Protein Transport through Nanopores Illuminated by Long-Time-Scale Simulations

The transport of molecules through nanoscale confined space is relevant in biology, biosensing, and industrial filtration. Microscopically modeling transport through nanopores is required for a fundamental understanding and guiding engineering, but the short duration and low replica number of existing simulation approaches limit statistically relevant insight. Here we explore protein transport in nanopores with a high-throughput computational method that realistically simulates hundreds of up to seconds-long protein trajectories by combining Brownian dynamics and continuum simulation and integrating both driving forces of electroosmosis and electrophoresis. Ionic current traces are computed to enable experimental comparison. By examining three biological and synthetic nanopores, our study answers questions about the kinetics and mechanism of protein transport and additionally reveals insight that is inaccessible from experiments yet relevant for pore design. The discovery of extremely frequent unhindered passage can guide the improvement of biosensor pores to enhance desired biomolecular recognition by pore-tethered receptors. Similarly, experimentally invisible nontarget adsorption to pore walls highlights how to improve recently developed DNA nanopores. Our work can be expanded to pressure-driven flow to model industrial nanofiltration processes

Analysis of a diffusive effective mass model for nanowires

We propose in this paper to derive and analyze a self-consistent model describing the diffusive transport in a nanowire. From a physical point of view, it describes the electron transport in an ultra-scaled confined structure, taking in account the interactions of charged particles with phonons. The transport direction is assumed to be large compared to the wire section and is described by a drift-diffusion equation including effective quantities computed from a Bloch problem in the crystal lattice. The electrostatic potential solves a Poisson equation where the particle density couples on each energy band a two dimensional confinement density with the monodimensional transport density given by the Boltzmann statistics. On the one hand, we study the derivation of this Nanowire Drift-Diffusion Poisson model from a kinetic level description. On the other hand, we present an existence result for this model in a bounded domain

Reverse Remodeling Following Valve Replacement in Coexisting Aortic Stenosis and Transthyretin Cardiac Amyloidosis

Background: Dual pathology of severe aortic stenosis (AS) and transthyretin cardiac amyloidosis (ATTR) is increasingly recognized. Evolution of symptoms, biomarkers, and myocardial mechanics in AS-ATTR following valve replacement is unknown. We aimed to characterize reverse remodeling in AS-ATTR and compared with lone AS. Methods: Consecutive patients referred for transcatheter aortic valve replacement (TAVR) underwent ATTR screening by blinded 99mTc-DPD bone scintigraphy (Perugini Grade-0 negative, 1-3 increasingly positive) before intervention. ATTR was diagnosed by DPD and absence of monoclonal protein. Reverse remodeling was assessed by comprehensive evaluation before TAVR and at 1 year. Results: One hundred twenty patients (81.8±6.3 years, 51.7% male, 95 lone AS, 25 AS-ATTR) with complete follow-up were studied. At 12 months (interquartile range, 7-17) after TAVR, both groups experienced significant symptomatic improvement by New York Heart Association functional class (both P<0.001). Yet, AS-ATTR remained more symptomatic (New York Heart Association ≥III: 36.0% versus 13.8; P=0.01) with higher residual NT-proBNP (N-terminal pro-brain natriuretic peptide) levels (P<0.001). Remodeling by echocardiography showed left ventricular mass regression only for lone AS (P=0.002) but not AS-ATTR (P=0.5). Global longitudinal strains improved similarly in both groups. Conversely, improvement of regional longitudinal strain showed a base-to-apex gradient in AS-ATTR, whereas all but apical segments improved in lone AS. This led to the development of an apical sparing pattern in AS-ATTR only after TAVR. Conclusions: Patterns of reverse remodeling differ from lone AS to AS-ATTR, with both groups experiencing symptomatic improvement by TAVR. After AS treatment, AS-ATTR transfers into a lone ATTR cardiomyopathy phenotype

Optimal operation of cryogenic calorimeters through deep reinforcement learning

Cryogenic phonon detectors with transition-edge sensors achieve the best sensitivity to light dark matter-nucleus scattering in current direct detection dark matter searches. In such devices, the temperature of the thermometer and the bias current in its readout circuit need careful optimization to achieve optimal detector performance. This task is not trivial and is typically done manually by an expert. In our work, we automated the procedure with reinforcement learning in two settings. First, we trained on a simulation of the response of three CRESST detectors used as a virtual reinforcement learning environment. Second, we trained live on the same detectors operated in the CRESST underground setup. In both cases, we were able to optimize a standard detector as fast and with comparable results as human experts. Our method enables the tuning of large-scale cryogenic detector setups with minimal manual interventions.Comment: 23 pages, 14 figures, 2 table

Benefit of isolated surgical valve repair or replacement for functional tricuspid regurgitation and long-term outcomes stratified by the TRI-SCORE

Background and AimsSevere tricuspid regurgitation is associated with increased mortality rates, but benefit of its correction and ideal timing are not clearly determined. This study aimed to identify patient subsets who might benefit from the surgery.MethodsIn TRIGISTRY, an international cohort study of consecutive patients with severe isolated functional tricuspid regurgitation (33 centres, 10 countries), survival rates up to 10 years were compared between patients who underwent isolated tricuspid valve surgery (repair or replacement) and those conservatively managed, overall and according to TRI-SCORE category (low: ≤3, intermediate: 4–5, and high: ≥6).ResultsOne thousand and two hundred seventeen were managed conservatively, and 551 underwent isolated tricuspid valve surgery (200 repairs and 351 replacements). TRI-SCORE distribution was 33% low, 32% intermediate, and 35% high. At 10 years, survival rates were similar between surgical and conservative management [41% vs. 36%; hazard ratio (HR) .97; 95% confidence interval (CI) .88–1.08, P = .57]. Surgery improved survival compared with conservative management in the low TRI-SCORE category (72% vs. 44%; HR .27; 95% CI .20–.37, P P = .09) or high categories (20% vs. 24%; HR 1.06; 95% CI .91–1.25, P = .45). Both repair and replacement improved survival in the low TRI-SCORE category (84% and 61% vs. 44%; HR .11; 95% CI .06–.19, P P = .009). Repair showed benefit in the intermediate category (59% vs. 37%; HR .49; 95% CI .35–.68, P P = .0002).ConclusionsHigher survival rates were observed with repair than replacement and benefit of intervention declined as TRI-SCORE increased with no benefit of any type of surgery in the high TRI-SCORE category. These results emphasize the importance of timely intervention and patient selection to achieve the best outcomes and the need for randomized controlled trials.Cardiolog

TRI-SCORE and benefit of intervention in patients with severe tricuspid regurgitation

Background and aimsBenefit of tricuspid regurgitation (TR) correction and timing of intervention are unclear. This study aimed to compare survival rates after surgical or transcatheter intervention to conservative management according to a TR clinical stage as assessed using the TRI-SCORE.MethodsA total of 2,413 patients with severe isolated functional TR were enrolled in TRIGISTRY (1217 conservatively managed, 551 isolated tricuspid valve surgery, and 645 transcatheter valve repair). The primary endpoint was survival at 2 years.ResultsThe TRI-SCORE was low (≤3) in 32%, intermediate (4–5) in 33%, and high (≥6) in 35%. A successful correction was achieved in 97% and 65% of patients in the surgical and transcatheter groups, respectively. Survival rates decreased with the TRI-SCORE in the three treatment groups (all P P = .0002). In the intermediate category, no significant difference between groups was observed overall (80%, 71%, and 71%, respectively, P = .13) but benefit of the intervention became significant when the analysis was restricted to patients with successful correction (80%, 81%, and 71%, respectively, P = .009). In the high TRI-SCORE category, survival was not different to conservative management in the surgical and successful repair group (61% and 68% vs 58%, P = .26 and P = .18 respectively).ConclusionsSurvival progressively decreased with the TRI-SCORE irrespective of treatment modality. Compared to conservative management, an early and successful surgical or transcatheter intervention improved 2-year survival in patients at low and, to a lower extent, intermediate TRI-SCORE, while no benefit was observed in the high TRI-SCORE category.Cardiolog

Automated Design of Photonic Crystal Demultiplexers

We describe an approach for the automated design of photonic crystals for various applications. Our approach includes gradient-based optimization for arbitrary objective functions, with the electromagnetic fields calculated by an accurate multiple-scattering approach. An example of a two-color silicon photonic crystal demultiplexer designed by our method is presented, with dozens of parameters chosen automatically in reasonable time. The optimized device exhibits strong focusing with low crosstalk for both frequencies