Time-Domain Topology Optimization of Arbitrary Dispersive Materials for Broadband 3D Nanophotonics Inverse Design

In the last decades, nanostructures have unlocked myriads of functionalities in nanophotonics by engineering light-matter interaction beyond what is possible with conventional bulk optics. The space of parameters available for design is practically unlimited due to the large variety of optical materials and nanofabrication techniques. Thus, computational approaches are necessary to efficiently search for the optimal solutions. In this paper, we enable the free-form inverse design in 3D of linear optical materials with arbitrary dispersion and anisotropy. This is achieved by (1) deriving an analytical adjoint scheme based on the complex-conjugate pole-residue pair model in the time domain and (2) its implementation in a parallel finite-difference time-domain framework with a topology optimization routine, efficiently running on high-performance computing systems. Our method is tested on the design problem of field confinement using dispersive nanostructures. The obtained designs satisfy the fundamental curiosity of how free-form metallic and dielectric nanostructures perform when optimized in 3D, also in comparison to fabrication-constrained designs. Unconventional free-form designs revealed by computational methods, although may be challenging or unfeasible to realize with current technology, bring new insights into how light can more efficiently interact with nanostructures and provide new ideas for forward design

Proteomic analysis in valvular cardiomyopathy: aortic regurgitation vs. aortic stenosis

Left ventricular (LV) reverse remodeling after aortic valve (AV) surgery is less predictable in chronic aortic regurgitation (AR) than in aortic stenosis (AS). We aimed to disclose specific LV myocardial protein signatures possibly contributing to differential disease progression. Global protein profiling of LV myocardial samples excised from the subaortic interventricular septum in patients with isolated AR or AS undergoing AV surgery was performed using liquid chromatography–electrospray ionization–tandem mass spectrometry. Based on label-free quantitation protein intensities, a logistic regression model was calculated and adjusted for age, sex and protein concentration. Web-based functional enrichment analyses of phenotype-associated proteins were performed utilizing g:Profiler and STRING. Data are available via ProteomeXchange with identifier PXD039662. Lysates from 38 patients, including 25 AR and 13 AS samples, were analyzed. AR patients presented with significantly larger LV diameters and volumes (end-diastolic diameter: 61 (12) vs. 48 (13) mm, p < 0.001; end-diastolic volume: 180.0 (74.6) vs. 92.3 (78.4), p = 0.001). A total of 171 proteins were associated with patient phenotype: 117 were positively associated with AR and the enrichment of intracellular compartment proteins (i.e., assigned to carbohydrate and nucleotide metabolism, protein biosynthesis and the proteasome) was detected. Additionally, 54 were positively associated with AS and the enrichment of extracellular compartment proteins (i.e., assigned to the immune and hematopoietic system) was observed. In summary, functional enrichment analysis revealed specific AR- and AS-associated signatures of LV myocardial proteins

Valvular cardiomyopathy in aortic valve regurgitation correlates with myocardial fibrosis

Objective: At the tissue level, disruption of the extracellular matrix network leads to irreversible cardiac fibrosis, which contributes to myocardial dysfunction. At the myocyte level, downregulation of beta-adrenoceptors (beta-AR) reduces adaptation to increased workload. The aim of our study was to analyse the correlation between myocardial fibrosis and beta-AR sensitivity in patients with aortic valve (AV) disease. Methods: A total of 92 consecutive patients who underwent elective AV surgery between 2017–2019 were included in our study (51 with aortic regurgitation (AR-group); 41 with aortic stenosis (AS-group) and left ventricular (LV) biopsies were obtained intraoperatively. In vitro force contractility testing was performed by measuring beta-AR sensitivity (−log EC50[ISO]). In parallel, a quantitative analysis of myocardial fibrosis burden was performed. Results: Mean age at the time of AV surgery was not statistically different in both groups (AR: 53.3 ± 15.3 years vs. AS: 58.7 ± 17.0 years; p = 0.116). The LV end-diastolic diameter was significantly enlarged in the AR-group when compared to the AS-group (59.4 ± 15.6 vs. 39.7 ± 21.2; p < 0.001). Analysis of beta-AR sensitivity (AR: −6.769 vs. AS: −6.659; p = 0.316) and myocardial fibrosis (AR: 8.9% vs. AS: 11.3%; p = 0.284) showed no significant differences between patients with AS and AR. There was no correlation between myocardial fibrosis and beta-AR sensitivity in the whole study cohort (R = 0.1987; p = 0.100) or in the AS-subgroup (R = 0.009; p = 0.960). However, significant correlation of fibrosis and beta-AR sensitivity was seen in AR-patients (R = 0.363; p = 0.023). Conclusion: More severe myocardial fibrosis was associated with reduced beta-AR sensitivity in patients presenting with AR but not with AS. Therefore, our results suggest that in patients with AR, cellular myocardial dysfunction is present and correlates with the extent of myocardial fibrosis in the myocardium

Identification of regulatory variants associated with genetic susceptibility to meningococcal disease.

Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes

Freeform topology optimized, dispersive nanostructures for field confinement

&lt;p&gt;Provides the 3D topology optimized nanostructures as STL files, as well as&nbsp;the Lumerical files used to validate their performance presented in the article&nbsp;"Time-Domain Topology Optimization of Arbitrary Dispersive Materials for Broadband 3D Nanophotonics Inverse Design" (https://doi.org/10.1021/acsphotonics.3c00572).&lt;/p&gt

Time-domain topology optimization of arbitrary dispersive materials for broadband 3D nanophotonics inverse design

In the last decades, nanostructures have unlocked myriads of functionalities in nanophotonics by engineering light–matter interaction beyond what is possible with conventional bulk optics. The space of parameters available for design is practically unlimited due to the large variety of optical materials and nanofabrication techniques. Thus, computational approaches are necessary to efficiently search for the optimal solutions. In this paper, we enable the free-form inverse design in 3D of linear optical materials with arbitrary dispersion and anisotropy. This is achieved by (1) deriving an analytical adjoint scheme based on the complex-conjugate pole-residue pair model in the time domain and (2) its implementation in a parallel finite-difference time-domain framework with a topology optimization routine, efficiently running on high-performance computing systems. Our method is tested on the design problem of field confinement using dispersive nanostructures. The obtained designs satisfy the fundamental curiosity of how free-form metallic and dielectric nanostructures perform when optimized in 3D, also in comparison to fabrication-constrained designs. Unconventional free-form designs revealed by computational methods, although may be challenging or unfeasible to realize with current technology, bring new insights into how light can more efficiently interact with nanostructures and provide new ideas for forward design

Dyggve–Melchior–Clausen syndrome: Chondrodysplasia resulting from defects in intracellular vesicle traffic

Dyggve–Melchior–Clausen syndrome and Smith-McCort dysplasia are recessive spondyloepimetaphyseal dysplasias caused by loss-of-function mutations in dymeclin (Dym), a gene with previously unknown function. Here we report that Dym-deficient mice display defects in endochondral bone formation similar to that of Dyggve–Melchior–Clausen syndrome and Smith-McCort dysplasia, demonstrating functional conservation between the two species. Dym-mutant cells display multiple defects in vesicle traffic, as evidenced by enhanced dispersal of Golgi markers in interphase cells, delayed Golgi reassembly after brefeldin A treatment, delayed retrograde traffic of an endoplasmic reticulum-targeted Shiga toxin B subunit, and altered furin trafficking; and the Dym protein associates with multiple cellular proteins involved in vesicular traffic. These results establish dymeclin as a novel protein involved in Golgi organization and intracellular vesicle traffic and clarify the molecular basis for chondrodysplasia in mice and men