Neuropilin 1 Involvement in Choroidal and Retinal Neovascularisation

Purpose Inhibiting VEGF is the gold standard treatment for neovascular age-related macular degeneration (AMD). It is also effective in preventing retinal oedema and neovascularisation (NV) in diabetic retinopathy (DR) and retinal vein occlusions (RVO). Neuropilin 1 (Nrp1) is a co-receptor for VEGF and many other growth factors, and therefore a possible alternative drug target in intra ocular neovascular disease. Here we assessed choroidal and retinal NV in an inducible, endothelial specific knock out model for Nrp1. Methods Crossing Nrp1 floxed mice with Pdgfb-CreERT2 mice produced tamoxifen-inducible, endothelial specific Nrp1 knock out mice (Nrp1ΔEC) and Cre-negative, control littermates. Cre-recombinase activity was confirmed in the Ai3(RCL-EYFP) reporter strain. Animals were subjected to laser-induced CNV (532 nm) and spectral domain-optical coherence tomography (SD-OCT) was performed immediately after laser and at day 7. Fluorescein angiography (FA) evaluated leakage and postmortem lectin staining in flat mounted RPE/choroid complexes was also used to measure CNV. Furthermore, retinal neovascularisation in the oxygen induced retinopathy (OIR) model was assessed by immunohistochemistry in retinal flatmounts. Results In vivo FA, OCT and post-mortem lectin staining showed a statistically significant reduction in leakage (p<0.05), CNV volume (p<0.05) and CNV area (p<0.05) in the Nrp1ΔEC mice compared to their Cre-negative littermates. Also the OIR model showed reduced retinal NV in the mutant animals compared to wild types (p<0.001). Conclusion We have demonstrated reduced choroidal and retinal NV in animals that lack endothelial Nrp1, confirming a role of Nrp1 in those processes. Therefore, Nrp1 may be a promising drug target for neovascular diseases in the eye

Spin-momentum locking from topological quantum chemistry: applications to multifold fermions

In spin-orbit coupled crystals, symmetries can protect multifold degeneracies with large Chern numbers and Brillouin zone spanning topological surface states. In this work, we explore the extent to which the nontrivial topology of chiral multifold fermions impacts the spin texture of bulk states. To do so, we formulate a definition of spin-momentum locking in terms of reduced density matrices. Using tools from the theory of topological quantum chemistry, we show how the reduced density matrix can be determined from the knowledge of the basis orbitals and band representation forming the multifold fermion. We show how on-site spin orbit coupling, crystal field splitting, and Wyckoff position multiplicity compete to determine the spin texture of states near chiral fermions. We compute the spin texture of multifold fermions in several representative examples from space groups $P432$ (207) and $P2_13$ (198). We show that the winding number of the spin around the Fermi surface can take many different integer values, from zero all the way to $\pm 7$. Finally, we conclude by showing how to apply our theory to real materials using the example of PtGa in space group $P2_13$.Comment: 28 pages, 6 figure

Vitamins C and E downregulate vascular VEGF and VEGFR-2 expression in apolipoprotein-E-deficient mice

Anti-angiogenic therapy reduces both plaque growth and intimal neovascularization in apolipoprotein-E-deficient mice (apoE-/-). Vascular endothelial growth factor (VEGF) has been suggested as playing a role in the development of atherosclerosis. We examined the hypothesis that VEGF and VEGF receptor-2 (VEGFR-2) expression is upregulated in apoE-/- and, since it could be driven by oxidative stress, tested whether dietary supplementation with vitamins C and E could downregulate it.Two-month-old apoE-/- received vitamin C combined with alpha- or beta-tocopherol for 4 weeks. Aortic VEGF and VEGFR-2 expression were measured by RT-qPCR and western blot.ApoE-/- showed significantly higher expression of aortic VEGF and VEGFR-2 mRNA (P<0.001) and protein (P<0.001) than wild-type mice, as well as increased plasma VEGF (P<0.001). Vitamin C and alpha-tocopherol significantly reduced aortic VEGF and VEGFR-2 expression in apoE-/- (P<0.001), circulating VEGF (P<0.01) and plasma lipid peroxidation (P<0.01). apoE-/- receiving vitamin C and beta-tocopherol showed diminished lipid peroxidation and VEGFR-2, but only partial reduction of VEGF expression. These data demonstrate that augmented VEGF and VEGFR-2 expression in apoE-/- vasculature can be downregulated by vitamins C and E, at least partially through oxidative stress reduction. This novel mechanism could contribute to explaining the beneficial effects of antioxidant vitamins in experimental atherosclerosis

Novel association of high C-reactive protein levels and A69S at risk alleles in wet age-related macular degeneration women

Purpose: To explore the relationship between plasma C-reactive protein (CRP) levels, the main ARMS2 gene single nucleotide polymorphism (SNP), and gender in patients with neovascular age-related macular degeneration (wet AMD). Methods: Our study included 131 patients with wetAMD [age-related eye disease study (AREDS) category 4] and 153 control participants (AREDS category 1) from two Spanish retinal units. CRP levels were determined on blood samples by high-sensitivity ELISA assay. According to their CRP level, subjects were categorized into three well-established CRP categories: low (3.00 mg/L, H-CRP). Genomic DNA was extracted from oral swabs using QIAcube (Qiagen, Hilden, Germany) and the A69S; rs10490924 of ARMS2 gene was genotyped by allelic discrimination with validated TaqMan assays (Applied Biosystems, Foster City, CA, USA). Univariate and multivariate logistic regression adjusted for age was used to analyze the genomic frequencies and to calculate odds ratio (OR) using SNPStats software. Results: Considering CRP risk categories, H-CRP group showed a significant [OR 4.0 (1.9-8.3)] association with wetAMD compared to L-CRP group. The risk genotypes of A69S (TT) SNPs showed an association with wetAMD risk [OR 14.0 (4.8-40.8)]. Interestingly, the gender stratification of the CRP categories showed a significant increase in CRP levels in wetAMD women compared with control women [OR 6.9 (2.2-22.3)] and with wetAMD men [OR 4.6 (1.3-16.9)]. In addition, the subgroup analysis of CRP within A69S genotype and gender showed a link in women between the A69S and CRP levels in the AMD group compared to controls [OR 4.2 (1.4-12.6)]. Conclusion: Our study shows, for the first time, that a different genetic association related with gender could contribute to AMD risk. As a consequence, the risk of female gender in the different CRP levels and A69S SNP frequencies could be taken into consideration to the established risk relationship of high levels of CRP and its association with risk A69S genotype

A randomized study of nutritional supplementation in patients with unilateral wet age-related macular degeneration

The purpose of this study is evaluate the efficacy and safety of medicinal products con-taining the original Age-Related Eye Disease group (AREDS) formulation at doses approved in Europe (EU, control group; n = 59) with a product that adds DHA, lutein, zeaxanthin, resveratrol and hydroxytyrosol to the formula (intervention group; n = 50). This was a multicenter, random-ized, observer-blinded trial conducted in patients aged 50 years or older diagnosed with unilateral exudative Age related Macular Degeneration AMD. At month 12, the intervention did not have a significant differential effect on visual acuity compared with the control group, with an estimated treatment difference in Early Treatment Diabetic Retinopathy Study (ETDRS) of -1.63 (95% CI -0.83 to 4.09; p = 0.192). The intervention exhibited a significant and, in most cases, relevant effect in terms of a reduction in some inflammatory cytokines and a greater improvement in the fatty acid profile and serum lutein and zeaxantin concentration. In patients with unilateral wet AMD, the addition of lutein, zeaxanthin, resveratrol, hydroxytyrosol and DHA to the AREDS EU recommended doses in the short-term did not have a differential effect on visual acuity compared to a standard AREDS EU formula but, in addition to improving the fatty acid profile and increasing carotenoid serum levels, may provide a beneficial effect in improving the proinflammatory and proangiogenic profile of patients with AMD. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

Weyl-fermions, Fermi-arcs, and minority-spin carriers in ferromagnetic CoS2

The pyrite compound CoS2 has been intensively studied in the past due to its itinerant ferromagnetism and potential for half-metallicity, which make it a promising material for spintronic applications. However, its electronic structure remains only poorly understood. Here we use complementary bulk- and surface-sensitive angle-resolved photoelectron spectroscopy and ab-initio calculations to provide a complete picture of its band structure. We discover Weyl-cones at the Fermi-level, which presents CoS2 in a new light as a rare member of the recently discovered class of magnetic topological metals. We directly observe the topological Fermi-arc surface states that link the Weyl-nodes, which will influence the performance of CoS2 as a spin-injector by modifying its spin-polarization at interfaces. Additionally, we are for the first time able to directly observe a minority-spin bulk electron pocket in the corner of the Brillouin zone, which proves that CoS2 cannot be a true half-metal. Beyond settling the longstanding debate about half-metallicity in CoS2, our results provide a prime example of how the topology of magnetic materials can affect their use in spintronic applications

Controllable orbital angular momentum monopoles in chiral topological semimetals

The emerging field of orbitronics aims at generating and controlling currents of electronic orbital angular momentum (OAM) for information processing. Structurally chiral topological crystals could be particularly suitable orbitronic materials because they have been predicted to host topological band degeneracies in reciprocal space that are monopoles of OAM. Around such a monopole, the OAM is locked isotopically parallel or antiparallel to the direction of the electron's momentum, which could be used to generate large and controllable OAM currents. However, OAM monopoles have not yet been directly observed in chiral crystals, and no handle to control their polarity has been discovered. Here, we use circular dichroism in angle-resolved photoelectron spectroscopy (CD-ARPES) to image OAM monopoles in the chiral topological semimetals PtGa and PdGa. Moreover, we also demonstrate that the polarity of the monopole can be controlled via the structural handedness of the host crystal by imaging OAM monopoles and anti-monopoles in the two enantiomers of PdGa, respectively. For most photon energies used in our study, we observe a sign change in the CD-ARPES spectrum when comparing positive and negative momenta along the light direction near the topological degeneracy. This is consistent with the conventional view that CD-ARPES measures the projection of the OAM monopole along the photon momentum. For some photon energies, however, this sign change disappears, which can be understood from our numerical simulations as the interference of polar atomic OAM contributions, consistent with the presence of OAM monopoles. Our results highlight the potential of chiral crystals for orbitronic device applications, and our methodology could enable the discovery of even more complicated nodal OAM textures that could be exploited for orbitronics.Comment: 16 pages, 8 figure

Cancer disparities in Southeast Asia: intersectionality and a call to action.

Southeast Asia has a population of over 680 million people—approximately half the population of India and twice the population of the United States—and is a region marked by rich and complex histories and cultures, dynamic growth, and unique and evolving health challenges.1 Despite the momentum of economic development, health inequalities persist. These inequities have been aggravated since the COVID-19 pandemic, which pushed millions further into poverty, possibly exacerbating health disparities, especially among populations who suffer vulnerabilities.2 Particularly salient are the challenges associated with providing adequate care for people with cancer, a leading cause of morbidity and mortality in the region.1,2 Cancer incidence and mortality in the region are projected to rise in the coming decades, given population growth and rapidly changing socioeconomic and geopolitical factors, as well as a host of interrelated and dynamic environmental, behavioral, and occupational risk factors.1, 2, 3 Large epidemiologic studies have demonstrated differences among Southeast Asian countries in terms of cancer incidence and mortality.3 Epidemiologic patterns can be attributed to variations in complex risk factors, access to screening and cancer care, and likely genetic predisposition.1, 2, 3 However, these differences also underscore that within each country exist richly diverse populations that experience disparities in cancer risk, screening, care access, outcomes, and survivorship in ways that require further examination. We draw attention to disparities in cancer in Southeast Asian countries. We highlight the need to study cancer disparities affecting minoritised groups in Southeast Asia—not only along lines of race/ethnicity, but also people minoritised along lines of sex/gender, socioeconomic status, religion, geography, and others. We highlight the intersectionality of elements of an individual's identity. Intersectionality, developed by critical race theorist Professor Kimberlé Crenshaw in 1989, is an analytic framework borne out of Black American feminist scholarship, that examines how a person's sociopolitical identities lead to disparate balances of privilege and discrimination.4 An intersectional approach would demonstrate that an individual or a community does not only experience economic poverty as the sole barrier to improved health; such an approach would examine how other identities such as religion or immigration status affect access to care. These different social determinants of health are not mutually exclusive; their interrelationships are complex, with consequences for health.5 We leverage the intersectional approach, which parallels the inherently syncretic cultures and histories of Southeast Asian nations, and explore how these identities impact access to cancer care. Meaningful cancer research focusing on peoples of Southeast Asia could present many opportunities for intervention and improvement