce the chronic HCV viremia prevalence by 46, 60 and 85%. In these later 3 scenarios, for every 100 treatment courses provided, a total of respectively 50, 61 and 94 new infections could be averted. These benefits were projected in the context of current low coverage of methadone maintenance therapy and needles/ syringes exchange programs, and these services expansion showed complementary preventive benefits to HCV therapy. The program treatment commitment associated with the various scenarios is deemed reasonable. Our model projections are robust under adjustment for uncertainty in the model parameter values. Conclusions: In this case study in Vietnam, we project that treatment of HCV for injecting drug users will have a preventative herd effect in addition to curing patients in need for therapy, achieving a substantial reduction in HCV transmission an

Evaluating deep learning architecture and data assimilation for improving water temperature forecasts at unmonitored locations

Deep learning (DL) models are increasingly used to forecast water quality variables for use in decision making. Ingesting recent observations of the forecasted variable has been shown to greatly increase model performance at monitored locations; however, observations are not collected at all locations, and methods are not yet well developed for DL models for optimally ingesting recent observations from other sites to inform focal sites. In this paper, we evaluate two different DL model structures, a long short-term memory neural network (LSTM) and a recurrent graph convolutional neural network (RGCN), both with and without data assimilation for forecasting daily maximum stream temperature 7 days into the future at monitored and unmonitored locations in a 70-segment stream network. All our DL models performed well when forecasting stream temperature as the root mean squared error (RMSE) across all models ranged from 2.03 to 2.11°C for 1-day lead times in the validation period, with substantially better performance at gaged locations (RMSE = 1.45–1.52°C) compared to ungaged locations (RMSE = 3.18–3.27°C). Forecast uncertainty characterization was near-perfect for gaged locations but all DL models were overconfident (i.e., uncertainty bounds too narrow) for ungaged locations. Our results show that the RGCN with data assimilation performed best for ungaged locations and especially at higher temperatures (&gt;18°C) which is important for management decisions in our study location. This indicates that the networked model structure and data assimilation techniques may help borrow information from nearby monitored sites to improve forecasts at unmonitored locations. Results from this study can help guide DL modeling decisions when forecasting other important environmental variables

Paracrine effects of embryo-derived FGF4 and BMP4 during pig trophoblast elongation

The crosstalk between the epiblast and the trophoblast is critical in supporting the early stages of conceptus development. FGF4 and BMP4 are inductive signals that participate in the communication between the epiblast and the extraembryonic ectoderm (ExE) of the developing mouse embryo. Importantly, however, it is unknown whether a similar crosstalk operates in species that lack a discernible ExE and develop a mammotypical embryonic disc (ED). Here we investigated the crosstalk between the epiblast and the trophectoderm (TE) during pig embryo elongation. FGF4 ligand and FGFR2 were detected primarily on the plasma membrane of TE cells of peri-elongation embryos. The binding of this growth factor to its receptor triggered a signal transduction response evidenced by an increase in phosphorylated MAPK/ERK. Particular enrichment was detected in the periphery of the ED in early ovoid embryos, indicating that active FGF signalling was operating during this stage. Gene expression analysis shows that CDX2 and ELF5, two genes expressed in the mouse ExE, are only co-expressed in the Rauber's layer, but not in the pig mural TE. Interestingly, these genes were detected in the nascent mesoderm of early gastrulating embryos. Analysis of BMP4 expression by in situ hybridisation shows that this growth factor is produced by nascent mesoderm cells. A functional test in differentiating epiblast shows that CDX2 and ELF5 are activated in response to BMP4. Furthermore, the effects of BMP4 were also demonstrated in the neighbouring TE cells, as demonstrated by an increase in phosphorylated SMAD1/5/8. These results show that BMP4 produced in the extraembryonic mesoderm is directly influencing the SMAD response in the TE of elongating embryos. These results demonstrate that paracrine signals from the embryo, represented by FGF4 and BMP4, induce a response in the TE prior to the extensive elongation. The study also confirms that expression of CDX2 and ELF5 is not conserved in the mural TE, indicating that although the signals that coordinate conceptus growth are similar between rodents and pigs, the gene regulatory network of the trophoblast lineage is not conserved in these species

Seeds, Agricultural Systems and Socio-natures: Towards an Actor-Network Theory Informed Political Ecology of Agriculture

Agriculture has recently been the subject of considerable research and policy attention. Events such as the 2008 ‘world food price crisis’ and concerns over the future of global food security have led to calls for a ‘New Green Revolution’, with an emphasis on boosting yields through new transgenic crop varieties. However, critics have raised concerns over the growing role of global agribusiness and transnational capital in agriculture, as well as the potential social and ecological impacts of new technologies. An analysis of emerging agricultural trends thus demands a framework that is able to negotiate the complex multi-scalar interplay between environmental, technological, scientific, political and economic factors. In this paper, we focus on the potential contribution of a synthesis between political ecology and Actor–Network Theory to our understanding of agricultural networks. We review the literature with a view to teasing out key insights and sketching out future research priorities. We focus on questions surrounding power and agency, the political ecology of scale and the role of situated knowledges and practices.Natasha Watts was supported by an Economic and Social Research Council Studentship (Award KFW/301419246). Ivan Scales was supported by an Early Career Fellowship from the Centre for Research on the Arts, Social Sciences and Humanities at the University of Cambridge and a Royal Geographical Society–Institute of British Geographers. Small Research Grant.This is the author accepted manuscript. The final version is available at http://onlinelibrary.wiley.com/doi/10.1111/gec3.12212/abstract